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Palma-Martínez MJ, Posadas-García YS, Shaukat A, López-Ángeles BE, Sohail M. Evolution, genetic diversity, and health. Nat Med 2025; 31:751-761. [PMID: 40055519 DOI: 10.1038/s41591-025-03558-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 02/03/2025] [Indexed: 03/21/2025]
Abstract
Human genetic diversity in today's world has been shaped by evolutionary history, demographic shifts and environmental exposures, influencing complex traits, disease susceptibility and drug responses. Capturing this diversity is essential for advancing precision medicine and promoting equitable healthcare. Despite the great progress achieved with initiatives such as the human Pangenome and large biobanks that aim for a better representation of human diversity, important challenges remain. In this Perspective, we discuss the importance of diversity in clinical genomics through an evolutionary lens. We highlight progress and challenges and outline key clinical applications of diverse genetic data. We argue that diversifying both datasets and methodologies-integrating ancestral and environmental factors-is crucial for fully understanding the genetic basis of human health and disease.
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Affiliation(s)
- María J Palma-Martínez
- Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, México
| | | | - Amara Shaukat
- Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, México
| | - Brenda E López-Ángeles
- Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, México
| | - Mashaal Sohail
- Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, México.
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Cosemans C, Alfano R, Sleurs H, Martens DS, Nawrot TS, Plusquin M. Exploring mitochondrial heteroplasmy in neonates: implications for growth patterns and overweight in the first years of life. Int J Obes (Lond) 2024; 48:1140-1147. [PMID: 38802661 DOI: 10.1038/s41366-024-01537-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 05/02/2024] [Accepted: 05/07/2024] [Indexed: 05/29/2024]
Abstract
BACKGROUND Mitochondrial heteroplasmy reflects genetic diversity within individuals due to the presence of varying mitochondrial DNA (mtDNA) sequences, possibly affecting mitochondrial function and energy production in cells. Rapid growth during early childhood is a critical development with long-term implications for health and well-being. In this study, we investigated if cord blood mtDNA heteroplasmy is associated with rapid growth at 6 and 12 months and overweight in childhood at 4-6 years. METHODS This study included 200 mother-child pairs of the ENVIRONAGE birth cohort. Whole mitochondrial genome sequencing was performed to determine mtDNA heteroplasmy levels (in variant allele frequency; VAF) in cord blood. Rapid growth was defined for each child as the difference between WHO-SD scores of predicted weight at either 6 or 12 months and birth weight. Logistic regression models were used to determine the association of mitochondrial heteroplasmy with rapid growth and childhood overweight. Determinants of relevant cord blood mitochondrial heteroplasmies were identified using multiple linear regression models. RESULTS One % increase in VAF of cord blood MT-D-Loop16362T > C heteroplasmy was associated with rapid growth at 6 months (OR = 1.03; 95% CI: 1.01-1.05; p = 0.001) and 12 months (OR = 1.02; 95% CI: 1.00-1.03; p = 0.02). Furthermore, this variant was associated with childhood overweight at 4-6 years (OR = 1.01; 95% CI 1.00-1.02; p = 0.05). Additionally, rapid growth at 6 months (OR = 3.00; 95% CI: 1.49-6.14; p = 0.002) and 12 months (OR = 4.05; 95% CI: 2.06-8.49; p < 0.001) was also associated with childhood overweight at 4-6 years. Furthermore, we identified maternal age, pre-pregnancy BMI, maternal education, parity, and gestational age as determinants of cord blood MT-D-Loop16362T > C heteroplasmy. CONCLUSIONS Our findings, based on mitochondrial DNA genotyping, offer insights into the molecular machinery leading to rapid growth in early life, potentially explaining a working mechanism of the development toward childhood overweight.
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Affiliation(s)
- Charlotte Cosemans
- Centre for Environmental Sciences, Hasselt University, 3590, Diepenbeek, Belgium
| | - Rossella Alfano
- Centre for Environmental Sciences, Hasselt University, 3590, Diepenbeek, Belgium
| | - Hanne Sleurs
- Centre for Environmental Sciences, Hasselt University, 3590, Diepenbeek, Belgium
| | - Dries S Martens
- Centre for Environmental Sciences, Hasselt University, 3590, Diepenbeek, Belgium
| | - Tim S Nawrot
- Centre for Environmental Sciences, Hasselt University, 3590, Diepenbeek, Belgium
- School of Public Health, Occupational & Environmental Medicine, Leuven University, 3000, Leuven, Belgium
| | - Michelle Plusquin
- Centre for Environmental Sciences, Hasselt University, 3590, Diepenbeek, Belgium.
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Ferreira T, Rodriguez S. Mitochondrial DNA: Inherent Complexities Relevant to Genetic Analyses. Genes (Basel) 2024; 15:617. [PMID: 38790246 PMCID: PMC11121663 DOI: 10.3390/genes15050617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 05/09/2024] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
Mitochondrial DNA (mtDNA) exhibits distinct characteristics distinguishing it from the nuclear genome, necessitating specific analytical methods in genetic studies. This comprehensive review explores the complex role of mtDNA in a variety of genetic studies, including genome-wide, epigenome-wide, and phenome-wide association studies, with a focus on its implications for human traits and diseases. Here, we discuss the structure and gene-encoding properties of mtDNA, along with the influence of environmental factors and epigenetic modifications on its function and variability. Particularly significant are the challenges posed by mtDNA's high mutation rate, heteroplasmy, and copy number variations, and their impact on disease susceptibility and population genetic analyses. The review also highlights recent advances in methodological approaches that enhance our understanding of mtDNA associations, advocating for refined genetic research techniques that accommodate its complexities. By providing a comprehensive overview of the intricacies of mtDNA, this paper underscores the need for an integrated approach to genetic studies that considers the unique properties of mitochondrial genetics. Our findings aim to inform future research and encourage the development of innovative methodologies to better interpret the broad implications of mtDNA in human health and disease.
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Affiliation(s)
- Tomas Ferreira
- Bristol Medical School, University of Bristol, Bristol BS8 1UD, UK
- Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SL, UK
| | - Santiago Rodriguez
- Bristol Medical School, University of Bristol, Bristol BS8 1UD, UK
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK
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Vikramdeo KS, Anand S, Sudan SK, Pramanik P, Singh S, Godwin AK, Singh AP, Dasgupta S. Profiling mitochondrial DNA mutations in tumors and circulating extracellular vesicles of triple-negative breast cancer patients for potential biomarker development. FASEB Bioadv 2023; 5:412-426. [PMID: 37810173 PMCID: PMC10551276 DOI: 10.1096/fba.2023-00070] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/14/2023] [Accepted: 08/22/2023] [Indexed: 10/10/2023] Open
Abstract
Early detection and recurrence prediction are challenging in triple-negative breast cancer (TNBC) patients. We aimed to develop mitochondrial DNA (mtDNA)-based liquid biomarkers to improve TNBC management. Mitochondrial genome (MG) enrichment and next-generation sequencing mapped the entire MG in 73 samples (64 tissues and 9 extracellular vesicles [EV] samples) from 32 metastatic TNBCs. We measured mtDNA and cardiolipin (CL) contents, NDUFB8, and SDHB protein expression in tumors and in corresponding circulating EVs. We identified 168 nonsynonymous mtDNA mutations, with 73% (123/186) coding and 27% (45/168) noncoding in nature. Twenty percent of mutations were nucleotide transversions. Respiratory complex I (RCI) was the key target, which harbored 44% (74/168) of the overall mtDNA mutations. A panel of 11 hotspot mtDNA mutations was identified among 19%-38% TNBCs, which were detectable in the serum-derived EVs with 82% specificity. Overall, 38% of the metastatic tumor-signature mtDNA mutations were traceable in the EVs. An appreciable number of mtDNA mutations were homoplasmic (18%, 31/168), novel (14%, 23/168), and potentially pathogenic (9%, 15/168). The overall and RCI-specific mtDNA mutational load was higher in women with African compared to European ancestry accompanied by an exclusive abundance of respiratory complex (RC) protein NDUFB8 (RCI) and SDHB (RCII) therein. Increased mtDNA (p < 0.0001) content was recorded in both tumors and EVs along with an abundance of CL (p = 0.0001) content in the EVs. Aggressive tumor-signature mtDNA mutation detection and measurement of mtDNA and CL contents in the EVs bear the potential to formulate noninvasive early detection and recurrence prediction strategies.
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Affiliation(s)
- Kunwar Somesh Vikramdeo
- Mitchell Cancer Institute, University of South AlabamaMobileAlabamaUSA
- Department of Pathology, College of MedicineUniversity of South AlabamaMobileAlabamaUSA
| | - Shashi Anand
- Mitchell Cancer Institute, University of South AlabamaMobileAlabamaUSA
- Department of Pathology, College of MedicineUniversity of South AlabamaMobileAlabamaUSA
| | - Sarabjeet Kour Sudan
- Mitchell Cancer Institute, University of South AlabamaMobileAlabamaUSA
- Department of Pathology, College of MedicineUniversity of South AlabamaMobileAlabamaUSA
| | - Paramahansa Pramanik
- Department of Mathematics and StatisticsUniversity of South AlabamaMobileAlabamaUSA
| | - Seema Singh
- Mitchell Cancer Institute, University of South AlabamaMobileAlabamaUSA
- Department of Pathology, College of MedicineUniversity of South AlabamaMobileAlabamaUSA
- Department of Biochemistry and Molecular BiologyUniversity of South AlabamaMobileAlabamaUSA
| | - Andrew K. Godwin
- Department of Pathology and Laboratory MedicineUniversity of Kansas Medical CenterKansas CityKansasUSA
- The University of Kansas Cancer Center, University of Kansas Medical CenterKansas CityKansasUSA
- Kansas Institute for Precision Medicine, University of Kansas Medical CenterKansas CityKansasUSA
| | - Ajay Pratap Singh
- Mitchell Cancer Institute, University of South AlabamaMobileAlabamaUSA
- Department of Pathology, College of MedicineUniversity of South AlabamaMobileAlabamaUSA
- Department of Biochemistry and Molecular BiologyUniversity of South AlabamaMobileAlabamaUSA
| | - Santanu Dasgupta
- Mitchell Cancer Institute, University of South AlabamaMobileAlabamaUSA
- Department of Pathology, College of MedicineUniversity of South AlabamaMobileAlabamaUSA
- Department of Biochemistry and Molecular BiologyUniversity of South AlabamaMobileAlabamaUSA
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Jing P, Mei X, Zhang YY, Zheng FJ, Luo XM, Liu LJ, Yu HH, Zhang XB. Major depressive disorder is correlated with the mitochondrial ND1 T3394C mutation in two Han Chinese families: Two case reports. World J Psychiatry 2023; 13:75-83. [PMID: 36925947 PMCID: PMC10011944 DOI: 10.5498/wjp.v13.i2.75] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/09/2022] [Accepted: 01/16/2023] [Indexed: 02/17/2023] Open
Abstract
BACKGROUND Major depressive disorder (MDD) is the most frequent reason of disabled people in the world, as reported by the World Health Organization. However, the diagnosis of MDD is mainly based on clinical symptoms. CASE SUMMARY The clinical, genetic, and molecular characteristics of two Chinese families with MDD are described in this study. There were variable ages of onset and severity in depression among the families. Both Chinese families had a very low pre-valence of MDD. The mitochondrial genomes of these pedigrees were sequenced and indicated a homoplasmic T3394C (Y30H) mutation, with the polymorphism located at a highly conserved tyrosine at position 30 of ND1. The analysis also revealed unique sets of mitochondrial DNA (mtDNA) polymorphisms orig-inating from haplogroups M9a3 and M9a. CONCLUSION This finding of the T3394C mutation in two unrelated depressed patients provides strong evidence that this mutation may have a part in the etiology of MDD. However, In these two Chinese families having the T3394C mutation, no functional mtDNA mutation was observed. Therefore, T3394C mutations are related with MDD, and the phenotypic manifestation of these mutations may be affected by changes in nuclear genes or environmental factors.
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Affiliation(s)
- Pan Jing
- Department of Psychiatric, Ningbo Kangning Hospital, Ningbo 315201, Zhejiang Province, China
| | - Xi Mei
- Department of Psychiatric, Ningbo Kangning Hospital, Ningbo 315201, Zhejiang Province, China
| | - Yuan-Yuan Zhang
- Department of Psychiatric, Ningbo Kangning Hospital, Ningbo 315201, Zhejiang Province, China
| | - Fei-Jie Zheng
- Department of Psychiatric, Ningbo Kangning Hospital, Ningbo 315201, Zhejiang Province, China
| | - Xiao-Min Luo
- Department of Psychiatric, Ningbo Kangning Hospital, Ningbo 315201, Zhejiang Province, China
| | - Ling-Jiang Liu
- Department of Psychiatric, Ningbo Kangning Hospital, Ningbo 315201, Zhejiang Province, China
| | - Hai-Hang Yu
- Department of Psychiatric, Ningbo Kangning Hospital, Ningbo 315201, Zhejiang Province, China
| | - Xiao-Bin Zhang
- Department of Psychiatry, Suzhou Guangji Hospital, Suzhou 215003, Jiangsu Province, China
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Cosemans C, Wang C, Alfano R, Martens DS, Sleurs H, Dockx Y, Vanbrabant K, Janssen BG, Vanpoucke C, Lefebvre W, Smeets K, Nawrot TS, Plusquin M. In utero particulate matter exposure in association with newborn mitochondrial ND4L 10550A>G heteroplasmy and its role in overweight during early childhood. Environ Health 2022; 21:88. [PMID: 36117180 PMCID: PMC9484069 DOI: 10.1186/s12940-022-00899-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 09/01/2022] [Indexed: 05/26/2023]
Abstract
BACKGROUND Mitochondria play an important role in the energy metabolism and are susceptible to environmental pollution. Prenatal air pollution exposure has been linked with childhood obesity. Placental mtDNA mutations have been associated with prenatal particulate matter exposure and MT-ND4L10550A>G heteroplasmy has been associated with BMI in adults. Therefore, we hypothesized that in utero PM2.5 exposure is associated with cord blood MT-ND4L10550A>G heteroplasmy and early life growth. In addition, the role of cord blood MT-ND4L10550A>G heteroplasmy in overweight during early childhood is investigated. METHODS This study included 386 mother-newborn pairs. Outdoor PM2.5 concentrations were determined at the maternal residential address. Cord blood MT-ND4L10550A>G heteroplasmy was determined using Droplet Digital PCR. Associations were explored using logistic regression models and distributed lag linear models. Mediation analysis was performed to quantify the effects of prenatal PM2.5 exposure on childhood overweight mediated by cord blood MT-ND4L10550A>G heteroplasmy. RESULTS Prenatal PM2.5 exposure was positively associated with childhood overweight during the whole pregnancy (OR = 2.33; 95% CI: 1.20 to 4.51; p = 0.01), which was mainly driven by the second trimester. In addition, prenatal PM2.5 exposure was associated with cord blood MT-ND4L10550A>G heteroplasmy from gestational week 9 - 13. The largest effect was observed in week 10, where a 5 µg/m3 increment in PM2.5 was linked with cord blood MT-ND4L10550A>G heteroplasmy (OR = 0.93; 95% CI: 0.87 to 0.99). Cord blood MT-ND4L10550A>G heteroplasmy was also linked with childhood overweight (OR = 3.04; 95% CI: 1.15 to 7.50; p = 0.02). The effect of prenatal PM2.5 exposure on childhood overweight was mainly direct (total effect OR = 1.18; 95% CI: 0.99 to 1.36; natural direct effect OR = 1.20; 95% CI: 1.01 to 1.36)) and was not mediated by cord blood MT-ND4L10550A>G heteroplasmy. CONCLUSIONS Cord blood MT-ND4L10550A>G heteroplasmy was linked with childhood overweight. In addition, in utero exposure to PM2.5 during the first trimester of pregnancy was associated with cord blood MT-ND4L10550A>G heteroplasmy in newborns. Our analysis did not reveal any mediation of cord blood MT-ND4L10550A>G heteroplasmy in the association between PM2.5 exposure and childhood overweight.
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Affiliation(s)
- Charlotte Cosemans
- Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium
| | - Congrong Wang
- Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium
| | - Rossella Alfano
- Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium
| | - Dries S Martens
- Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium
| | - Hanne Sleurs
- Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium
| | - Yinthe Dockx
- Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium
| | - Kenneth Vanbrabant
- Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium
| | - Bram G Janssen
- Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium
| | | | - Wouter Lefebvre
- Flemish Institute for Technological Research, VITO, Mol, Belgium
| | - Karen Smeets
- Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium
| | - Tim S Nawrot
- Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium
- School of Public Health, Occupational & Environmental Medicine, Leuven University, Leuven, Belgium
| | - Michelle Plusquin
- Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium.
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Castañeda V, Haro-Vinueza A, Salinas I, Caicedo A, Méndez MÁ. The MitoAging Project: Single nucleotide polymorphisms (SNPs) in mitochondrial genes and their association to longevity. Mitochondrion 2022; 66:13-26. [PMID: 35817296 DOI: 10.1016/j.mito.2022.06.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 06/20/2022] [Accepted: 06/26/2022] [Indexed: 11/26/2022]
Abstract
Mitochondrial dysfunction is a major hallmark of aging. Mitochondrial DNA (mtDNA) mutations (inherited or acquired) may cause a malfunction of the respiratory chain (RC), and thus negatively affect cell metabolism and function. In contrast, certain mtDNA single nucleotide polymorphisms (SNPs) may be beneficial to mitochondrial electron transport chain function and the extension of cellular health as well as lifespan. The goal of the MitoAging project is to detect key physiological characteristics and mechanisms that improve mitochondrial function and use them to develop therapies to increase longevity and a healthy lifespan. We chose to perform a systematic literature review (SLR) as a tool to collect key mtDNA SNPs associated with an increase in lifespan. Then validated our results by comparing them to the MitoMap database. Next, we assessed the effect of relevant SNPs on protein stability. A total of 28 SNPs were found in protein coding regions. These SNPs were reported in Japan, China, Turkey, and India. Among the studied SNPs, the C5178A mutation in the ND2 gene of Complex I of the RC was detected in all the reviewed reports except in Uygur Chinese centenarians. Then, we found that G9055A (ATP6 gene) and A10398G (ND3 gene) polymorphisms have been associated with a protective effect against Parkinson's disease (PD). Additionally, C8414T in ATP8 was significantly associated with longevity in three Japanese reports. Interestingly, using MitoMap we found that G9055A (ATP6 gene) was the only SNP promoting longevity not associated with any pathology. The identification of SNPs associated with an increase in lifespan opens the possibility to better understand individual differences regarding a decrease in illness susceptibility and find strategies that contribute to healthy aging.
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Affiliation(s)
- Verónica Castañeda
- PhD Program in Biomedicine, Faculty of Medicine, Universidad de los Andes, Santiago, Chile; Instituto de Investigaciones en Biomedicina iBioMed, Universidad San Francisco de Quito USFQ, Quito, Ecuador; Biología, Colegio de Ciencias Biológicas y Ambientales COCIBA, Universidad San Francisco de Quito USFQ, Quito, Ecuador; Mito-Act Research Consortium, Quito, Ecuador
| | - Alissen Haro-Vinueza
- Instituto de Investigaciones en Biomedicina iBioMed, Universidad San Francisco de Quito USFQ, Quito, Ecuador; Biología, Colegio de Ciencias Biológicas y Ambientales COCIBA, Universidad San Francisco de Quito USFQ, Quito, Ecuador; Mito-Act Research Consortium, Quito, Ecuador
| | - Ivonne Salinas
- Instituto de Investigaciones en Biomedicina iBioMed, Universidad San Francisco de Quito USFQ, Quito, Ecuador; Escuela de Medicina, Colegio de Ciencias de la Salud COCSA, Universidad San Francisco de Quito USFQ, Quito, Ecuador
| | - Andrés Caicedo
- Instituto de Investigaciones en Biomedicina iBioMed, Universidad San Francisco de Quito USFQ, Quito, Ecuador; Escuela de Medicina, Colegio de Ciencias de la Salud COCSA, Universidad San Francisco de Quito USFQ, Quito, Ecuador; Sistemas Médicos SIME, Universidad San Francisco de Quito USFQ, Quito, Ecuador; Mito-Act Research Consortium, Quito, Ecuador.
| | - Miguel Ángel Méndez
- Instituto de Investigaciones en Biomedicina iBioMed, Universidad San Francisco de Quito USFQ, Quito, Ecuador; Mito-Act Research Consortium, Quito, Ecuador; Grupo de Química Computacional y Teórica, Departamento de Ingeniería Química, Colegio de Ciencias e Ingenierías, Politécnico, Universidad San Francisco de Quito, Quito, Ecuador.
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Pravenec M, Šilhavý J, Mlejnek P, Šimáková M, Mráček T, Pecinová A, Tauchmannová K, Hütl M, Malínská H, Kazdová L, Neckář J, Kolář F, Žurmanová J, Novotný J, Houštěk J. Conplastic strains for identification of retrograde effects of mitochondrial dna variation on cardiometabolic traits in the spontaneously hypertensive rat. Physiol Res 2021; 70:S471-S484. [DOI: 10.33549/physiolres.934740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Mitochondrial retrograde signaling is a pathway of communication from mitochondria to the nucleus. Recently, natural mitochondrial genome (mtDNA) polymorphisms (haplogroups) received increasing attention in the pathophysiology of human common diseases. However, retrograde effects of mtDNA variants on such traits are difficult to study in humans. The conplastic strains represent key animal models to elucidate regulatory roles of mtDNA haplogroups on defined nuclear genome background. To analyze the relationship between mtDNA variants and cardiometabolic traits, we derived a set of rat conplastic strains (SHR-mtBN, SHR-mtF344 and SHR-mtLEW), harboring all major mtDNA haplotypes present in common inbred strains on the nuclear background of the spontaneously hypertensive rat (SHR). The BN, F344 and LEW mtDNA differ from the SHR in multiple amino acid substitutions in protein coding genes and also in variants of tRNA and rRNA genes. Different mtDNA haplotypes were found to predispose to various sets of cardiometabolic phenotypes which provided evidence for significant retrograde effects of mtDNA in the SHR. In the future, these animals could be used to decipher individual biochemical components involved in the retrograde signaling.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - J Houštěk
- Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic. ,
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9
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Yang L, Guo Q, Leng J, Wang K, Ding Y. Late onset of type 2 diabetes is associated with mitochondrial tRNA Trp A5514G and tRNA Ser(AGY) C12237T mutations. J Clin Lab Anal 2021; 36:e24102. [PMID: 34811812 PMCID: PMC8761459 DOI: 10.1002/jcla.24102] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 10/19/2021] [Accepted: 10/26/2021] [Indexed: 12/16/2022] Open
Abstract
Background Mitochondrial dysfunctions caused by mitochondrial DNA (mtDNA) pathogenic mutations play putative roles in type 2 diabetes mellitus (T2DM) progression. But the underlying mechanism remains poorly understood. Methods A large Chinese family with maternally inherited diabetes and deafness (MIDD) underwent clinical, genetic, and molecular assessment. PCR and sequence analysis are carried out to detect mtDNA variants in affected family members, in addition, phylogenetic conservation analysis, haplogroup classification, and pathogenicity scoring system are performed. Moreover, the GJB2, GJB3, GJB6, and TRMU genes mutations are screened by PCR‐Sanger sequencing. Results Six of 18 matrilineal subjects manifested different clinical phenotypes of diabetes. The average age at onset of diabetic patients is 52 years. Screening for the entire mitochondrial genomes suggests the co‐existence of two possibly pathogenic mutations: tRNATrp A5514G and tRNASer(AGY) C12237T, which belongs to East Asia haplogroup G2a. By molecular level, m.A5514G mutation resides at acceptor stem of tRNATrp (position 3), which is critical for steady‐state level of tRNATrp. Conversely, m.C12237T mutation occurs in the variable region of tRNASer(AGY) (position 31), which creates a novel base‐pairing (11A‐31T). Thus, the mitochondrial dysfunctions caused by tRNATrp A5514G and tRNASer(AGY) C12237T mutations, may be associated with T2DM in this pedigree. But we do not find any functional mutations in those nuclear genes. Conclusion Our findings suggest that m.A5514G and m.C12337T mutations are associated with T2DM, screening for mt‐tRNA mutations is useful for molecular diagnosis and prevention of mitochondrial diabetes.
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Affiliation(s)
- Liuchun Yang
- Central Laboratory, the Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qinxian Guo
- Central Laboratory, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianhang Leng
- Central Laboratory, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Keyi Wang
- Central Laboratory, the Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China.,Central Laboratory, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yu Ding
- Central Laboratory, the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
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10
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Laaksonen J, Mishra PP, Seppälä I, Raitoharju E, Marttila S, Mononen N, Lyytikäinen LP, Kleber ME, Delgado GE, Lepistö M, Almusa H, Ellonen P, Lorkowski S, März W, Hutri-Kähönen N, Raitakari O, Kähönen M, Salonen JT, Lehtimäki T. Mitochondrial genome-wide analysis of nuclear DNA methylation quantitative trait loci. Hum Mol Genet 2021; 31:1720-1732. [PMID: 35077545 PMCID: PMC9122653 DOI: 10.1093/hmg/ddab339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 11/12/2021] [Accepted: 11/16/2021] [Indexed: 11/13/2022] Open
Abstract
Abstract
Mitochondria have a complex communication network with the surrounding cell and can alter nuclear DNA methylation (DNAm). Variation in the mitochondrial DNA (mtDNA) has also been linked to differential DNAm. Genome-wide association studies have identified numerous DNAm quantitative trait loci, but these studies have not examined the mitochondrial genome. Herein, we quantified nuclear DNAm from blood and conducted a mitochondrial genome-wide association study of DNAm, with an additional emphasis on sex- and prediabetes-specific heterogeneity. We used the Young Finns Study (n = 926) with sequenced mtDNA genotypes as a discovery sample and sought replication in the Ludwigshafen Risk and Cardiovascular Health study (n = 2317). We identified numerous significant associations in the discovery phase (P < 10−9), but they were not replicated when accounting for multiple testing. In total, 27 associations were nominally replicated with a P < 0.05. The replication analysis presented no evidence of sex- or prediabetes-specific heterogeneity. The 27 associations were included in a joint meta-analysis of the two cohorts, and 19 DNAm sites associated with mtDNA variants, while four other sites showed haplogroup associations. An expression quantitative trait methylation analysis was performed for the identified DNAm sites, pinpointing two statistically significant associations. This study provides evidence of a mitochondrial genetic control of nuclear DNAm with little evidence found for sex- and prediabetes-specific effects. The lack of a comparable mtDNA data set for replication is a limitation in our study and further studies are needed to validate our results.
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Affiliation(s)
- Jaakko Laaksonen
- To whom correspondence should be addressed at: Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpön katu 34, PO Box 100, Tampere FI-33014, Finland. Tel: +358 504080774; E-mail:
| | - Pashupati P Mishra
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33520, Finland
| | - Ilkka Seppälä
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33520, Finland
| | - Emma Raitoharju
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33520, Finland
- Molecular Epidemiology, Faculty of Medicine and Health Technology, Tampere University, Tampere 33520, Finland
| | - Saara Marttila
- Molecular Epidemiology, Faculty of Medicine and Health Technology, Tampere University, Tampere 33520, Finland
- Gerontology Research Center, Tampere University, Tampere 33520, Finland
| | - Nina Mononen
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33520, Finland
| | - Leo-Pekka Lyytikäinen
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33520, Finland
| | - Marcus E Kleber
- Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany
| | - Graciela E Delgado
- Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany
| | - Maija Lepistö
- Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki 00290, Finland
| | - Henrikki Almusa
- Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki 00290, Finland
| | - Pekka Ellonen
- Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki 00290, Finland
| | - Stefan Lorkowski
- Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena 07743, Germany
- Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig, Jena 07743, Germany
| | - Winfried März
- Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany
- Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig, Jena 07743, Germany
- SYNLAB Academy, SYNLAB Holding Deutschland GmbH, Augsburg 86156, Germany
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8010, Austria
| | - Nina Hutri-Kähönen
- Tampere Centre for Skills Training and Simulation, Tampere University, Tampere 33520, Finland
| | - Olli Raitakari
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku 20520, Finland
- Research Centre for Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland
- Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku 20520, Finland
| | - Mika Kähönen
- Department of Clinical Physiology, Tampere University Hospital, Tampere 33520, Finland
- Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33520, Finland
| | - Jukka T Salonen
- Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland
- MAS-Metabolic Analytical Services Oy, Helsinki 00990, Finland
| | - Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33520, Finland
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11
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Gupta R, Karczewski KJ, Howrigan D, Neale BM, Mootha VK. Human genetic analyses of organelles highlight the nucleus in age-related trait heritability. eLife 2021; 10:68610. [PMID: 34467851 PMCID: PMC8476128 DOI: 10.7554/elife.68610] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 08/30/2021] [Indexed: 12/15/2022] Open
Abstract
Most age-related human diseases are accompanied by a decline in cellular organelle integrity, including impaired lysosomal proteostasis and defective mitochondrial oxidative phosphorylation. An open question, however, is the degree to which inherited variation in or near genes encoding each organelle contributes to age-related disease pathogenesis. Here, we evaluate if genetic loci encoding organelle proteomes confer greater-than-expected age-related disease risk. As mitochondrial dysfunction is a 'hallmark' of aging, we begin by assessing nuclear and mitochondrial DNA loci near genes encoding the mitochondrial proteome and surprisingly observe a lack of enrichment across 24 age-related traits. Within nine other organelles, we find no enrichment with one exception: the nucleus, where enrichment emanates from nuclear transcription factors. In agreement, we find that genes encoding several organelles tend to be 'haplosufficient,' while we observe strong purifying selection against heterozygous protein-truncating variants impacting the nucleus. Our work identifies common variation near transcription factors as having outsize influence on age-related trait risk, motivating future efforts to determine if and how this inherited variation then contributes to observed age-related organelle deterioration.
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Affiliation(s)
- Rahul Gupta
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States.,Broad Institute of MIT and Harvard, Cambridge, United States.,Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States
| | - Konrad J Karczewski
- Broad Institute of MIT and Harvard, Cambridge, United States.,Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States
| | - Daniel Howrigan
- Broad Institute of MIT and Harvard, Cambridge, United States.,Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States
| | - Benjamin M Neale
- Broad Institute of MIT and Harvard, Cambridge, United States.,Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States
| | - Vamsi K Mootha
- Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States.,Broad Institute of MIT and Harvard, Cambridge, United States
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12
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Saha SK, Saba AA, Hasib M, Rimon RA, Hasan I, Alam MS, Mahmud I, Nabi AN. Evaluation of D-loop hypervariable region I variations, haplogroups and copy number of mitochondrial DNA in Bangladeshi population with type 2 diabetes. Heliyon 2021; 7:e07573. [PMID: 34377852 PMCID: PMC8327661 DOI: 10.1016/j.heliyon.2021.e07573] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/01/2021] [Accepted: 07/12/2021] [Indexed: 10/24/2022] Open
Abstract
The profound impact of mitochondrion in cellular metabolism has been well documented. Since type 2 diabetes (T2D) is a metabolic disorder, mitochondrial dysfunction is intricately linked with the disease pathogenesis. Mitochondrial DNA (mtDNA) variants are involved with functional dysfunction of mitochondrion and play a pivotal role in the susceptibility to T2D. In this study, we opted to find the association of mtDNA variants within the D-loop hypervariable region I (HVI), haplogroups and mtDNA copy number with T2D in Bangladeshi population. A total of 300 unrelated Bangladeshi individuals (150 healthy and 150 patients with T2D) were recruited in the present study, their HVI regions were amplified and sequenced using Sanger chemistry. Haplogrep2 and Phylotree17 tools were employed to determine the haplogroups. MtDNA copy number was measured using primers of mitochondrial tRNALeu (UUR) gene and nuclear β2-microglobulin gene. Variants G16048A (OR:0.12, p = 0.04) and G16129A (OR: 0.42, p = 0.007) were found to confer protective role against T2D according to logistic regression analysis. However along with G16129A, two new variants C16294T and T16325C demonstrated protective role against T2D when age and gender were adjusted. Haplogroups A and H showed significant association with the risk of T2D after adjustments out of total 19 major haplogroups identified. The mtDNA copy numbers were stratified into 4 groups according to the quartiles (groups with lower, medium, upper and higher mtDNA copy numbers were respectively designated as LCN, MCN, UCN and HCN). Patients with T2D had significantly lower mtDNA copy number compared to their healthy counterparts in HCN group. Moreover, six mtDNA variants were significantly associated with mtDNA copy number in the participants. Thus, our study confers that certain haplogroups and novel variants of mtDNA are significantly associated with T2D while decreased mtDNA copy number (though not significant) has been observed in patients with T2D. However, largescale studies are warranted to establish association of novel variants and haplogroup with type 2 diabetes.
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Affiliation(s)
- Sajoy Kanti Saha
- Laboratory of Population Genetics, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh
| | - Abdullah Al Saba
- Laboratory of Population Genetics, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh
| | - Md. Hasib
- Laboratory of Population Genetics, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh
| | - Razoan Al Rimon
- Laboratory of Population Genetics, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh
| | - Imrul Hasan
- Laboratory of Population Genetics, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh
| | - Md. Sohrab Alam
- Department of Immunology, Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders, Shahbagh, Dhaka, Bangladesh
| | - Ishtiaq Mahmud
- Laboratory of Population Genetics, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh
| | - A.H.M. Nurun Nabi
- Laboratory of Population Genetics, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh
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13
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Kozakiewicz P, Grzybowska-Szatkowska L, Ciesielka M, Rzymowska J. The Role of Mitochondria in Carcinogenesis. Int J Mol Sci 2021; 22:ijms22105100. [PMID: 34065857 PMCID: PMC8151940 DOI: 10.3390/ijms22105100] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 04/30/2021] [Accepted: 05/06/2021] [Indexed: 12/20/2022] Open
Abstract
The mitochondria are essential for normal cell functioning. Changes in mitochondrial DNA (mtDNA) may affect the occurrence of some chronic diseases and cancer. This process is complex and not entirely understood. The assignment to a particular mitochondrial haplogroup may be a factor that either contributes to cancer development or reduces its likelihood. Mutations in mtDNA occurring via an increase in reactive oxygen species may favour the occurrence of further changes both in mitochondrial and nuclear DNA. Mitochondrial DNA mutations in postmitotic cells are not inherited, but may play a role both in initiation and progression of cancer. One of the first discovered polymorphisms associated with cancer was in the gene NADH-ubiquinone oxidoreductase chain 3 (mt-ND3) and it was typical of haplogroup N. In prostate cancer, these mutations and polymorphisms involve a gene encoding subunit I of respiratory complex IV cytochrome c oxidase subunit 1 gene (COI). At present, a growing number of studies also address the impact of mtDNA polymorphisms on prognosis in cancer patients. Some of the mitochondrial DNA polymorphisms occur in both chronic disease and cancer, for instance polymorphism G5913A characteristic of prostate cancer and hypertension.
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Affiliation(s)
- Paulina Kozakiewicz
- Department of Radiotherapy, Medical University in Lublin, Chodźki 7, 20-093 Lublin, Poland; (L.G.-S.); (M.C.)
- Department of Radiotherapy, St. John’s Cancer Centre, The Regional Oncology Centre of Lublin Jaczewskiego 7, 20-090 Lublin, Poland
- Correspondence:
| | - Ludmiła Grzybowska-Szatkowska
- Department of Radiotherapy, Medical University in Lublin, Chodźki 7, 20-093 Lublin, Poland; (L.G.-S.); (M.C.)
- Department of Radiotherapy, St. John’s Cancer Centre, The Regional Oncology Centre of Lublin Jaczewskiego 7, 20-090 Lublin, Poland
| | - Marzanna Ciesielka
- Department of Radiotherapy, Medical University in Lublin, Chodźki 7, 20-093 Lublin, Poland; (L.G.-S.); (M.C.)
- Chair and Department of Forensic Medicine, Medical University in Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland
| | - Jolanta Rzymowska
- Chair and Department of Biology and Genetics, Medical University of Lublin, Chodźki 4A, 20-093 Lublin, Poland;
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14
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Laaksonen J, Mishra PP, Seppälä I, Lyytikäinen LP, Raitoharju E, Mononen N, Lepistö M, Almusa H, Ellonen P, Hutri-Kähönen N, Juonala M, Raitakari O, Kähönen M, Salonen JT, Lehtimäki T. Examining the effect of mitochondrial DNA variants on blood pressure in two Finnish cohorts. Sci Rep 2021; 11:611. [PMID: 33436758 PMCID: PMC7804469 DOI: 10.1038/s41598-020-79931-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 12/10/2020] [Indexed: 12/12/2022] Open
Abstract
High blood pressure (BP) is a major risk factor for many noncommunicable diseases. The effect of mitochondrial DNA single-nucleotide polymorphisms (mtSNPs) on BP is less known than that of nuclear SNPs. We investigated the mitochondrial genetic determinants of systolic, diastolic, and mean arterial BP. MtSNPs were determined from peripheral blood by sequencing or with genome-wide association study SNP arrays in two independent Finnish cohorts, the Young Finns Study and the Finnish Cardiovascular Study, respectively. In total, over 4200 individuals were included. The effects of individual common mtSNPs, with an additional focus on sex-specificity, and aggregates of rare mtSNPs grouped by mitochondrial genes were evaluated by meta-analysis of linear regression and a sequence kernel association test, respectively. We accounted for the predicted pathogenicity of the rare variants within protein-encoding and the tRNA regions. In the meta-analysis of 87 common mtSNPs, we did not observe significant associations with any of the BP traits. Sex-specific and rare-variant analyses did not pinpoint any significant associations either. Our results are in agreement with several previous studies suggesting that mtDNA variation does not have a significant role in the regulation of BP. Future studies might need to reconsider the mechanisms thought to link mtDNA with hypertension.
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Affiliation(s)
- Jaakko Laaksonen
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpön katu 34, PO Box 100, 33014, Tampere, Finland.
| | - Pashupati P Mishra
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpön katu 34, PO Box 100, 33014, Tampere, Finland
| | - Ilkka Seppälä
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpön katu 34, PO Box 100, 33014, Tampere, Finland
| | - Leo-Pekka Lyytikäinen
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpön katu 34, PO Box 100, 33014, Tampere, Finland
| | - Emma Raitoharju
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpön katu 34, PO Box 100, 33014, Tampere, Finland
| | - Nina Mononen
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpön katu 34, PO Box 100, 33014, Tampere, Finland
| | - Maija Lepistö
- Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland
| | - Henrikki Almusa
- Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland
| | - Pekka Ellonen
- Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland
| | - Nina Hutri-Kähönen
- Department of Paediatrics, Tampere University Hospital and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Markus Juonala
- Department of Medicine, University of Turku, Turku, Finland.,Division of Medicine, Turku University Hospital, Turku, Finland.,Murdoch Children's Research Institute, Parkville, VIC, Australia
| | - Olli Raitakari
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland.,Research Centre for Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.,Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland
| | - Mika Kähönen
- Department of Clinical Physiology, Tampere University Hospital and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Jukka T Salonen
- Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,MAS-Metabolic Analytical Services Oy, Helsinki, Finland
| | - Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Arvo Ylpön katu 34, PO Box 100, 33014, Tampere, Finland
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15
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Vanlalhruaii Tonsing M, Vanlalbiakdiki Sailo C, Zothansanga, Chhakchhuak L, Chhakchhuak Z, Pandit B, Kumar D, Pratim Mazumder P, Senthil Kumar N. Analysis of variants in mitochondrial genome and their putative pathogenicity in tuberculosis patients from Mizoram, North east India. Mitochondrion 2020; 54:21-25. [DOI: 10.1016/j.mito.2020.06.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 05/02/2020] [Accepted: 06/26/2020] [Indexed: 11/28/2022]
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16
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Nagao T, Shintani Y, Hayashi T, Kioka H, Kato H, Nishida Y, Yamazaki S, Tsukamoto O, Yashirogi S, Yazawa I, Asano Y, Shinzawa-Itoh K, Imamura H, Suzuki T, Suzuki T, Goto YI, Takashima S. Higd1a improves respiratory function in the models of mitochondrial disorder. FASEB J 2019; 34:1859-1871. [PMID: 31914602 DOI: 10.1096/fj.201800389r] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 05/26/2018] [Accepted: 06/12/2018] [Indexed: 12/22/2022]
Abstract
The respiratory chain (RC) transports electrons to form a proton motive force that is required for ATP synthesis in the mitochondria. RC disorders cause mitochondrial diseases that have few effective treatments; therefore, novel therapeutic strategies are critically needed. We previously identified Higd1a as a positive regulator of cytochrome c oxidase (CcO) in the RC. Here, we test that Higd1a has a beneficial effect by increasing CcO activity in the models of mitochondrial dysfunction. We first demonstrated the tissue-protective effects of Higd1a via in situ measurement of mitochondrial ATP concentrations ([ATP]mito) in a zebrafish hypoxia model. Heart-specific Higd1a overexpression mitigated the decline in [ATP]mito under hypoxia and preserved cardiac function in zebrafish. Based on the in vivo results, we examined the effects of exogenous HIGD1A on three cellular models of mitochondrial disease; notably, HIGD1A improved respiratory function that was coupled with increased ATP synthesis and demonstrated cellular protection in all three models. Finally, enzyme kinetic analysis revealed that Higd1a significantly increased the maximal velocity of the reaction between CcO and cytochrome c without changing the affinity between them, indicating that Higd1a is a positive modulator of CcO. These results corroborate that Higd1a, or its mimic, provides therapeutic options for the treatment of mitochondrial diseases.
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Affiliation(s)
- Takemasa Nagao
- Department of Medical Biochemistry, Graduate School of Frontier Biological Science, Osaka University, Suita, Japan
| | - Yasunori Shintani
- Department of Medical Biochemistry, Graduate School of Frontier Biological Science, Osaka University, Suita, Japan
| | - Takaharu Hayashi
- Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Hidetaka Kioka
- Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Hisakazu Kato
- Department of Medical Biochemistry, Graduate School of Frontier Biological Science, Osaka University, Suita, Japan
| | - Yuya Nishida
- Department of Medical Biochemistry, Graduate School of Frontier Biological Science, Osaka University, Suita, Japan.,Japan Science and Technology Agency-Core Research for Evolutional Science and Technology (CREST), Kawaguchi, Japan
| | - Satoru Yamazaki
- Department of Cell Biology, National Cerebral and Cardiovascular Center, Suita, Japan
| | - Osamu Tsukamoto
- Department of Medical Biochemistry, Graduate School of Frontier Biological Science, Osaka University, Suita, Japan
| | - Shohei Yashirogi
- Department of Medical Biochemistry, Graduate School of Frontier Biological Science, Osaka University, Suita, Japan
| | - Issei Yazawa
- Department of Medical Biochemistry, Graduate School of Frontier Biological Science, Osaka University, Suita, Japan
| | - Yoshihiro Asano
- Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
| | | | - Hiromi Imamura
- Graduate School of Biostudies, Kyoto University, Kyoto, Japan
| | - Takeo Suzuki
- Department of Chemistry and Biotechnology, Graduate School of Engineering, University of Tokyo, Tokyo, Japan
| | - Tsutomu Suzuki
- Department of Chemistry and Biotechnology, Graduate School of Engineering, University of Tokyo, Tokyo, Japan
| | - Yu-Ichi Goto
- Department of Child Neurology, National Center Hospital of Neurology and Psychiatry (NCNP), Kodaira, Japan
| | - Seiji Takashima
- Department of Medical Biochemistry, Graduate School of Frontier Biological Science, Osaka University, Suita, Japan.,Japan Science and Technology Agency-Core Research for Evolutional Science and Technology (CREST), Kawaguchi, Japan
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17
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Jancic J, Rovcanin B, Djuric V, Pepic A, Samardzic J, Nikolic B, Novakovic I, Kostic VS. Analysis of secondary mtDNA mutations in families with Leber's hereditary optic neuropathy: Four novel variants and their association with clinical presentation. Mitochondrion 2019; 50:132-138. [PMID: 31743754 DOI: 10.1016/j.mito.2019.10.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 10/12/2019] [Accepted: 10/30/2019] [Indexed: 01/16/2023]
Abstract
Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by subacute optic atrophy which results in severe visual impairment. The penetrance, clinical expression and disease onset are variable, and frequently associated with other extraocular symptoms. The disease phenotype remains to be an intriguing question which is dependent upon primary as well as secondary mtDNA mutations. In this study we analyzed the whole mtDNA sequence in six LHON families from Serbian population. The mtDNA sequencing was performed by Sanger's method and various bioinformatic tools were used for analysis of detected mutations. LHON patients carry all three (m.3460G > A, m.11778G > A and m.14484 T > C) primary mutations, together with numerous secondary mtDNA mutations. Four novel mutations (m.4516G > A, m.8779C > T, m.13138G > A and m.15986insG) in four different families were discovered. The m.8779C > T and m.13138G > A mutations could have a potential influence on LHON symptoms, but the issue of effect of secondary mtDNA mutations in LHON patients needs to be better clarified in future studies.
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Affiliation(s)
- Jasna Jancic
- Clinic of Neurology and Psychiatry for Children and Youth, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
| | - Branislav Rovcanin
- Center for Endocrine Surgery, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Vesna Djuric
- Clinic of Neurology and Psychiatry for Children and Youth, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Ana Pepic
- Clinic of Neurology and Psychiatry for Children and Youth, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Janko Samardzic
- Institute of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Blazo Nikolic
- Clinic of Neurology and Psychiatry for Children and Youth, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Ivana Novakovic
- Institute for Human Genetics, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Vladimir S Kostic
- Clinic of Neurology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
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18
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Li Y, Giorgi EE, Beckman KB, Caberto C, Kazma R, Lum-Jones A, Haiman CA, Marchand LL, Stram DO, Saxena R, Cheng I. Association between mitochondrial genetic variation and breast cancer risk: The Multiethnic Cohort. PLoS One 2019; 14:e0222284. [PMID: 31577800 PMCID: PMC6774509 DOI: 10.1371/journal.pone.0222284] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 08/26/2019] [Indexed: 01/17/2023] Open
Abstract
Background The mitochondrial genome encodes for thirty-seven proteins, among them thirteen are essential for the oxidative phosphorylation (OXPHOS) system. Inherited variation in mitochondrial genes may influence cancer development through changes in mitochondrial proteins, altering the OXPHOS process and promoting the production of reactive oxidative species. Methods To investigate the association between mitochondrial genetic variation and breast cancer risk, we tested 314 mitochondrial SNPs (mtSNPs), capturing four complexes of the mitochondrial OXPHOS pathway and mtSNP groupings for rRNA and tRNA, in 2,723 breast cancer cases and 3,260 controls from the Multiethnic Cohort Study. Results We examined the collective set of 314 mtSNPs as well as subsets of mtSNPs grouped by mitochondrial OXPHOS pathway, complexes, and genes, using the sequence kernel association test and adjusting for age, sex, and principal components of global ancestry. We also tested haplogroup associations using unconditional logistic regression and adjusting for the same covariates. Stratified analyses were conducted by self-reported maternal race/ethnicity. No significant mitochondrial OXPHOS pathway, gene, and haplogroup associations were observed in African Americans, Asian Americans, Latinos, and Native Hawaiians. In European Americans, a global test of all genetic variants of the mitochondrial genome identified an association with breast cancer risk (P = 0.017, q = 0.102). In mtSNP-subset analysis, the gene MT-CO2 (P = 0.001, q = 0.09) in Complex IV (cytochrome c oxidase) and MT-ND2 (P = 0.004, q = 0.19) in Complex I (NADH dehydrogenase (ubiquinone)) were significantly associated with breast cancer risk. Conclusions In summary, our findings suggest that collective mitochondrial genetic variation and particularly in the MT-CO2 and MT-ND2 may play a role in breast cancer risk among European Americans. Further replication is warranted in larger populations and future studies should evaluate the contribution of mitochondrial proteins encoded by both the nuclear and mitochondrial genomes to breast cancer risk.
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Affiliation(s)
- Yuqing Li
- Department of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco, California, United States of America
| | - Elena E. Giorgi
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico
| | - Kenneth B. Beckman
- University of Minnesota Genomics Center, Minneapolis, Minnesota, United States of America
| | - Christian Caberto
- Epidemiology Program, University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii, United States of America
| | - Remi Kazma
- Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Switzerland
| | - Annette Lum-Jones
- Epidemiology Program, University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii, United States of America
| | - Christopher A. Haiman
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Loïc Le Marchand
- Epidemiology Program, University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii, United States of America
| | - Daniel O. Stram
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Richa Saxena
- Center for Human Genetic Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Program of Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America
| | - Iona Cheng
- Department of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco, California, United States of America
- * E-mail:
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19
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Mitochondrial miR-762 regulates apoptosis and myocardial infarction by impairing ND2. Cell Death Dis 2019; 10:500. [PMID: 31235686 PMCID: PMC6591419 DOI: 10.1038/s41419-019-1734-7] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 05/01/2019] [Accepted: 05/28/2019] [Indexed: 12/11/2022]
Abstract
Mitochondrial dysfunction plays a major role in the pathogenesis of cardiovascular diseases. MicroRNAs (miRNAs) are small RNAs that act as negative regulators of gene expression, but how miRNAs affect mitochondrial function in the heart is unclear. Using a miRNA microarray assay, we found that miR-762 predominantly translocated in the mitochondria and was significantly upregulated upon anoxia/reoxygenation (A/R) treatment. Knockdown of endogenous miR-762 significantly attenuated the decrease in intracellular ATP levels, the increase in ROS levels, the decrease in mitochondrial complex I enzyme activity and the increase in apoptotic cell death in cardiomyocytes, which was induced by A/R treatment. In addition, knockdown of miR-762 ameliorated myocardial ischemia/reperfusion (I/R) injury in mice. Mechanistically, we showed that enforced expression of miR-762 dramatically decreased the protein levels of endogenous NADH dehydrogenase subunit 2 (ND2) but had no effect on the transcript levels of ND2. The luciferase reporter assay showed that miR-762 bound to the coding sequence of ND2. In addition, knockdown of endogenous ND2 significantly decreased intracellular ATP levels, increased ROS levels, reduced mitochondrial complex I enzyme activity and increased apoptotic cell death in cardiomyocytes, which was induced by A/R treatment. Furthermore, we found that the inhibitory effect of miR-762 downregulation was attenuated by ND2 knockdown. Thus, our findings suggest that miR-762 participates in the regulation of mitochondrial function and cardiomyocyte apoptosis by ND2, a core assembly subunit of mitochondrial complex I. Our results revealed that mitochondrial miR-762, as a new player in mitochondrial dysfunction, may provide a new therapeutic target for myocardial infarction.
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20
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Altafi D, Sadeghi S, Hojatian H, Torabi Afra M, Pakizeh Kar S, Gorji M, Houshmand M. Mitochondrial Polymorphisms, in The D-Loop Area, Are Associated with Brain Tumors. CELL JOURNAL 2019; 21:350-356. [PMID: 31210442 PMCID: PMC6582428 DOI: 10.22074/cellj.2019.5947] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Accepted: 10/29/2018] [Indexed: 11/18/2022]
Abstract
Objective This study was carried out to evaluate the relationship between mtDNA D-loop variations and the
pathogenesis of a brain tumor.
Materials and Methods In this experimental study, 25 specimens of brain tumor tissue with their adjacent tissues
from patients and 454 blood samples from different ethnic groups of the Iranian population, as the control group, were
analysed by the polymerase chain reaction (PCR)-sequencing method.
Results Thirty-six variations of the D-loop area were observed in brain tumor tissues as well as the adjacent normal
tissues. A significant difference of A750G (P=0.046), T15936C (P=0.013), C15884G (P=0.013), C16069T (P=0.049),
T16126C (P=0.006), C16186T (P=0.022), T16189C (P=0.041), C16193T (P=0.045), C16223T (P=0.001), T16224C
(P=0.013), C16234T (P=0.013), G16274A (P=0.009), T16311C (P=0.038), C16327T (P=0.045), C16355T (P=0.003),
T16362C (P=0.006), G16384A (P=0.042), G16392A (P=0.013), G16394A (P=0.013), and G16477A (P=0.013) variants
was found between the patients and the controls.
Conclusion The results indicated individuals with C16069T [odds ratio (OR): 2.048], T16126C (OR: 2.226), C16186T
(OR: 3.586), G16274A (OR: 4.831), C16355T (OR: 7.322), and T16362C (OR: 6.682) variants with an OR more than
one are probably associated with a brain tumor. However, given the multifactorial nature of cancer, more investigation
needs to be done to confirm this association.
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Affiliation(s)
- Donya Altafi
- Molecular Biology Department, NourDanesh Institute of Higher Education, Esfahan, Iran. Electronic Address:
| | - Soha Sadeghi
- Molecular Biology Department, NourDanesh Institute of Higher Education, Esfahan, Iran
| | - Hamed Hojatian
- Molecular Biology Department, NourDanesh Institute of Higher Education, Esfahan, Iran
| | - Maryam Torabi Afra
- Molecular Biology Department, NourDanesh Institute of Higher Education, Esfahan, Iran
| | | | - Mojtaba Gorji
- Department of Hematology and Oncology, Lorestan Medical University, Lorestan, Iran
| | - Massoud Houshmand
- Department of Medical Genetics, National Institutes for Genetic Engineering and Biotechnology, Tehran, Iran.,Research Center, Knowledge University, Erbil, Kurdistan Region, Iraq.Electronic Address:
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21
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Laaksonen J, Seppälä I, Raitoharju E, Mononen N, Lyytikäinen LP, Waldenberger M, Illig T, Lepistö M, Almusa H, Ellonen P, Hutri-Kähönen N, Juonala M, Kähönen M, Raitakari O, Salonen JT, Lehtimäki T. Discovery of mitochondrial DNA variants associated with genome-wide blood cell gene expression: a population-based mtDNA sequencing study. Hum Mol Genet 2019; 28:1381-1391. [PMID: 30629177 DOI: 10.1093/hmg/ddz011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 12/14/2018] [Accepted: 01/07/2019] [Indexed: 01/01/2023] Open
Abstract
The effect of mitochondrial DNA (mtDNA) variation on peripheral blood transcriptomics in health and disease is not fully known. Sex-specific mitochondrially controlled gene expression patterns have been shown in Drosophila melanogaster but in humans, evidence is lacking. Functional variation in mtDNA may also have a role in the development of type 2 diabetes and its precursor state, i.e. prediabetes. We examined the associations between mitochondrial single-nucleotide polymorphisms (mtSNPs) and peripheral blood transcriptomics with a focus on sex- and prediabetes-specific effects. The genome-wide blood cell expression data of 19 637 probes, 199 deep-sequenced mtSNPs and nine haplogroups of 955 individuals from a population-based Young Finns Study cohort were used. Significant associations were identified with linear regression and analysis of covariance. The effects of sex and prediabetes on the associations between gene expression and mtSNPs were studied using random-effect meta-analysis. Our analysis identified 53 significant expression probe-mtSNP associations after Bonferroni correction, involving 7 genes and 31 mtSNPs. Eight probe-mtSNP signals remained independent after conditional analysis. In addition, five genes showed differential expression between haplogroups. The meta-analysis did not show any significant differences in linear model effect sizes between males and females but identified the association between the OASL gene and mtSNP C16294T to show prediabetes-specific effects. This study pinpoints new independent mtSNPs associated with peripheral blood transcriptomics and replicates six previously reported associations, providing further evidence of the mitochondrial genetic control of blood cell gene expression. In addition, we present evidence that prediabetes might lead to perturbations in mitochondrial control.
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Affiliation(s)
- Jaakko Laaksonen
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Ilkka Seppälä
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Emma Raitoharju
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Nina Mononen
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Leo-Pekka Lyytikäinen
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Melanie Waldenberger
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.,Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Thomas Illig
- Hannover Unified Biobank, Hannover Medical School, Hannover Germany.,Institute for Human Genetics, Hannover Medical School, Hannover, Germany
| | - Maija Lepistö
- Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland
| | - Henrikki Almusa
- Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland
| | - Pekka Ellonen
- Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland
| | - Nina Hutri-Kähönen
- Department of Pediatrics, Tampere University Hospital and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Markus Juonala
- Department of Medicine, University of Turku, Turku, Finland.,Division of Medicine, Turku University Hospital, Turku, Finland.,Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Mika Kähönen
- Department of Clinical Physiology, Tampere University Hospital and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Olli Raitakari
- Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland.,Research Centre for Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
| | - Jukka T Salonen
- Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,MAS-Metabolic Analytical Services Oy, Helsinki, Finland
| | - Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
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22
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Saha SK, Akther J, Huda N, Yasmin T, Alam MS, Hosen MI, Hasan AM, Nabi AN. Genetic association study of C5178A and G10398A mitochondrial DNA variants with type 2 diabetes in Bangladeshi population. Meta Gene 2019; 19:23-31. [DOI: 10.1016/j.mgene.2018.10.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
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23
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Hagen CM, Gonçalves VF, Hedley PL, Bybjerg-Grauholm J, Bækvad-Hansen M, Hansen CS, Kanters JK, Nielsen J, Mors O, Demur AB, Als TD, Nordentoft M, Børglum A, Mortensen PB, Kennedy J, Werge TM, Hougaard DM, Christiansen M. Schizophrenia-associated mt-DNA SNPs exhibit highly variable haplogroup affiliation and nuclear ancestry: Bi-genomic dependence raises major concerns for link to disease. PLoS One 2018; 13:e0208828. [PMID: 30532134 PMCID: PMC6287820 DOI: 10.1371/journal.pone.0208828] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 11/23/2018] [Indexed: 11/19/2022] Open
Abstract
Mitochondria play a significant role in human diseases. However, disease associations with mitochondrial DNA (mtDNA) SNPs have proven difficult to replicate. An analysis of eight schizophrenia-associated mtDNA SNPs, in 23,743 Danes without a psychiatric diagnosis and 2,538 schizophrenia patients, revealed marked inter-allelic differences in mitochondrial haplogroup affiliation and nuclear ancestry. This bi-genomic dependence could entail population stratification. Only two mitochondrial SNPs, m.15043A and m.15218G, were significantly associated with schizophrenia. However, these associations disappeared when corrected for haplogroup affiliation and nuclear ancestry. The extensive bi-genomic dependence documented here is a major concern when interpreting historic, as well as designing future, mtDNA association studies.
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Affiliation(s)
- Christian M. Hagen
- Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
| | | | - Paula L. Hedley
- Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
| | | | - Marie Bækvad-Hansen
- Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
| | - Christine S. Hansen
- Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
| | - Jørgen K. Kanters
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jimmi Nielsen
- Aalborg Psychiatric Hospital, Aalborg University Hospital, Aalborg, Denmark
| | - Ole Mors
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Alfonso B. Demur
- Mental Health Centre, Sct Hans, Capital Region of Denmark, Denmark
| | - Thomas D. Als
- Institute of Medical Genetics, Aarhus University, Aarhus, Denmark
| | | | - Anders Børglum
- Institute of Medical Genetics, Aarhus University, Aarhus, Denmark
| | - Preben B. Mortensen
- Center for Register Research, Institute of Economics, Aarhus University, Aarhus, Denmark
| | - James Kennedy
- Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada
| | - Thomas M. Werge
- Mental Health Centre, Sct Hans, Capital Region of Denmark, Denmark
| | - David M. Hougaard
- Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
| | - Michael Christiansen
- Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- * E-mail:
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24
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Diaz-Morales N, Lopez-Domenech S, Iannantuoni F, Lopez-Gallardo E, Sola E, Morillas C, Rocha M, Ruiz-Pesini E, Victor VM. Mitochondrial DNA Haplogroup JT is Related to Impaired Glycaemic Control and Renal Function in Type 2 Diabetic Patients. J Clin Med 2018; 7:jcm7080220. [PMID: 30115863 PMCID: PMC6111716 DOI: 10.3390/jcm7080220] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 08/13/2018] [Accepted: 08/14/2018] [Indexed: 12/25/2022] Open
Abstract
The association between mitochondrial DNA (mtDNA) haplogroup and risk of type 2 diabetes (T2D) is undetermined and controversial. This study aims to evaluate the impact of the main mtDNA haplogroups on glycaemic control and renal function in a Spanish population of 303 T2D patients and 153 healthy controls. Anthropometrical and metabolic parameters were assessed and mtDNA haplogroup was determined in each individual. Distribution of the different haplogroups was similar in diabetic and healthy populations and, as expected, T2D patients showed poorer glycaemic control and renal function than controls. T2D patients belonging to the JT haplogroup (polymorphism m.4216T>C) displayed statistically significant higher levels of fasting glucose and HbA1c than those of the other haplogroups, suggesting a poorer glycaemic control. Furthermore, diabetic patients with the JT haplogroup showed a worse kidney function than those with other haplogroups, evident by higher levels of serum creatinine, lower estimated glomerular filtration rate (eGFR), and slightly higher (although not statistically significant) urinary albumin-to-creatinine ratio. Our results suggest that JT haplogroup (in particular, change at position 4216 of the mtDNA) is associated with poorer glycaemic control in T2D, which can trigger the development of diabetic nephropathy.
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Affiliation(s)
- Noelia Diaz-Morales
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain.
| | - Sandra Lopez-Domenech
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain.
| | - Francesca Iannantuoni
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain.
| | - Ester Lopez-Gallardo
- Department of Biochemistry and Molecular and Cell Biology, University of Zaragoza, 50013 Zaragoza, Spain.
- Instituto de Investigación Sanitaria de Aragón (IIS Aragón), 50013 Zaragoza, Spain.
- Centro de Investigaciones Biomédicas En Red de Enfermedades Raras (CIBERER), 50013 Zaragoza, Spain.
| | - Eva Sola
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain.
| | - Carlos Morillas
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain.
| | - Milagros Rocha
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain.
- CIBERehd-Department of Pharmacology and Physiology, University of Valencia, 46010 Valencia, Spain.
| | - Eduardo Ruiz-Pesini
- Department of Biochemistry and Molecular and Cell Biology, University of Zaragoza, 50013 Zaragoza, Spain.
- Instituto de Investigación Sanitaria de Aragón (IIS Aragón), 50013 Zaragoza, Spain.
- Centro de Investigaciones Biomédicas En Red de Enfermedades Raras (CIBERER), 50013 Zaragoza, Spain.
- Fundación ARAID, 50018 Zaragoza, Spain.
| | - Victor M Victor
- Service of Endocrinology, University Hospital Doctor Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46017 Valencia, Spain.
- CIBERehd-Department of Pharmacology and Physiology, University of Valencia, 46010 Valencia, Spain.
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25
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Fang H, Hu N, Zhao Q, Wang B, Zhou H, Fu Q, Shen L, Chen X, Shen F, Lyu J. mtDNA Haplogroup N9a Increases the Risk of Type 2 Diabetes by Altering Mitochondrial Function and Intracellular Mitochondrial Signals. Diabetes 2018; 67:1441-1453. [PMID: 29735607 DOI: 10.2337/db17-0974] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 04/26/2018] [Indexed: 11/13/2022]
Abstract
Mitochondrial DNA (mtDNA) haplogroups have been associated with the incidence of type 2 diabetes (T2D); however, their underlying role in T2D remains poorly elucidated. Here, we report that mtDNA haplogroup N9a was associated with an increased risk of T2D occurrence in Southern China (odds ratio 1.999 [95% CI 1.229-3.251], P = 0.005). By using transmitochondrial technology, we demonstrated that the activity of respiratory chain complexes was lower in the case of mtDNA haplogroup N9a (N9a1 and N9a10a) than in three non-N9a haplogroups (D4j, G3a2, and Y1) and that this could lead to alterations in mitochondrial function and mitochondrial redox status. Transcriptome analysis revealed that OXPHOS function and metabolic regulation differed markedly between N9a and non-N9a cybrids. Furthermore, in N9a cybrids, insulin-stimulated glucose uptake might be inhibited at least partially through enhanced stimulation of ERK1/2 phosphorylation and subsequent TLR4 activation, which was found to be mediated by the elevated redox status in N9a cybrids. Although it remains unclear whether other signaling pathways (e.g., Wnt pathway) contribute to the T2D susceptibility of haplogroup N9a, our data indicate that in the case of mtDNA haplogroup N9a, T2D is affected, at least partially through ERK1/2 overstimulation and subsequent TLR4 activation.
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Affiliation(s)
- Hezhi Fang
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Nianqi Hu
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qiongya Zhao
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Bingqian Wang
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Huaibin Zhou
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qingzi Fu
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lijun Shen
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiong Chen
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Feixia Shen
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jianxin Lyu
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China
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26
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Meta-analysis of mitochondrial T16189C polymorphism for cancer and Type 2 diabetes risk. Clin Chim Acta 2018; 482:136-143. [PMID: 29627487 DOI: 10.1016/j.cca.2018.03.041] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 03/30/2018] [Accepted: 03/30/2018] [Indexed: 11/23/2022]
Abstract
AIM Whereas many previous studies have revealed that mitochondrial DNA (mtDNA) polymorphism T16189C is associated with the risk of cancer and Type 2 diabetes mellitus (T2DM), there are others that have disputed the same. As a result, clarity on the role of mitochondrial T16189C in these disorders is missing. The aim of this study is to evaluate the association of T16189C polymorphism with the risk of cancer and T2DM development by pooling all case-control studies available. METHODS Published studies till November 2017 were searched from PubMed, Google scholar, Google and EMBASE and isolated a total of 36 studies having 44,203 subjects (20,439 cases and 23,764 controls) based on strict inclusion and exclusion criteria. We used the statistical software "R" to calculate the Pooled Odds Ratios and 95% confidence intervals to evaluate the association of T16189C polymorphism with a possible risk towards cancer and T2DM development. RESULT From the meta-analysis, we obtained Pooled Odds Ratios using Random effect model for cancer (OR: 1.20, 95% CI: 0.96-1.49, P = 0.104) and for T2DM (OR: 1.22, 95% CI: 1.09-1.36, P = 0.0004). In the subgroup analysis with Random effect model, we found that both Asians and Caucasians were at a statistically significant risk (OR: 1.25, P < 0.0001 and OR: 1.20, P < 0.0001, respectively) for the development of T2DM, whereas, a statistically non-significant risk (OR: 1.28 P = 0.1965 and OR: 1.16, P = 0.1148) emerged for the development of cancer. There was no evidence of a significant publication bias (Egger's and Begg's test) in this meta-analysis. Further sensitivity analysis also demonstrated that our meta-analysis was relatively stable and credible. CONCLUSION Individuals with 'C' allele at position 16,189 within the mitochondrial D-loop are seemingly at a higher risk of developing T2DM and cancer. However, before arriving at generalizations, it would be pertinent to conduct similar studies in different populations with larger numbers to corroborate these results, especially in cancer.
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27
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Chen X, Wang F, Maerhaba A, Li Q, Wang J, Liu X, Zheng J, Chen Y, Guo Y. Novel mitochondrial gene variants in Northwestern Chinese probands with non-syndromic hearing loss by whole mitochondrial genome screening. Gene 2018; 652:59-65. [DOI: 10.1016/j.gene.2018.01.098] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Revised: 01/16/2018] [Accepted: 01/29/2018] [Indexed: 11/28/2022]
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28
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Fex M, Nicholas LM, Vishnu N, Medina A, Sharoyko VV, Nicholls DG, Spégel P, Mulder H. The pathogenetic role of β-cell mitochondria in type 2 diabetes. J Endocrinol 2018; 236:R145-R159. [PMID: 29431147 DOI: 10.1530/joe-17-0367] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 01/15/2018] [Indexed: 12/17/2022]
Abstract
Mitochondrial metabolism is a major determinant of insulin secretion from pancreatic β-cells. Type 2 diabetes evolves when β-cells fail to release appropriate amounts of insulin in response to glucose. This results in hyperglycemia and metabolic dysregulation. Evidence has recently been mounting that mitochondrial dysfunction plays an important role in these processes. Monogenic dysfunction of mitochondria is a rare condition but causes a type 2 diabetes-like syndrome owing to β-cell failure. Here, we describe novel advances in research on mitochondrial dysfunction in the β-cell in type 2 diabetes, with a focus on human studies. Relevant studies in animal and cell models of the disease are described. Transcriptional and translational regulation in mitochondria are particularly emphasized. The role of metabolic enzymes and pathways and their impact on β-cell function in type 2 diabetes pathophysiology are discussed. The role of genetic variation in mitochondrial function leading to type 2 diabetes is highlighted. We argue that alterations in mitochondria may be a culprit in the pathogenetic processes culminating in type 2 diabetes.
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Affiliation(s)
- Malin Fex
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Lisa M Nicholas
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Neelanjan Vishnu
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Anya Medina
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Vladimir V Sharoyko
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - David G Nicholls
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Peter Spégel
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
- Department of ChemistryCenter for Analysis and Synthesis, Lund University, Sweden
| | - Hindrik Mulder
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
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29
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Liu C, Fetterman JL, Liu P, Luo Y, Larson MG, Vasan RS, Zhu J, Levy D. Deep sequencing of the mitochondrial genome reveals common heteroplasmic sites in NADH dehydrogenase genes. Hum Genet 2018; 137:203-213. [PMID: 29423652 DOI: 10.1007/s00439-018-1873-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 01/30/2018] [Indexed: 12/17/2022]
Abstract
Increasing evidence implicates mitochondrial dysfunction in aging and age-related conditions. But little is known about the molecular basis for this connection. A possible cause may be mutations in the mitochondrial DNA (mtDNA), which are often heteroplasmic-the joint presence of different alleles at a single locus in the same individual. However, the involvement of mtDNA heteroplasmy in aging and age-related conditions has not been investigated thoroughly. We deep-sequenced the complete mtDNA genomes of 356 Framingham Heart Study participants (52% women, mean age 43, mean coverage 4570-fold), identified 2880 unique mutations and comprehensively annotated them by MITOMAP and PolyPhen-2. We discovered 11 heteroplasmic "hot" spots [NADH dehydrogenase (ND) subunit 1, 4, 5 and 6 genes, n = 7; cytochrome c oxidase I (COI), n = 2; 16S rRNA, n = 1; D-loop, n = 1] for which the alternative-to-reference allele ratios significantly increased with advancing age (Bonferroni correction p < 0.001). Four of these heteroplasmic mutations in ND and COI genes were predicted to be deleterious nonsynonymous mutations which may have direct impact on ATP production. We confirmed previous findings that healthy individuals carry many low-frequency heteroplasmy mutations with potentially deleterious effects. We hypothesize that the effect of a single deleterious heteroplasmy may be minimal due to a low mutant-to-wildtype allele ratio, whereas the aggregate effects of many deleterious mutations may cause changes in mitochondrial function and contribute to age-related diseases. The identification of age-related mtDNA mutations is an important step to understand the genetic architecture of age-related diseases and may uncover novel therapeutic targets for such diseases.
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Affiliation(s)
- Chunyu Liu
- Population Sciences Branch, NHLBI/NHI, Bethesda, MD, USA. .,Framingham Heart Study, Framingham, MA, USA. .,Department of Biostatistics, Boston University, Boston, MA, USA.
| | | | - Poching Liu
- DNA Sequencing and Genomics Core, NHLBI/NIH, Bethesda, MD, USA
| | - Yan Luo
- DNA Sequencing and Genomics Core, NHLBI/NIH, Bethesda, MD, USA
| | - Martin G Larson
- Framingham Heart Study, Framingham, MA, USA.,Department of Biostatistics, Boston University, Boston, MA, USA
| | - Ramachandran S Vasan
- Framingham Heart Study, Framingham, MA, USA.,School of Medicine, Boston University, Boston, MA, USA
| | - Jun Zhu
- System Biology Center, NHLBI/NHI, Bethesda, MD, USA
| | - Daniel Levy
- Population Sciences Branch, NHLBI/NHI, Bethesda, MD, USA. .,Framingham Heart Study, Framingham, MA, USA.
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Thyagarajan B, Guan W, Fedirko V, Barcelo H, Ramasubramaian R, Gross M, Goodman M, Bostick RM. Associations of mitochondrial polymorphisms with sporadic colorectal adenoma. Mol Carcinog 2018; 57:598-605. [PMID: 29323753 DOI: 10.1002/mc.22783] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 01/09/2018] [Indexed: 11/12/2022]
Abstract
Somatic mutations in mitochondrial DNA have been reported in colorectal adenomatous polyps (adenomas), the precursors to most colorectal cancers. However, there are no reports of associations of germline variation in mitochondrial DNA with adenoma risk. We investigated associations of germline polymorphisms in the displacement loop (D-loop) and non-D-loop region of the mitochondrial genome with incident, sporadic colorectal adenoma in three pooled colonoscopy-based case-control studies (n = 327 adenoma cases, 420 controls) that used identical methods for case and risk factor ascertainment. We sequenced a 1124 bp fragment to identify all genetic variation in the mitochondrial D-loop region, and used the Sequenom platform to genotype 64 tagSNPs in the non-D-loop region. We used multivariable unconditional logistic regression to estimate associations of the polymorphisms with adenoma. The odds ratios (OR) for associations of four polymorphisms in the HV1 region (mt16294, mt16296, mt16278, mt16069) with adenoma were 2.30, 2.63, 3.34, and 0.56, respectively; all 95% confidence intervals (CI) excluded 1.0, however, after correction for multiple comparisons, none of the findings remained statistically significant. Similar results were found for six polymorphisms in the non-D-loop region. In the HV1 region poly C tract, relative to those with 5 repeats, the ORs for those with fewer or more repeats were, respectively, 2.29 (95%CI 1.07-4.89) and 0.63 (95%CI 0.36-1.08), but repeat numbers in the HV2 region were not associated with adenoma. These findings suggest that mitochondrial D-loop HV1 region polymorphisms may be associated with colorectal adenoma risk and support further investigation.
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Affiliation(s)
- Bharat Thyagarajan
- Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, Minnesota
| | - Weihua Guan
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota
| | - Veronika Fedirko
- Department of Epidemiology, Rollins School of Public Health, Winship Cancer Institute, Emory University, Atlanta, Georgia
| | - Helene Barcelo
- Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, Minnesota
| | - Ramya Ramasubramaian
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota
| | - Myron Gross
- Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, Minnesota
| | - Michael Goodman
- Department of Epidemiology, Rollins School of Public Health, Winship Cancer Institute, Emory University, Atlanta, Georgia
| | - Roberd M Bostick
- Department of Epidemiology, Rollins School of Public Health, Winship Cancer Institute, Emory University, Atlanta, Georgia
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Gonçalves VF, Giamberardino SN, Crowley JJ, Vawter MP, Saxena R, Bulik CM, Yilmaz Z, Hultman CM, Sklar P, Kennedy JL, Sullivan PF, Knight J. Examining the role of common and rare mitochondrial variants in schizophrenia. PLoS One 2018; 13:e0191153. [PMID: 29370225 PMCID: PMC5784966 DOI: 10.1371/journal.pone.0191153] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 12/30/2017] [Indexed: 12/17/2022] Open
Abstract
Oxidative phosphorylation within mitochondria is the main source of aerobic energy for neuronal functioning, and the key genes are located in mitochondrial DNA. Deficits in oxidative phosphorylation functioning have been reported for schizophrenia, but efforts in the identification of genetic markers within the mitochondrial DNA that predispose to schizophrenia have been limited. We genotyped a set of mitochondrial SNPs using Illumina HumanExome arrays and tested for association in the Swedish schizophrenia sample (N> 10,000). We developed a novel approach for mitochondrial DNA imputation in order to increase the number of common SNPs available for association analysis. The most significant findings were for the mitochondrial SNPs C15452A (GRCh38.p10; rs527236209; p = 0.007; gene MT-CYB; defining haplogroup JT); A11251G (rs869096886; p = 0.007; gene MT-ND4; defining haplogroup JT), and T4216C (rs1599988; p = 0.008, gene MT-ND1, defining haplogroup R2'JT). We also conducted rare variant burden analyses and obtained a p-value of 0.007. For multimarker haplotypes analysis, the most significant finding was for the J group (OR: 0.86, p = 0.02). We conducted the largest association study of mitochondrial DNA variants and schizophrenia but did not find an association that survived multiple testing correction. Analysis of a larger sample is required and will allow a better understanding of the role of mitochondria in schizophrenia.
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Affiliation(s)
- Vanessa F Gonçalves
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
- * E-mail:
| | | | - James J. Crowley
- Department of Genetics, University of North Carolina, Chapel Hill, NC, United States of America
| | - Marquis P. Vawter
- Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, University of California, Irvine, CA, United States of America
| | - Richa Saxena
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States of America
| | - Cynthia M. Bulik
- Department of Psychiatry, University of North Carolina, Chapel Hill, NC, United States of America
- Department of Nutrition, University of North Carolina, Chapel Hill, NC, United States of America
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Zeynep Yilmaz
- Department of Psychiatry, University of North Carolina, Chapel Hill, NC, United States of America
| | - Christina M. Hultman
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Pamela Sklar
- Division of Psychiatric Genomics, Department of Psychiatry, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - James L. Kennedy
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Patrick F. Sullivan
- Department of Genetics, University of North Carolina, Chapel Hill, NC, United States of America
- Department of Psychiatry, University of North Carolina, Chapel Hill, NC, United States of America
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Jo Knight
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
- Data Science Institute and Medical School, Lancaster University, Bailrigg, Lancaster, LA1 4YW, United Kingdom
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Shao J, Chen C, Lin W, Dong Z, Gao R, Chen C, Lin B, Chen J, Xu J. Clinical and molecular features of a Han Chinese family with maternally transmitted hypertension. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2017; 10:7384-7389. [PMID: 31966580 PMCID: PMC6965253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 01/11/2017] [Indexed: 06/10/2023]
Abstract
Mutations in mitochondrial DNA (mtDNA) were found to be associated with hypertension. We reported here clinical, genetic and molecular characterization of a Han Chinese family with maternally inherited hypertension. Most strikingly, this family exhibited a high penetrance of hypertension. Sequence analysis of the entire mitochondrial genome showed the presence of the well-known T4363C mutation in tRNAGln, as well as the ND1 T3394C mutation, and a set of polymorphisms belonging to human mitochondrial haplogroup M7b. Of these, the T4363C mutation was localized at the highly conserved nucleotide in the anticodon stem of tRNAGln (position 38), may result the failure in tRNA metabolism. Moreover, the homoplasmic ND1 T3394C mutation, which had been reported to be associated with Leber's hereditary optic neuropathy (LHON), was regarded as a pathogenic mutation associated with mitochondrial diseases. Thus, the combination of ND1 T3394C and tRNAGln T4363C mutations may contribute to the high penetrance and expressivity of hypertension in this Chinese family.
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Affiliation(s)
- Jianzhi Shao
- Department of Cardiology, Affiliated Wenling Hospital, Wenzhou Medical UniversityChina
| | - Changgong Chen
- Department of Cardiology, Taizhou First People’s HospitalChina
| | - Wenhui Lin
- Department of Cardiology, Affiliated Wenling Hospital, Wenzhou Medical UniversityChina
| | - Zhibing Dong
- Department of Cardiology, Affiliated Wenling Hospital, Wenzhou Medical UniversityChina
| | - Ranran Gao
- Department of Cardiology, Affiliated Wenling Hospital, Wenzhou Medical UniversityChina
| | - Caiming Chen
- Department of Clinical Pharmacy, Affiliated Wenling Hospital, Wenzhou Medical UniversityChina
| | - Bin Lin
- Department of Cardiology, Affiliated Wenling Hospital, Wenzhou Medical UniversityChina
| | - Junzheng Chen
- Department of Surgery, Affiliated Wenling Hospital, Wenzhou Medical UniversityChina
| | - Jinzhong Xu
- Department of Clinical Pharmacy, Affiliated Wenling Hospital, Wenzhou Medical UniversityChina
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Mulder H. Transcribing β-cell mitochondria in health and disease. Mol Metab 2017; 6:1040-1051. [PMID: 28951827 PMCID: PMC5605719 DOI: 10.1016/j.molmet.2017.05.014] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Revised: 05/13/2017] [Accepted: 05/22/2017] [Indexed: 12/17/2022] Open
Abstract
Background The recent genome-wide association studies (GWAS) of Type 2 Diabetes (T2D) have identified the pancreatic β-cell as the culprit in the pathogenesis of the disease. Mitochondrial metabolism plays a crucial role in the processes controlling release of insulin and β-cell mass. This notion implies that mechanisms controlling mitochondrial function have the potential to play a decisive pathogenetic role in T2D. Scope of the review This article reviews studies demonstrating that there is indeed mitochondrial dysfunction in islets in T2D, and that GWAS have identified a variant in the gene encoding transcription factor B1 mitochondrial (TFB1M), predisposing to T2D due to mitochondrial dysfunction and impaired insulin secretion. Mechanistic studies of the nature of this pathogenetic link, as well as of other mitochondrial transcription factors, are described. Major conclusions Based on this, it is argued that transcription and translation in mitochondria are critical processes determining mitochondrial function in β-cells in health and disease.
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Key Words
- AMPK, AMP-dependent protein kinase
- ATGL, adipocyte triglyceride lipase
- COX, Cytochrome c oxidase
- CYTB, Cytochrome b
- ERR-α, Estrogen-related receptor-α
- Expression quantitative trait locus (eQTL)
- GDH, Glutamate dehydrogenase
- GSIS, Glucose-stimulated insulin secretion
- GWAS, Genome-wide association study
- Genome-wide association study (GWAS)
- HSL, Hormone-sensitive lipase
- ICDc, Cytosolic isocitrate dehydrogenase
- Insulin secretion
- Islets
- KATP, ATP-dependent K+-channel
- MTERF, Mitochondrial transcription termination factor
- Mitochondria
- ND, NADH dehydrogenase
- NRF, Nuclear respiratory factor
- NSUN4, NOP2/Sun RNA methyltransferase family member 4
- OXPHOS, Oxidative phosphorylation
- PC, Pyruvate carboxylase
- PDH, pyruvate dehydrogenase
- PGC, Peroxisome proliferator-activated receptor-γ co-activator
- POLRMT, Mitochondrial RNA polymerase
- POLγ, DNA polymerase-γ
- PPARγ, Peroxisome proliferator-activated receptor-γ
- PRC, PGC1-related coactivator
- SENP1, Sentrin/SUMO-specific protease-1
- SNP, Single Nucleotide Polymorphism
- SUR1, Sulphonylurea receptor-1
- T2D, Type 2 Diabetes
- TCA, Tricarboxylic acid
- TEFM, Mitochondrial transcription elongation factor
- TFAM, Transcription factor A mitochondrial
- TFB1M, Transcription factor B1 mitochondrial
- TFB2M, Transcription factor B2 mitochondrial
- eQTL, Expression quantitative trait locus
- β-Cell
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Affiliation(s)
- Hindrik Mulder
- Unit of Molecular Metabolism, Lund University Diabetes Centre, Malmö, Sweden
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Ziaaldini MM, Hosseini SR, Fathi M. Mitochondrial adaptations in aged skeletal muscle: effect of exercise training. Physiol Res 2016; 66:1-14. [PMID: 27982690 DOI: 10.33549/physiolres.933329] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The aging process is associated with a decline in mitochondrial functions. Mitochondria dysfunction is involved in initiation and progression of many health problems including neuromuscular, metabolic and cardiovascular diseases. It is well known that endurance exercise improves mitochondrial function, especially in the elderly. However, recent studies have demonstrated that resistance training lead also to substantial increases in mitochondrial function in skeletal muscle. A comprehensive understanding of the cellular mechanisms involved in the skeletal muscle mitochondrial adaptations to exercise training in healthy elderly subjects, can help practitioners to design and prescribe more effective exercise trainings.
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Affiliation(s)
- M M Ziaaldini
- Faculty of Sport Sciences, Ferdowsi University of Mashhad, Mashhad, Iran.
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Male-specific association between MT-ND4 11719 A/G polymorphism and ulcerative colitis: a mitochondria-wide genetic association study. BMC Gastroenterol 2016; 16:118. [PMID: 27716073 PMCID: PMC5048482 DOI: 10.1186/s12876-016-0509-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 08/02/2016] [Indexed: 12/17/2022] Open
Abstract
Background Ulcerative colitis (UC) is a chronic inflammatory disorder of still unknown pathogenesis. Increasing evidence indicates that alterations in mitochondrial respiration and thus adenosine triphosphate (ATP) production are involved. This may contribute to mucosal energy deficiency and subsequently intestinal barrier malfunction, which is accepted to be a major hallmark of UC. Genetic alterations of the mitochondrial genome are one cause of mitochondrial dysfunction. However, less is known about mitochondrial gene polymorphisms in UC. Therefore, we aimed at identifying genetic associations between mitochondrial polymorphisms and UC. Methods German UC cases (n = 1062) and German healthy controls (n = 3030) were genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0. The primary association analysis was to test for associations between mitochondrial single nucleotide polymorphisms (SNPs) and UC using Fisher’s exact test in the total sample and stratified by sex. In addition, we tested for associations between mitochondrial haplogroups and UC and for interactions between the most promising mitochondrial SNPs and nuclear SNPs. An independent set of German subjects with 1625 UC cases and 3575 controls was used for replication. Results We identified a genetic association between the MT-ND4 11719 A/G polymorphism and UC in the subgroup of males (rs2853495; odds ratio, 1.40; 95 % confidence interval, 1.13 to 1.73; p = 0.002). This association was replicated in the second independent cohort. In the association analysis based on mitochondrial haplogroups the lowest p values were reached for haplogroups HV and T (p = 0.029 and 0.035). Haplogroup HV is determined by the mitochondrial 11719 A/G polymorphism. Accordingly, this association was only found in the subgroup of males (p = 0.009). Conclusions For the first time, we observed an association between the MT-ND4 11719 A/G polymorphism and UC. The gene MT-ND4 encodes for a subunit of the mitochondrial electron transport chain complex I, which is pivotal for ATP production and might therefore contribute to mucosal energy deficiency. The male-specific association indicates differences between males and females concerning the impact of mitochondrial gene polymorphisms on the development of UC. Further investigations of the functional mechanism underlying this association and the relevance of the gender-specificity are highly warranted. Electronic supplementary material The online version of this article (doi:10.1186/s12876-016-0509-1) contains supplementary material, which is available to authorized users.
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May-Panloup P, Boucret L, Chao de la Barca JM, Desquiret-Dumas V, Ferré-L'Hotellier V, Morinière C, Descamps P, Procaccio V, Reynier P. Ovarian ageing: the role of mitochondria in oocytes and follicles. Hum Reprod Update 2016; 22:725-743. [PMID: 27562289 DOI: 10.1093/humupd/dmw028] [Citation(s) in RCA: 378] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 07/15/2016] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND There is a great inter-individual variability of ovarian ageing, and almost 20% of patients consulting for infertility show signs of premature ovarian ageing. This feature, taken together with delayed childbearing in modern society, leads to the emergence of age-related ovarian dysfunction concomitantly with the desire for pregnancy. Assisted reproductive technology is frequently inefficacious in cases of ovarian ageing, thus raising the economic, medical and societal costs of the procedures. OBJECTIVE AND RATIONAL Ovarian ageing is characterized by quantitative and qualitative alteration of the ovarian oocyte reserve. Mitochondria play a central role in follicular atresia and could be the main target of the ooplasmic factors determining oocyte quality adversely affected by ageing. Indeed, the oocyte is the richest cell of the body in mitochondria and depends largely on these organelles to acquire competence for fertilization and early embryonic development. Moreover, the oocyte ensures the uniparental transmission and stability of the mitochondrial genome across the generations. This review focuses on the role played by mitochondria in ovarian ageing and on the possible consequences over the generations. SEARCH METHODS PubMed was used to search the MEDLINE database for peer-reviewed original articles and reviews concerning mitochondria and ovarian ageing, in animal and human species. Searches were performed using keywords belonging to three groups: 'mitochondria' or 'mitochondrial DNA'; 'ovarian reserve', 'oocyte', 'ovary' or 'cumulus cells'; and 'ageing' or 'ovarian ageing'. These keywords were combined with other search phrases relevant to the topic. References from these articles were used to obtain additional articles. OUTCOMES There is a close relationship, in mammalian models and humans, between mitochondria and the decline of oocyte quality with ageing. Qualitatively, ageing-related mitochondrial (mt) DNA instability, which leads to the accumulation of mtDNA mutations in the oocyte, plays a key role in the deterioration of oocyte quality in terms of competence and of the risk of transmitting mitochondrial abnormalities to the offspring. In contrast, some mtDNA haplogroups are protective against the decline of ovarian reserve. Quantitatively, mitochondrial biogenesis is crucial during oogenesis for constituting a mitochondrial pool sufficiently large to allow normal early embryonic development and to avoid the untimely activation of mitochondrial biogenesis. Ovarian ageing also seriously affects the dynamic nature of mitochondrial biogenesis in the surrounding granulosa cells that may provide interesting alternative biomarkers of oocyte quality. WIDER IMPLICATIONS A fuller understanding of the involvement of mitochondria in cases of infertility linked to ovarian ageing would contribute to a better management of the disorder in the future.
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Affiliation(s)
- Pascale May-Panloup
- Laboratoire de Biologie de la Reproduction, Centre Hospitalier Universitaire d'Angers, 49933 Angers Cedex 9, France .,PREMMi/Pôle de Recherche et d'Enseignement en Médecine Mitochondriale, Institut MITOVASC, CNRS 6214, INSERM U1083, Université d'Angers, Angers, France
| | - Lisa Boucret
- Laboratoire de Biologie de la Reproduction, Centre Hospitalier Universitaire d'Angers, 49933 Angers Cedex 9, France.,PREMMi/Pôle de Recherche et d'Enseignement en Médecine Mitochondriale, Institut MITOVASC, CNRS 6214, INSERM U1083, Université d'Angers, Angers, France
| | - Juan-Manuel Chao de la Barca
- PREMMi/Pôle de Recherche et d'Enseignement en Médecine Mitochondriale, Institut MITOVASC, CNRS 6214, INSERM U1083, Université d'Angers, Angers, France.,Département de Biochimie et Génétique, Centre Hospitalier Universitaire d'Angers, 49933 Angers Cedex 9, France
| | - Valérie Desquiret-Dumas
- PREMMi/Pôle de Recherche et d'Enseignement en Médecine Mitochondriale, Institut MITOVASC, CNRS 6214, INSERM U1083, Université d'Angers, Angers, France.,Département de Biochimie et Génétique, Centre Hospitalier Universitaire d'Angers, 49933 Angers Cedex 9, France
| | - Véronique Ferré-L'Hotellier
- Laboratoire de Biologie de la Reproduction, Centre Hospitalier Universitaire d'Angers, 49933 Angers Cedex 9, France
| | - Catherine Morinière
- Service de Gynécologie-Obstétrique, Centre Hospitalier Universitaire d'Angers, 49933 Angers Cedex 9, France
| | - Philippe Descamps
- Service de Gynécologie-Obstétrique, Centre Hospitalier Universitaire d'Angers, 49933 Angers Cedex 9, France
| | - Vincent Procaccio
- PREMMi/Pôle de Recherche et d'Enseignement en Médecine Mitochondriale, Institut MITOVASC, CNRS 6214, INSERM U1083, Université d'Angers, Angers, France.,Département de Biochimie et Génétique, Centre Hospitalier Universitaire d'Angers, 49933 Angers Cedex 9, France
| | - Pascal Reynier
- PREMMi/Pôle de Recherche et d'Enseignement en Médecine Mitochondriale, Institut MITOVASC, CNRS 6214, INSERM U1083, Université d'Angers, Angers, France.,Département de Biochimie et Génétique, Centre Hospitalier Universitaire d'Angers, 49933 Angers Cedex 9, France
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Identification of lactate dehydrogenase as a mammalian pyrroloquinoline quinone (PQQ)-binding protein. Sci Rep 2016; 6:26723. [PMID: 27230956 PMCID: PMC4882622 DOI: 10.1038/srep26723] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 04/27/2016] [Indexed: 11/18/2022] Open
Abstract
Pyrroloquinoline quinone (PQQ), a redox-active o-quinone, is an important nutrient involved in numerous physiological and biochemical processes in mammals. Despite such beneficial functions, the underlying molecular mechanisms remain to be established. In the present study, using PQQ-immobilized Sepharose beads as a probe, we examined the presence of protein(s) that are capable of binding PQQ in mouse NIH/3T3 fibroblasts and identified five cellular proteins, including l-lactate dehydrogenase (LDH) A chain, as potential mammalian PQQ-binding proteins. In vitro studies using a purified rabbit muscle LDH show that PQQ inhibits the formation of lactate from pyruvate in the presence of NADH (forward reaction), whereas it enhances the conversion of lactate to pyruvate in the presence of NAD+ (reverse reaction). The molecular mechanism underlying PQQ-mediated regulation of LDH activity is attributed to the oxidation of NADH to NAD+ by PQQ. Indeed, the PQQ-bound LDH oxidizes NADH, generating NAD+, and significantly catalyzes the conversion of lactate to pyruvate. Furthermore, PQQ attenuates cellular lactate release and increases intracellular ATP levels in the NIH/3T3 fibroblasts. Our results suggest that PQQ, modulating LDH activity to facilitate pyruvate formation through its redox-cycling activity, may be involved in the enhanced energy production via mitochondrial TCA cycle and oxidative phosphorylation.
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Ouyang Y, Qiao L, Liu K, Zang Y, Sun Y, Dong Y, Liu D, Guo X, Wei F, Lin M, Zhang F, Chen D. Mitochondrial DNA mutations in blood samples from HIV-1-infected children undergoing long-term antiretroviral therapy. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2016; 805:1-6. [PMID: 27402477 DOI: 10.1016/j.mrgentox.2016.05.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Accepted: 05/10/2016] [Indexed: 11/25/2022]
Abstract
We have analyzed mutations in whole mitochondrial (mt) genomes of blood samples from HIV-1-infected children treated with long-term antiretroviral therapy (ART), who had an excellent virological response. HIV-1-infected children who have undergone ART for 4 y with an excellent virological response (group A; 15 children) and ten healthy children (controls) without HIV-1 infection were enrolled retrospectively. Peripheral blood mononuclear cells (PBMCs) were obtained and mt DNA mutations were studied. The total number of mtDNA mutations in group A was 3 H more than in the controls (59 vs. 19, P<0.001) and the same trend was seen in all mtDNA regions. Among these mtDNA mutations, 140 and 28 mutations were detected in group A and the controls, respectively. The D-loop, CYTB and 12s rRNA were the three most common mutation regions in both groups, with significant differences between the groups observed at nucleotide positions C309CC, T489C CA514deletion, T16249C and G16474GG (D-loop); T14783C, G15043A, G15301A, and A15662G (CYTB); and G709A (12s rRNA). G15043A and A15662G had been associated with mitochondrial diseases. Our findings suggest that mtDNA mutations occur frequently in long-term ART-treated, HIV-1-infected children who have an excellent virological response, although they did not have obvious current symptoms. The CYTB region may play an important role in mtDNA mutation during ART, which might contribute to the development of subsequent mitochondrial diseases.
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Affiliation(s)
- Yabo Ouyang
- Beijing You An Hospital, Capital Medical University, Beijing, China; Beijing Institute of Hepatology, Beijing, China
| | - Luxin Qiao
- Beijing You An Hospital, Capital Medical University, Beijing, China; Beijing Institute of Hepatology, Beijing, China
| | - Kai Liu
- Beijing You An Hospital, Capital Medical University, Beijing, China; Beijing Institute of Hepatology, Beijing, China
| | - Yunjin Zang
- Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Yu Sun
- Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Yaowu Dong
- Branch of Shang Cai, Henan province, Division of Treatment and Care, National Center for AIDS/STD Control and Prevention, China
| | - Daojie Liu
- Beijing You An Hospital, Capital Medical University, Beijing, China; Beijing Institute of Hepatology, Beijing, China
| | - Xianghua Guo
- Beijing You An Hospital, Capital Medical University, Beijing, China; Beijing Institute of Hepatology, Beijing, China
| | - Feili Wei
- Beijing You An Hospital, Capital Medical University, Beijing, China; Beijing Institute of Hepatology, Beijing, China
| | - Minghua Lin
- Beijing You An Hospital, Capital Medical University, Beijing, China; Beijing Institute of Hepatology, Beijing, China
| | - Fujie Zhang
- Division of Treatment and Care, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, China
| | - Dexi Chen
- Beijing You An Hospital, Capital Medical University, Beijing, China; Beijing Institute of Hepatology, Beijing, China.
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Liu Z, Jeppesen PB, Gregersen S, Bach Larsen L, Hermansen K. Chronic Exposure to Proline Causes Aminoacidotoxicity and Impaired Beta-Cell Function: Studies In Vitro. Rev Diabet Stud 2016; 13:66-78. [PMID: 27563695 DOI: 10.1900/rds.2016.13.66] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Pancreatic islet-cell dysfunction is a hallmark in the development of diabetes, but the reasons for the primary β-cell defect are still elusive. Elevated circulating proline levels have been found in subjects with insulin resistance, obesity, and type 2 diabetes. Therefore, we assessed β-cell function, gene expressions, and cell death after long-term exposure of pancreatic β-cells to excess proline in vitro. METHODS Isolated mouse islets and INS-1E cells were incubated with and without excess proline. After 72 h, we examined: (1) β-cell function, including basal insulin secretion (BIS) and glucose-stimulated insulin secretion (GSIS), (2) transcription factors related to insulin gene expression and enzymes involved in the tricarboxylic acid cycle and cholesterol biogenesis, (3) cellular triglycerides (TG) and cholesterol content, (4) the death of INS-1E cells and 3H thymidine incorporation, and (5) protein expression of INS-1E cells in response to proline by proteomics. RESULTS We found that high doses of proline increased BIS and decreased GSIS in both isolated mouse islets and INS-1E cells. MafA, insulin 1, and the cytochrome c oxidase subunit VIa polypeptide 2 mRNA expressions were all downregulated, indicating that proline impaired insulin gene transcription and mitochondrial oxidative phosphorylation. In contrast, mevalonate decarboxylase gene expression was upregulated, and simultaneously, cholesterol content in INS-1E cells was enhanced. Protein profiling of INS-1E cells revealed that cytosolic non-specific dipeptidase and α enolase were differentially expressed. CONCLUSIONS Our results indicate that proline-induced insulin transcription and mitochondrial oxidative phosphorylation impairment may contribute to the β-cell dysfunction observed in type 2 diabetes. Caution should be applied in interpreting the pathophysiological role of proline since very high proline concentrations were used in the experiments.
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Affiliation(s)
- Zhenping Liu
- Department of Medicine and Endocrinology, Aarhus University Hospital, Tage-Hansens Gade 2, DK-8000 Aarhus C, Denmark
| | - Per B Jeppesen
- Department of Medicine and Endocrinology, Aarhus University Hospital, Tage-Hansens Gade 2, DK-8000 Aarhus C, Denmark
| | - Søren Gregersen
- Department of Medicine and Endocrinology, Aarhus University Hospital, Tage-Hansens Gade 2, DK-8000 Aarhus C, Denmark
| | - Lotte Bach Larsen
- Department of Food Science, Faculty of Agricultural Sciences, Aarhus University, DK-8230 Tjele, Denmark
| | - Kjeld Hermansen
- Department of Medicine and Endocrinology, Aarhus University Hospital, Tage-Hansens Gade 2, DK-8000 Aarhus C, Denmark
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Muir R, Diot A, Poulton J. Mitochondrial content is central to nuclear gene expression: Profound implications for human health. Bioessays 2016; 38:150-6. [PMID: 26725055 PMCID: PMC4819685 DOI: 10.1002/bies.201500105] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
We review a recent paper in Genome Research by Guantes et al. showing that nuclear gene expression is influenced by the bioenergetic status of the mitochondria. The amount of energy that mitochondria make available for gene expression varies considerably. It depends on: the energetic demands of the tissue; the mitochondrial DNA (mtDNA) mutant load; the number of mitochondria; stressors present in the cell. Hence, when failing mitochondria place the cell in energy crisis there are major effects on gene expression affecting the risk of degenerative diseases, cancer and ageing. In 2015 the UK parliament approved a change in the regulation of IVF techniques, allowing "Mitochondrial replacement therapy" to become a reproductive choice for women at risk of transmitting mitochondrial disease to their children. This is the first time that this technique will be available. Therefore understanding the interaction between mitochondria and the nucleus has never been more important.
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Affiliation(s)
- Rebecca Muir
- Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Alan Diot
- Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Joanna Poulton
- Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford, UK
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Perspectives on pharmacogenomics of antiretroviral medications and HIV-associated comorbidities. Curr Opin HIV AIDS 2015; 10:116-22. [PMID: 25565175 DOI: 10.1097/coh.0000000000000134] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
PURPOSE OF REVIEW To summarize current knowledge and provide perspective on relationships between human genetic variants, antiretroviral medications, and aging-related complications of HIV-1 infection. RECENT FINDINGS Human genetic variants have been convincingly associated with interindividual variability in antiretroviral toxicities, drug disposition, and aging-associated complications in HIV-1 infection. Screening for HLA-B5701 to avoid abacavir hypersensitivity reactions has become a routine part of clinical care, and has markedly improved drug safety. There are well established pharmacogenetic associations with other agents (efavirenz, nevirapine, atazanavir, dolutegravir, and others), but this knowledge has yet to have substantial impact on HIV-1 clinical care. As metabolic complications including diabetes mellitus, dyslipidemia, osteoporosis, and cardiovascular disease are becoming an increasing concern among individuals who are aging with well controlled HIV-1 infection, human genetic variants that predispose to these complications also become more relevant in this population. SUMMARY Pharmacogenetic knowledge has already had considerable impact on antiretroviral prescribing. With continued advances in the field of human genomics, the impact of pharmacogenomics on HIV-1 clinical care and research is likely to continue to grow in importance and scope.
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Niu Q, Zhang W, Wang H, Guan X, Lu J, Li W. Effects of mitochondrial haplogroup N9a on type 2 diabetes mellitus and its associated complications. Exp Ther Med 2015; 10:1918-1924. [PMID: 26640573 DOI: 10.3892/etm.2015.2751] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 07/13/2015] [Indexed: 11/05/2022] Open
Abstract
A case-control study was conducted with the aim of identifying the predominant haplogroups associated with type 2 diabetes mellitus (T2DM) and its complications. In addition, the role of N9a in T2DM risk and complications was analyzed. Sequencing of the entire mitochondrial DNA was conducted in 235 patients and 244 controls in cohort 1, and six haplogroups (F, B4, D4, D5, M8a and N9a) associated with T2DM were classified. The frequency of N9a was further determined in cohort 2 (440 patients and 244 controls) and examined in two combined cohorts, including 675 patients with T2DM and 649 non-diabetic controls. Multivariate logistic regression analysis and association analysis were performed to investigate the association between genotypes, T2DM and diabetic nephropathy. M8a [P=0.011; odds ratio (OR), 3.49; 95% confidence interval (CI), 1.26-9.69] and haplogroup N9a (P=0.023; OR, 2.60; 95% CI, 1.11-6.05) were associated with an increased risk of T2DM. The frequency of N9a was higher in T2DM patients compared with that in the controls (6.2% vs. 4.3%) and associated with a mild risk (P=0.10; OR, 1.51; 95% CI, 0.92-2.49). N9a was significantly associated with an increased risk of diabetic nephropathy (P=0.024; OR, 2.15; 95% CI, 1.11-4.19). Previous findings of N9a being protective against T2DM were not replicated in the present study, although this haplogroup was associated with an increased risk of diabetic nephropathy.
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Affiliation(s)
- Qing Niu
- Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Biochemistry and Molecular Biology, Wenzhou Medical University School of Laboratory Medicine and Life Sciences, Wenzhou, Zhejiang 325025, P.R. China
| | - Wanlin Zhang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Biochemistry and Molecular Biology, Wenzhou Medical University School of Laboratory Medicine and Life Sciences, Wenzhou, Zhejiang 325025, P.R. China
| | - Hailing Wang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Biochemistry and Molecular Biology, Wenzhou Medical University School of Laboratory Medicine and Life Sciences, Wenzhou, Zhejiang 325025, P.R. China
| | - Xiaomin Guan
- Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Biochemistry and Molecular Biology, Wenzhou Medical University School of Laboratory Medicine and Life Sciences, Wenzhou, Zhejiang 325025, P.R. China
| | - Jianxin Lu
- Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Biochemistry and Molecular Biology, Wenzhou Medical University School of Laboratory Medicine and Life Sciences, Wenzhou, Zhejiang 325025, P.R. China
| | - Wei Li
- Zhejiang Provincial Key Laboratory of Medical Genetics, Department of Biochemistry and Molecular Biology, Wenzhou Medical University School of Laboratory Medicine and Life Sciences, Wenzhou, Zhejiang 325025, P.R. China
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Zhang W, Hou L, Wang T, Lu W, Tao Y, Chen W, Du X, Huang Y. The expression characteristics of mt-ND2 gene in chicken. Mitochondrial DNA A DNA Mapp Seq Anal 2015; 27:3787-92. [PMID: 26332376 DOI: 10.3109/19401736.2015.1079904] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Subunit 2 of NADH dehydrogenase (ND2) is encoded by the mt-ND2 gene and plays a critical role in controlling the production of the mitochondrial reactive oxygen species. Our study focused on exploring the mt-ND2 tissue expression patterns and the effects of energy restriction and dietary fat (linseed oil, corn oil, sesame oil or lard) level (2.5% and 5%) on its expression in chicken. The results showed that mt-ND2 gene was expressed in the 15 tissues of hybrid chickens with the highest level in heart and lowest level in pancreas tissue; 30% energy restriction did not significantly affect mt-ND2 mRNA level in chicken liver tissue. Both the mt-ND2 mRNA levels in chicken pectoralis (p < 0.05) and hepatic tissues (p < 0.05) at 42 d-old were affected by the type of dietary fats in 5% level, while not in abdominal fat tissues. The expression of mt-ND2 in hepatic tissues was down-regulated with chicken age (p < 0.01). The interactive effect of dietary fat types with chicken age (p < 0.05) was significant on mt-ND2 mRNA level. The study demonstrated that mt-ND2 gene was extensively expressed in tissues, and the expression was affected by dietary fat types and chicken age.
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Affiliation(s)
- Wenwen Zhang
- a College of Livestock Husbandry and Veterinary Engineering, Henan Agricultural University , Zhengzhou, Henan , China and
| | - Lingling Hou
- b Animal Science College, Sichuan Agricultural University , Ya'an, Sichuan China
| | - Ting Wang
- a College of Livestock Husbandry and Veterinary Engineering, Henan Agricultural University , Zhengzhou, Henan , China and
| | - Weiwei Lu
- a College of Livestock Husbandry and Veterinary Engineering, Henan Agricultural University , Zhengzhou, Henan , China and
| | - Yafei Tao
- a College of Livestock Husbandry and Veterinary Engineering, Henan Agricultural University , Zhengzhou, Henan , China and
| | - Wen Chen
- a College of Livestock Husbandry and Veterinary Engineering, Henan Agricultural University , Zhengzhou, Henan , China and
| | - Xiaohui Du
- b Animal Science College, Sichuan Agricultural University , Ya'an, Sichuan China
| | - Yanqun Huang
- a College of Livestock Husbandry and Veterinary Engineering, Henan Agricultural University , Zhengzhou, Henan , China and
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Ebner S, Mangge H, Langhof H, Halle M, Siegrist M, Aigner E, Paulmichl K, Paulweber B, Datz C, Sperl W, Kofler B, Weghuber D. Mitochondrial Haplogroup T Is Associated with Obesity in Austrian Juveniles and Adults. PLoS One 2015; 10:e0135622. [PMID: 26322975 PMCID: PMC4556186 DOI: 10.1371/journal.pone.0135622] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 07/24/2015] [Indexed: 12/20/2022] Open
Abstract
Background Recent publications have reported contradictory data regarding mitochondrial DNA (mtDNA) variation and its association with body mass index. The aim of the present study was to compare the frequencies of mtDNA haplogroups as well as control region (CR) polymorphisms of obese juveniles (n = 248) and obese adults (n = 1003) versus normal weight controls (njuvenile = 266, nadults = 595) in a well-defined, ethnically homogenous, age-matched comparative cohort of Austrian Caucasians. Methodology and Principal Findings Using SNP analysis and DNA sequencing, we identified the nine major European mitochondrial haplogroups and CR polymorphisms. Of these, only the T haplogroup frequency was increased in the juvenile obese cohort versus the control subjects [11.7% in obese vs. 6.4% in controls], although statistical significance was lost after adjustment for sex and age. Similar data were observed in a local adult cohort, in which haplogroup T was found at a significantly higher frequency in the overweight and obese subjects than in the normal weight group [9.7% vs. 6.2%, p = 0.012, adjusted for sex and age]. When all obese subjects were considered together, the difference in the frequency of haplogroup T was even more clearly seen [10.1% vs. 6.3%, p = 0.002, OR (95% CI) 1.71 (1.2–2.4), adjusted for sex and age]. The frequencies of the T haplogroup-linked CR polymorphisms C16294T and the C16296T were found to be elevated in both the juvenile and the adult obese cohort compared to the controls. Nevertheless, no mtDNA haplogroup or CR polymorphism was robustly associated with any of several investigated metabolic and cardiovascular parameters (e.g., blood pressure, blood glucose concentration, triglycerides, cholesterol) in all obese subjects. Conclusions and Significance By investigation of this large ethnically and geographically homogenous cohort of Middle European Caucasians, only mtDNA haplogroup T was identified as an obesity risk factor.
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Affiliation(s)
- Sabine Ebner
- Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
| | - Harald Mangge
- Clinical Institute for Medical and Chemical Laboratory Diagnostics, Medical University Graz, Graz, Austria
- BioTechMed-Graz, Graz, Austria
| | | | - Martin Halle
- Department of Prevention, Rehabilitation and Sports Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
- Else Kröner-Fresenius-Zentrum, Klinikum rechts der Isar, Munich, Germany
| | - Monika Siegrist
- Department of Prevention, Rehabilitation and Sports Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Elmar Aigner
- Department of Internal Medicine, Paracelsus Medical University, Salzburg, Austria
- Obesity Research Unit, Paracelsus Medical University and Salzburger Landeskliniken, Salzburg, Austria
| | - Katharina Paulmichl
- Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
- Obesity Research Unit, Paracelsus Medical University and Salzburger Landeskliniken, Salzburg, Austria
| | - Bernhard Paulweber
- Department of Internal Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Christian Datz
- Department of Internal Medicine, General Hospital Oberndorf, Oberndorf, Austria
| | - Wolfgang Sperl
- Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
| | - Barbara Kofler
- Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
| | - Daniel Weghuber
- Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
- Obesity Research Unit, Paracelsus Medical University and Salzburger Landeskliniken, Salzburg, Austria
- * E-mail:
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The prevalence of an interrupted poly-C tract variant harboring mitochondrial DNA haplogroup B and its association with reduced susceptibility to type 2 diabetes in Korea. Genes Genomics 2015. [DOI: 10.1007/s13258-015-0323-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Tranah GJ, Santaniello A, Caillier SJ, D'Alfonso S, Martinelli Boneschi F, Hauser SL, Oksenberg JR. Mitochondrial DNA sequence variation in multiple sclerosis. Neurology 2015; 85:325-30. [PMID: 26136518 DOI: 10.1212/wnl.0000000000001744] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Accepted: 04/07/2015] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE To assess the influence of common mitochondrial DNA (mtDNA) sequence variation on multiple sclerosis (MS) risk in cases and controls part of an international consortium. METHODS We analyzed 115 high-quality mtDNA variants and common haplogroups from a previously published genome-wide association study among 7,391 cases from the International Multiple Sclerosis Genetics Consortium and 14,568 controls from the Wellcome Trust Case Control Consortium 2 project from 7 countries. Significant single nucleotide polymorphism and haplogroup associations were replicated in 3,720 cases and 879 controls from the University of California, San Francisco. RESULTS An elevated risk of MS was detected among haplogroup JT carriers from 7 pooled clinic sites (odds ratio [OR] = 1.15, 95% confidence interval [CI] = 1.07-1.24, p = 0.0002) included in the discovery study. The increased risk of MS was observed for both haplogroup T (OR = 1.17, 95% CI = 1.06-1.29, p = 0.002) and haplogroup J carriers (OR = 1.11, 95% CI = 1.01-1.22, p = 0.03). These haplogroup associations with MS were not replicated in the independent sample set. An elevated risk of primary progressive (PP) MS was detected for haplogroup J participants from 3 European discovery populations (OR = 1.49, 95% CI = 1.10-2.01, p = 0.009). This elevated risk was borderline significant in the US replication population (OR = 1.43, 95% CI = 0.99-2.08, p = 0.058) and remained significant in pooled analysis of discovery and replication studies (OR = 1.43, 95% CI = 1.14-1.81, p = 0.002). No common individual mtDNA variants were associated with MS risk. CONCLUSIONS Identification and validation of mitochondrial genetic variants associated with MS and PPMS may lead to new targets for treatment and diagnostic tests for identifying potential responders to interventions that target mitochondria.
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Affiliation(s)
- Gregory J Tranah
- From the California Pacific Medical Center Research Institute (G.J.T.), San Francisco, CA; Department of Neurology (A.S., S.J.C., S.L.H., J.R.O.), University of California, San Francisco; Department of Health Sciences (S.D.), UPO and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Avogadro, Novara, Italy; and Department of Neuro-rehabilitation and INSPE (Institute of Experimental Neurology) (F.M.B.), Scientific Institute San Raffaele, Milan, Italy.
| | - Adam Santaniello
- From the California Pacific Medical Center Research Institute (G.J.T.), San Francisco, CA; Department of Neurology (A.S., S.J.C., S.L.H., J.R.O.), University of California, San Francisco; Department of Health Sciences (S.D.), UPO and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Avogadro, Novara, Italy; and Department of Neuro-rehabilitation and INSPE (Institute of Experimental Neurology) (F.M.B.), Scientific Institute San Raffaele, Milan, Italy
| | - Stacy J Caillier
- From the California Pacific Medical Center Research Institute (G.J.T.), San Francisco, CA; Department of Neurology (A.S., S.J.C., S.L.H., J.R.O.), University of California, San Francisco; Department of Health Sciences (S.D.), UPO and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Avogadro, Novara, Italy; and Department of Neuro-rehabilitation and INSPE (Institute of Experimental Neurology) (F.M.B.), Scientific Institute San Raffaele, Milan, Italy
| | - Sandra D'Alfonso
- From the California Pacific Medical Center Research Institute (G.J.T.), San Francisco, CA; Department of Neurology (A.S., S.J.C., S.L.H., J.R.O.), University of California, San Francisco; Department of Health Sciences (S.D.), UPO and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Avogadro, Novara, Italy; and Department of Neuro-rehabilitation and INSPE (Institute of Experimental Neurology) (F.M.B.), Scientific Institute San Raffaele, Milan, Italy
| | - Filippo Martinelli Boneschi
- From the California Pacific Medical Center Research Institute (G.J.T.), San Francisco, CA; Department of Neurology (A.S., S.J.C., S.L.H., J.R.O.), University of California, San Francisco; Department of Health Sciences (S.D.), UPO and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Avogadro, Novara, Italy; and Department of Neuro-rehabilitation and INSPE (Institute of Experimental Neurology) (F.M.B.), Scientific Institute San Raffaele, Milan, Italy
| | - Stephen L Hauser
- From the California Pacific Medical Center Research Institute (G.J.T.), San Francisco, CA; Department of Neurology (A.S., S.J.C., S.L.H., J.R.O.), University of California, San Francisco; Department of Health Sciences (S.D.), UPO and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Avogadro, Novara, Italy; and Department of Neuro-rehabilitation and INSPE (Institute of Experimental Neurology) (F.M.B.), Scientific Institute San Raffaele, Milan, Italy
| | - Jorge R Oksenberg
- From the California Pacific Medical Center Research Institute (G.J.T.), San Francisco, CA; Department of Neurology (A.S., S.J.C., S.L.H., J.R.O.), University of California, San Francisco; Department of Health Sciences (S.D.), UPO and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Avogadro, Novara, Italy; and Department of Neuro-rehabilitation and INSPE (Institute of Experimental Neurology) (F.M.B.), Scientific Institute San Raffaele, Milan, Italy
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Abstract
Cytochrome c oxidase (CcO) is the only enzyme that uses oxygen to produce a proton gradient for ATP production during mitochondrial oxidative phosphorylation. Although CcO activity increases in response to hypoxia, the underlying regulatory mechanism remains elusive. By screening for hypoxia-inducible genes in cardiomyocytes, we identified hypoxia inducible domain family, member 1A (Higd1a) as a positive regulator of CcO. Recombinant Higd1a directly integrated into highly purified CcO and increased its activity. Resonance Raman analysis revealed that Higd1a caused structural changes around heme a, the active center that drives the proton pump. Using a mitochondria-targeted ATP biosensor, we showed that knockdown of endogenous Higd1a reduced oxygen consumption and subsequent mitochondrial ATP synthesis, leading to increased cell death in response to hypoxia; all of these phenotypes were rescued by exogenous Higd1a. These results suggest that Higd1a is a previously unidentified regulatory component of CcO, and represents a therapeutic target for diseases associated with reduced CcO activity.
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Maternally inherited diabetes is associated with a homoplasmic T10003C mutation in the mitochondrial tRNA(Gly) gene. Mitochondrion 2015; 21:49-57. [PMID: 25615420 DOI: 10.1016/j.mito.2015.01.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 01/13/2015] [Accepted: 01/13/2015] [Indexed: 12/27/2022]
Abstract
In this report, we investigate molecular pathogenic mechanism of a diabetes-associated homoplasmic mitochondrial tRNA mutation in a Han Chinese family with maternally transmitted diabetes mellitus. Of 10 adult matrilineal relatives, 5 individuals suffered from diabetes (4 subjects with only diabetes, one subject with both diabetes and hearing impairment), while other five matrilineal relatives (one with hearing loss) had glucose intolerance. The average age at onset of diabetes in matrilineal relatives was 50 years. Molecular analysis of their mitochondrial genomes identified the novel homoplasmic T10003C mutation in the tRNA(Gly) gene belonging to haplogroup M11b. The T10003C mutation is expected to form a base-pairing (13C-22G) at the highly conserved D-stem of tRNA(Gly), thereby affecting secondary structure and function of this tRNA. A tRNA Northern analysis revealed that the T10003C mutation caused ~70% reduction in the steady-state level of tRNA(Gly). An in vivo translation analysis showed ~33% reduction in the rate of mitochondrial translation in mutant cells. Oxygen consumption analysis showed the defects in overall respiratory capacity or the ATP-linked, proton leak, and maximal respiration in mutant cells. As a result, the cellular energy deficiency contributes to the development of diabetes in subjects carrying the T10003C mutation. These data provide the first direct evidence that the tRNA(Gly) mutation might be associated with diabetes. Thus, our findings may provide new insights into the understanding of pathophysiology of maternally inherited diabetes.
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Lu WW, Hou LL, Zhang WW, Zhang PF, Chen W, Kang X, Huang Y. Study on heteroplasmic variation and the effect of chicken mitochondrial ND2. Mitochondrial DNA A DNA Mapp Seq Anal 2014; 27:2303-9. [PMID: 25319280 DOI: 10.3109/19401736.2014.971022] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
NADH dehydrogenase subunit 2 gene (ND2) is one of the mitochondrial DNA (mtDNA) protein coding genes, which is a subunit of NADH dehydrogenase. The main purpose of this study was to investigate the variation/heteroplasmic sites of chicken ND2, and thus to evaluate the association with chicken growth traits, carcass traits, and serum biochemical indexes. Seventeen variants were detected in the ND2 gene by Sanger sequencing, which constructed 15 haplotypes; the haplotype diversity (hd) was 0.7692. Mt.A5703T and mt.T5727G in the ND2 gene had been detected as the heteroplasmic sites via the created restriction site restriction fragment length polymorphism (CRS-PCR-RFLP) method. Moreover, the study on distribution of two heteroplasmic variants in the Gushi chicken F2 resource population revealed that the heteroplasmic ratio of mt.A5703T and mt.T5727G was 9% and 40%, respectively. It showed that there was obvious heteroplasmic difference between two sites. Association analysis of the variation/heteroplasmy with the related traits in Gushi chicken F2 population showed that the mt.A5703T and mt.T5727G were significantly associated with the pectoral muscle fat content and the duodenum length, but no significance was found with body weight (BW). It was the first time to indicate that heteroplasmic variation had significant effect on growth traits, carcass parameters, and meat quality traits, which showed the potential importance of related variation.
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Affiliation(s)
- Wei-Wei Lu
- a College of Livestock Husbandry and Veterinary Engineering , Henan Agricultural University , Zhengzhou , Henan , China
| | - Ling-Ling Hou
- a College of Livestock Husbandry and Veterinary Engineering , Henan Agricultural University , Zhengzhou , Henan , China
| | - Wen-Wen Zhang
- a College of Livestock Husbandry and Veterinary Engineering , Henan Agricultural University , Zhengzhou , Henan , China
| | - Peng-Fei Zhang
- a College of Livestock Husbandry and Veterinary Engineering , Henan Agricultural University , Zhengzhou , Henan , China
| | - Wen Chen
- a College of Livestock Husbandry and Veterinary Engineering , Henan Agricultural University , Zhengzhou , Henan , China
| | - Xiangtao Kang
- a College of Livestock Husbandry and Veterinary Engineering , Henan Agricultural University , Zhengzhou , Henan , China
| | - Yanqun Huang
- a College of Livestock Husbandry and Veterinary Engineering , Henan Agricultural University , Zhengzhou , Henan , China
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Gershoni M, Levin L, Ovadia O, Toiw Y, Shani N, Dadon S, Barzilai N, Bergman A, Atzmon G, Wainstein J, Tsur A, Nijtmans L, Glaser B, Mishmar D. Disrupting mitochondrial-nuclear coevolution affects OXPHOS complex I integrity and impacts human health. Genome Biol Evol 2014; 6:2665-80. [PMID: 25245408 PMCID: PMC4224335 DOI: 10.1093/gbe/evu208] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The mutation rate of the mitochondrial DNA (mtDNA), which is higher by an order of magnitude as compared with the nuclear genome, enforces tight mitonuclear coevolution to maintain mitochondrial activities. Interruption of such coevolution plays a role in interpopulation hybrid breakdown, speciation events, and disease susceptibility. Previously, we found an elevated amino acid replacement rate and positive selection in the nuclear DNA-encoded oxidative phosphorylation (OXPHOS) complex I subunit NDUFC2, a phenomenon important for the direct interaction of NDUFC2 with the mtDNA-encoded complex I subunit ND4. This finding underlines the importance of mitonuclear coevolution to physical interactions between mtDNA and nuclear DNA-encoded factors. Nevertheless, it remains unclear whether this interaction is important for the stability and activity of complex I. Here, we show that siRNA silencing of NDUFC2 reduced growth of human D-407 retinal pigment epithelial cells, significantly diminished mitochondrial membrane potential, and interfered with complex I integrity. Moreover, site-directed mutagenesis of a positively selected amino acid in NDUFC2 significantly interfered with the interaction of NDUFC2 with its mtDNA-encoded partner ND4. Finally, we show that a genotype combination involving this amino acid (NDUFC2 residue 46) and the mtDNA haplogroup HV likely altered susceptibility to type 2 diabetes mellitus in Ashkenazi Jews. Therefore, mitonuclear coevolution is important for maintaining mitonuclear factor interactions, OXPHOS, and for human health.
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Affiliation(s)
- Moran Gershoni
- Department of Life Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
| | - Liron Levin
- Department of Life Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
| | - Ofer Ovadia
- Department of Life Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
| | - Yasmin Toiw
- Department of Life Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
| | - Naama Shani
- Department of Life Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
| | - Sara Dadon
- Department of Life Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
| | - Nir Barzilai
- Institute of Aging, Division of Endocrinology, Departments of Medicine and Genetics, Albert Einstein College of Medicine, New York, NY, USA
| | - Aviv Bergman
- Department of Systems and Computational Biology, Albert Einstein College of Medicine, New York, NY, USA
| | - Gil Atzmon
- Institute of Aging, Division of Endocrinology, Departments of Medicine and Genetics, Albert Einstein College of Medicine, New York, NY, USA
| | | | - Anat Tsur
- Endocrine Clinic, Clalit Health Services, Jerusalem, Israel
| | - Leo Nijtmans
- Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Benjamin Glaser
- Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Dan Mishmar
- Department of Life Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
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