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Epifane-de-Assunção MC, Bispo AG, Ribeiro-Dos-Santos Â, Cavalcante GC. Molecular Alterations in Core Subunits of Mitochondrial Complex I and Their Relation to Parkinson's Disease. Mol Neurobiol 2025; 62:6968-6982. [PMID: 39331353 DOI: 10.1007/s12035-024-04526-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 09/23/2024] [Indexed: 09/28/2024]
Abstract
Among the myriad of neurodegenerative diseases, mitochondrial dysfunction represents a nexus regarding their pathogenic processes, in which Parkinson's disease (PD) is notable for inherent vulnerability of the dopaminergic pathway to energy deficits and oxidative stress. Underlying this dysfunction, the occurrence of defects in complex I (CI) derived from molecular alterations in its subunits has been described in the literature. However, the mechanistic understanding of the processes mediating the occurrence of mitochondrial dysfunction mediated by CI deficiency in PD remains uncertain and subject to some inconsistencies. Therefore, this review analyzed existing evidence that may explain the relationship between molecular alterations in the core subunits of CI, recognized for their direct contribution to its enzymatic performance, and the pathogenesis of PD. As a result, we discussed 47 genetic variants in the 14 core subunits of CI, which, despite some discordant results, were predominantly associated with varying degrees of deficiency in complex enzymatic activity, as well as defects in supercomplex biogenesis and CI itself. Finally, we hypothesized about the relationship of the described alterations with the pathogenesis of PD and offered some suggestions that may aid in the design of future studies aimed at elucidating the relationship between such alterations and PD.
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Affiliation(s)
- Matheus Caetano Epifane-de-Assunção
- Laboratório de Genética Humana e Médica, Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal Do Pará, Belém, 66075-110, Brazil
| | - Ana Gabrielle Bispo
- Laboratório de Genética Humana e Médica, Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal Do Pará, Belém, 66075-110, Brazil
| | - Ândrea Ribeiro-Dos-Santos
- Laboratório de Genética Humana e Médica, Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal Do Pará, Belém, 66075-110, Brazil
| | - Giovanna C Cavalcante
- Laboratório de Genética Humana e Médica, Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal Do Pará, Belém, 66075-110, Brazil.
- Laboratório de Metabolismo Energético, Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, 05508-000, Brazil.
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Luo L, Wang M, Liu Y, Li J, Bu F, Yuan H, Tang R, Liu C, He G. Sequencing and characterizing human mitochondrial genomes in the biobank-based genomic research paradigm. SCIENCE CHINA. LIFE SCIENCES 2025:10.1007/s11427-024-2736-7. [PMID: 39843848 DOI: 10.1007/s11427-024-2736-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 09/18/2024] [Indexed: 01/24/2025]
Abstract
Human mitochondrial DNA (mtDNA) harbors essential mutations linked to aging, neurodegenerative diseases, and complex muscle disorders. Due to its uniparental and haploid inheritance, mtDNA captures matrilineal evolutionary trajectories, playing a crucial role in population and medical genetics. However, critical questions about the genomic diversity patterns, inheritance models, and evolutionary and medical functions of mtDNA remain unresolved or underexplored, particularly in the transition from traditional genotyping to large-scale genomic analyses. This review summarizes recent advancements in data-driven genomic research and technological innovations that address these questions and clarify the biological impact of nuclear-mitochondrial segments (NUMTs) and mtDNA variants on human health, disease, and evolution. We propose a streamlined pipeline to comprehensively identify mtDNA and NUMT genomic diversity using advanced sequencing and computational technologies. Haplotype-resolved mtDNA sequencing and assembly can distinguish authentic mtDNA variants from NUMTs, reduce diagnostic inaccuracies, and provide clearer insights into heteroplasmy patterns and the authenticity of paternal inheritance. This review emphasizes the need for integrative multi-omics approaches and emerging long-read sequencing technologies to gain new insights into mutation mechanisms, the influence of heteroplasmy and paternal inheritance on mtDNA diversity and disease susceptibility, and the detailed functions of NUMTs.
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Affiliation(s)
- Lintao Luo
- Institute of Rare Diseases, West China Hospital of Sichuan University, Sichuan University, Chengdu, 610000, China
- Department of Forensic Medicine, College of Basic Medicine, Chongqing Medical University, Chongqing, 400331, China
| | - Mengge Wang
- Institute of Rare Diseases, West China Hospital of Sichuan University, Sichuan University, Chengdu, 610000, China.
- Center for Archaeological Science, Sichuan University, Chengdu, 610000, China.
- Anti-Drug Technology Center of Guangdong Province, Guangzhou, 510230, China.
| | - Yunhui Liu
- Institute of Rare Diseases, West China Hospital of Sichuan University, Sichuan University, Chengdu, 610000, China
- Department of Forensic Medicine, College of Basic Medicine, Chongqing Medical University, Chongqing, 400331, China
| | - Jianbo Li
- Department of Forensic Medicine, College of Basic Medicine, Chongqing Medical University, Chongqing, 400331, China
| | - Fengxiao Bu
- Institute of Rare Diseases, West China Hospital of Sichuan University, Sichuan University, Chengdu, 610000, China
- Center for Archaeological Science, Sichuan University, Chengdu, 610000, China
| | - Huijun Yuan
- Institute of Rare Diseases, West China Hospital of Sichuan University, Sichuan University, Chengdu, 610000, China.
- Center for Archaeological Science, Sichuan University, Chengdu, 610000, China.
| | - Renkuan Tang
- Department of Forensic Medicine, College of Basic Medicine, Chongqing Medical University, Chongqing, 400331, China.
| | - Chao Liu
- Department of Forensic Medicine, College of Basic Medicine, Chongqing Medical University, Chongqing, 400331, China.
- Anti-Drug Technology Center of Guangdong Province, Guangzhou, 510230, China.
| | - Guanglin He
- Institute of Rare Diseases, West China Hospital of Sichuan University, Sichuan University, Chengdu, 610000, China.
- Center for Archaeological Science, Sichuan University, Chengdu, 610000, China.
- Anti-Drug Technology Center of Guangdong Province, Guangzhou, 510230, China.
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Kabelikova P, Ivovic D, Sumbalova Z, Karhanek M, Tatayova L, Skopkova M, Cagalinec M, Bruderova V, Roska J, Jurkovicova D. Mitochondrial genome variability and metabolic alterations reveal new biomarkers of resistance in testicular germ cell tumors. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2024; 7:54. [PMID: 39802950 PMCID: PMC11724352 DOI: 10.20517/cdr.2024.141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 11/11/2024] [Accepted: 11/29/2024] [Indexed: 01/16/2025]
Abstract
Aim: Mutations in the mitochondrial (mt) genome contribute to metabolic dysfunction and their accumulation relates to disease progression and resistance development in cancer cells. This study explores the mutational status of the mt genome of cisplatin-resistant vs. -sensitive testicular germ cell tumor (TGCT) cells and explores its association with their respiration parameters, expression of respiratory genes, and preferences for metabolic pathways to reveal new markers of therapy resistance in TGCTs. Methods: Using Illumina sequencing with Twist Enrichment Panel, the mutations of mt genomes of sensitive 2102EP, H12.1, NTERA-2, T-cam and resistant 2102EP Cis, H12.1 ODM, 1411HP, 1777NRpmet, NTERA-2 Cis and T-cam Cis cell lines were identified. The mt respiration of the cells was assessed using high-resolution respirometry method (O2k-respirometer Oroboros) and the differential expression profiles of mt respiratory genes were determined using RT-qPCR. Associated preferences for metabolic pathways were compared using Glycolysis/OXPHOS assay. Results: In resistant TGCT cells, new mutations in mt genes MT-ND1-6, MT-RNR, MT-CO1-3, MT-ATP6, and MT-CYB were recognized. The respiratory rates of the 1777NRpmet cell line were the highest, while those of the 1411HP line the lowest; rates of the control and all other TGCT cell lines fell between these two lines. The statistically significant differences in gene expression of the respiratory genes were recorded only in NTERA-2 Cis and T-cam Cis cell lines. Sensitive cell lines NTERA-2 and 2102EP preferred oxidative phosphorylation (OXPHOS), while glycolysis was typical for resistant NTERA-2 Cis, 2102EP Cis and 1411HP cell lines. Metastatic 1777NRpmet cells seem to utilize both. An isogenic pair of cell lines H12.1 and H12.1ODM showed the opposite dependence, sensitive H12.1 preferring glycolysis, while resistant H12.1ODM OXPHOS. Conclusion: In summary, our study identified new mutations in mt genes of resistant TGCT cell lines that are associated with different mt respiration parameters, gene expression patterns and preferences for metabolic pathways, providing potential novel molecular biomarkers that distinguish the resistant TGCT phenotype or specify its histological classification.
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Affiliation(s)
- Pavlina Kabelikova
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava 84505, Slovak Republic
| | - Danica Ivovic
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava 84505, Slovak Republic
| | - Zuzana Sumbalova
- Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry, Faculty of Medicine, Comenius University in Bratislava, Bratislava 81108, Slovak Republic
| | - Miloslav Karhanek
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava 84505, Slovak Republic
| | - Lucia Tatayova
- Department of Medical Genetics, Medirex Inc., Bratislava 82104, Slovak Republic
| | - Martina Skopkova
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava 84505, Slovak Republic
| | - Michal Cagalinec
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava 84505, Slovak Republic
| | - Vladimira Bruderova
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava 84505, Slovak Republic
| | - Jan Roska
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava 84505, Slovak Republic
- Co-senior authors
| | - Dana Jurkovicova
- Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Bratislava 84505, Slovak Republic
- Co-senior authors
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Tamvaka N, Heckman MG, Johnson PW, Soto-Beasley AI, Walton RL, Koga S, Uitti RJ, Parfitt F, Graff-Radford MR, Wszolek ZK, Graff-Radford N, Valentino RR, Ross OA. Associations of mitochondrial genomic variation with successful neurological aging. Mitochondrion 2024; 78:101948. [PMID: 39179138 DOI: 10.1016/j.mito.2024.101948] [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: 03/01/2024] [Revised: 07/25/2024] [Accepted: 08/18/2024] [Indexed: 08/26/2024]
Abstract
Mitochondrial health is an integral factor in aging, with mitochondrial dysfunction known to increase with age and contribute to the development of age-related neurodegenerative disorders. Additionally, the mitochondrial genome (mtDNA) has been shown to acquire potentially damaging somatic variation as part of the aging process, while mtDNA single nucleotide polymorphism (SNPs) have been shown to be both protective and detrimental for various neurodegenerative diseases. Yet, little is known about the involvement of mtDNA variation in longevity and successful neurological aging. In this study, we examined the association of mtDNA SNPs, in the form of mitochondrial haplogroups, with successful neurological aging in 1,405 unrelated neurologically healthy subjects. Although not quite significant after correcting for multiple testing (P < 0.0017 considered as significant), we detected a nominally significant association between the I haplogroup (N = 45, 3.2 %) and a younger age (β: -5.00, P = 0.006), indicating that this haplogroup is observed less frequently in older neurologically healthy individuals and may be associated with decreased survival. Replication of this finding in independent neurologically healthy cohorts will be imperative for shaping our understanding of the biological processes underlying healthy neurological aging.
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Affiliation(s)
- Nicole Tamvaka
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Mayo Graduate School, Neuroscience Track, Mayo Clinic, Jacksonville, FL, USA
| | - Michael G Heckman
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Patrick W Johnson
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL 32224, USA
| | | | - Ronald L Walton
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Shunsuke Koga
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Ryan J Uitti
- Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Francine Parfitt
- Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA
| | | | | | | | | | - Owen A Ross
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Mayo Graduate School, Neuroscience Track, Mayo Clinic, Jacksonville, FL, USA; Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, USA; Department of Biology, University of North Florida, Jacksonville, FL 32224, USA; Department of Medicine, University College Dublin, Dublin, Ireland.
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5
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Sena-Dos-Santos C, Moura DD, Epifane-de-Assunção MC, Ribeiro-Dos-Santos Â, Santos-Lobato BL. Mitochondrial DNA variants, haplogroups and risk of Parkinson's disease: A systematic review and meta-analysis. Parkinsonism Relat Disord 2024; 125:107044. [PMID: 38917640 DOI: 10.1016/j.parkreldis.2024.107044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 06/18/2024] [Accepted: 06/18/2024] [Indexed: 06/27/2024]
Abstract
BACKGROUND Growing evidence has shown that mitochondrial dysfunction is part of the pathogenesis of Parkinson's disease (PD). However, the role of mitochondrial DNA (mtDNA) variants on PD onset is unclear. OBJECTIVES The present study aims to evaluate the effect of mtDNA variants and haplogroups on risk of developing PD. METHODS Systematic review and meta-analysis of studies investigating associations between PD and mtDNA variants and haplogroups. RESULTS A total of 33 studies were eligible from 957 screened studies. Among 13,640 people with PD and 22,588 control individuals, the association with PD was consistently explored in 13 mtDNA variants in 10 genes and 19 macrohaplogroups. Four mtDNA variants were associated with PD: m.4336C (odds ratio [OR] = 2.99; 95 % confidence interval [CI] = 1.79-5.02), m.7028T (OR = 0.80; 95 % CI = 0.70-0.91), m.10398G (OR = 0.92; 95 % CI = 0.85-0.98), and m.13368A (OR = 0.74; 95 % CI = 0.56-0.98). Four mtDNA macrohaplogroups were associated with PD: R (OR = 2.25; 95 % CI = 1.92-2.65), F (OR = 1.18; 95 % CI = 1.01-1.38), H (OR = 1.12; 95 % CI = 1.06-1.18), and B (OR = 0.77; 95 % CI = 0.65-0.92). CONCLUSIONS Despite most studies may be underpowered by the underrepresentation of people without dominant European- and Asian-ancestry, low use of next-generation sequencing for genotyping and small sample sizes, the identification of mtDNA variants and macrohaplogroups associated with PD strengthens the link between the disease and mitochondrial dysfunction and mtDNA genomic instability.
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Affiliation(s)
| | - Dafne Dalledone Moura
- Laboratório de Neuropatologia Experimental, Universidade Federal do Pará, Belém, Pará, Brazil
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Lan MY, Lin TK, Lace B, Utkus A, Burnyte B, Grigalioniene K, Lin YH, Inashkina I, Liou CW. Unraveling the Pathogenetic Mechanisms Underlying the Association between Specific Mitochondrial DNA Haplogroups and Parkinson's Disease. Cells 2024; 13:694. [PMID: 38667309 PMCID: PMC11049488 DOI: 10.3390/cells13080694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 04/08/2024] [Accepted: 04/14/2024] [Indexed: 04/28/2024] Open
Abstract
Variants of mitochondrial DNA (mtDNA) have been identified as risk factors for the development of Parkinson's disease (PD). However, the underlying pathogenetic mechanisms remain unclear. Cybrid models carrying various genotypes of mtDNA variants were tested for resistance to PD-simulating MPP+ treatment. The most resistant line was selected for transcriptome profiling, revealing specific genes potentially influencing the resistant characteristic. We then conducted protein validation and molecular biological studies to validate the related pathways as the influential factor. Cybrids carrying the W3 mtDNA haplogroup demonstrated the most resistance to the MPP+ treatment. In the transcriptome study, PPP1R15A was identified, while further study noted elevated expressions of the coding protein GADD34 across all cybrids. In the study of GADD34-related mitochondrial unfolding protein response (mtUPR), we found that canonical mtUPR, launched by the phosphate eIF2a, is involved in the resistant characteristic of specific mtDNA to MPP+ treatment. Our study suggests that a lower expression of GADD34 in the late phase of mtUPR may prolong the mtUPR process, thereby benefitting protein homeostasis and facilitating cellular resistance to PD development. We herein demonstrate that GADD34 plays an important role in PD development and should be further investigated as a target for the development of therapies for PD.
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Affiliation(s)
- Min-Yu Lan
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (M.-Y.L.); (T.-K.L.)
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan;
| | - Tsu-Kung Lin
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (M.-Y.L.); (T.-K.L.)
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan;
| | - Baiba Lace
- Riga East Clinical University Hospital, Latvia Institute of Clinical and Preventive Medicine, University of Latvia, LV-1038 Riga, Latvia
| | - Algirdas Utkus
- Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania; (A.U.); (B.B.); (K.G.)
| | - Birute Burnyte
- Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania; (A.U.); (B.B.); (K.G.)
| | - Kristina Grigalioniene
- Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania; (A.U.); (B.B.); (K.G.)
| | - Yu-Han Lin
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan;
| | - Inna Inashkina
- Latvian Biomedical Research and Study Center, LV-1067 Riga, Latvia
| | - Chia-Wei Liou
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (M.-Y.L.); (T.-K.L.)
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan;
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7
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Bľandová G, Janoštiaková N, Kodada D, Pastorek M, Lipták R, Hodosy J, Šebeková K, Celec P, Krasňanská G, Eliaš V, Wachsmannová L, Konečný M, Repiská V, Baldovič M. Mitochondrial DNA variability and Covid-19 in the Slovak population. Mitochondrion 2024; 75:101827. [PMID: 38135240 DOI: 10.1016/j.mito.2023.101827] [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: 08/07/2023] [Revised: 11/27/2023] [Accepted: 12/16/2023] [Indexed: 12/24/2023]
Abstract
Recent studies have shown that mitochondria are involved in the pathogenesis of Covid-19. Mitochondria play a role in production of reactive oxygen species and induction of an innate immune response, both important during infections. Common variability of mitochondrial DNA (mtDNA) can affect oxidative phosphorylation and the risk or lethality of cardiovascular, neurodegenerative diseases and sepsis. However, it is unclear whether susceptibility of severe Covid-19 might be affected by mtDNA variation. Thus, we have analyzed mtDNA in a sample of 446 Slovak patients hospitalized due to Covid-19 and a control population group consisting of 1874 individuals. MtDNA variants in the HVRI region have been analyzed and classified into haplogroups at various phylogenetic levels. Binary logistic regression was used to assess the risk of Covid-19. Haplogroups T1, H11, K and variants 16256C > T, 16265A > C, 16293A > G, 16311 T > C and 16399A > G were associated with an increased Covid-19 risk. On contrary, Haplogroup J1, haplogroup clusters H + U5b and T2b + U5b, and the mtDNA variant 16189 T > C were associated with decreased risk of Covid-19. Following the application of the Bonferroni correction, statistical significance was observed exclusively for the cluster of haplogroups H + U5b. Unsurprisingly, the most significant factor contributing to the mortality of patients with Covid-19 is the age of patients. Our findings suggest that mtDNA haplogroups can play a role in Covid-19 pathogenesis, thus potentially useful in identifying susceptibility to its severe form. To confirm these associations, further studies taking into account the nuclear genome or other non-biological influences are needed.
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Affiliation(s)
- Gabriela Bľandová
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
| | - Nikola Janoštiaková
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Dominik Kodada
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Michal Pastorek
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Róbert Lipták
- Department of Emergency Medicine, University Hospital, Bratislava, Slovakia
| | - Július Hodosy
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia; Department of Emergency Medicine, University Hospital, Bratislava, Slovakia
| | - Katarína Šebeková
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Peter Celec
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia; Institute of Pathophysiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Gabriela Krasňanská
- Laboratory of Genomic Medicine, GHC GENETICS SK, Science Park Comenius University, Bratislava, Slovakia; Department of Biology, Institute of Biology and Biotechnology, Faculty of Natural Sciences, University of St. Cyril and Methodius, Trnava, Slovakia
| | - Vladimír Eliaš
- Laboratory of Genomic Medicine, GHC GENETICS SK, Science Park Comenius University, Bratislava, Slovakia
| | - Lenka Wachsmannová
- Laboratory of Genomic Medicine, GHC GENETICS SK, Science Park Comenius University, Bratislava, Slovakia
| | - Michal Konečný
- Laboratory of Genomic Medicine, GHC GENETICS SK, Science Park Comenius University, Bratislava, Slovakia; Department of Biology, Institute of Biology and Biotechnology, Faculty of Natural Sciences, University of St. Cyril and Methodius, Trnava, Slovakia
| | - Vanda Repiská
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Marian Baldovič
- Laboratory of Genomic Medicine, GHC GENETICS SK, Science Park Comenius University, Bratislava, Slovakia; Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia.
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8
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Citrigno L, Qualtieri A, Cerantonio A, De Benedittis S, Gallo O, Di Palma G, Spadafora P, Cavalcanti F. Genomics landscape of mitochondrial DNA variations in patients from South Italy affected by mitochondriopathies. J Neurol Sci 2024; 457:122869. [PMID: 38215527 DOI: 10.1016/j.jns.2024.122869] [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: 10/09/2023] [Revised: 12/20/2023] [Accepted: 01/04/2024] [Indexed: 01/14/2024]
Abstract
Mitochondrial DNA (mtDNA) is a 16,569 base pairs, double-stranded, circular molecule that contains 37 genes coding for 13 subunits of the respiratory chain plus 2 rRNAs and 22 tRNAs. Mutations in these genes have been identified in patients with a variety of disorders affecting every system in the body. The advent of next generation sequencing technologies has provided the possibility to perform the whole mitochondrial DNA sequencing, allowing the identification of disease-causing pathogenic variants in a single platform. In this study, the whole mtDNA of 100 patients from South Italy affected by mitochondrial diseases was analyzed by using an amplicon-based approach and then the enriched libraries were deeply sequenced on the ION Torrent platform (Thermofisher Scientific Waltham, MA, USA). After bioinformatics analysis and filtering, we were able to find 26 nonsynonymous variants with a MAF <1% that were associated with different pathological phenotypes, expanding the mutational spectrum of these diseases. Moreover, among the new mutations found, we have also analyzed the 3D structure of the MT-ATP6 A200T gene variation in order to confirm suspected functional alterations. This work brings light on new variants possibly associated with several mitochondriopathies in patients from South Italy and confirms that deep sequencing approach, compared to the standard methods, is a reliable and time-cost reducing strategy to detect all the variants present in the mitogenome, making the possibility to create a genomics landscape of mitochondrial DNA variations in human diseases.
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Affiliation(s)
- Luigi Citrigno
- Institute for Biomedical Research and Innovation (IRIB), Department of Biomedical Sciences, National Research Council (CNR), Mangone (CS), Italy.
| | - Antonio Qualtieri
- Institute for Biomedical Research and Innovation (IRIB), Department of Biomedical Sciences, National Research Council (CNR), Mangone (CS), Italy
| | - Annamaria Cerantonio
- Institute for Biomedical Research and Innovation (IRIB), Department of Biomedical Sciences, National Research Council (CNR), Mangone (CS), Italy
| | - Selene De Benedittis
- Institute for Biomedical Research and Innovation (IRIB), Department of Biomedical Sciences, National Research Council (CNR), Mangone (CS), Italy
| | - Olivier Gallo
- Institute for Biomedical Research and Innovation (IRIB), Department of Biomedical Sciences, National Research Council (CNR), Mangone (CS), Italy
| | - Gemma Di Palma
- Institute for Biomedical Research and Innovation (IRIB), Department of Biomedical Sciences, National Research Council (CNR), Mangone (CS), Italy
| | - Patrizia Spadafora
- Institute for Biomedical Research and Innovation (IRIB), Department of Biomedical Sciences, National Research Council (CNR), Mangone (CS), Italy
| | - Francesca Cavalcanti
- Institute for Biomedical Research and Innovation (IRIB), Department of Biomedical Sciences, National Research Council (CNR), Mangone (CS), Italy
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Kim SJ, Miller B, Hartel NG, Ramirez R, Braniff RG, Leelaprachakul N, Huang A, Wang Y, Arpawong TE, Crimmins EM, Wang P, Sun X, Liu C, Levy D, Yen K, Petzinger GM, Graham NA, Jakowec MW, Cohen P. A naturally occurring variant of SHLP2 is a protective factor in Parkinson's disease. Mol Psychiatry 2024; 29:505-517. [PMID: 38167865 PMCID: PMC11116102 DOI: 10.1038/s41380-023-02344-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 11/20/2023] [Accepted: 11/27/2023] [Indexed: 01/05/2024]
Abstract
Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) have been associated with a reduced risk of developing Parkinson's disease (PD), yet the underlying mechanisms remain elusive. In this study, we investigate the functional role of a PD-associated mtSNP that impacts the mitochondrial-derived peptide (MDP) Small Humanin-like Peptide 2 (SHLP2). We identify m.2158 T > C, a mtSNP associated with reduced PD risk, within the small open reading frame encoding SHLP2. This mtSNP results in an alternative form of SHLP2 (lysine 4 replaced with arginine; K4R). Using targeted mass spectrometry, we detect specific tryptic fragments of SHLP2 in neuronal cells and demonstrate its binding to mitochondrial complex 1. Notably, we observe that the K4R variant, associated with reduced PD risk, exhibits increased stability compared to WT SHLP2. Additionally, both WT and K4R SHLP2 show enhanced protection against mitochondrial dysfunction in in vitro experiments and confer protection against a PD-inducing toxin, a mitochondrial complex 1 inhibitor, in a mouse model. This study sheds light on the functional consequences of the m.2158 T > C mtSNP on SHLP2 and provides insights into the potential mechanisms by which this mtSNP may reduce the risk of PD.
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Affiliation(s)
- Su-Jeong Kim
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Brendan Miller
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Nicolas G Hartel
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA
| | - Ricardo Ramirez
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Regina Gonzalez Braniff
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Naphada Leelaprachakul
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
- Environmental Toxicology Program, Chulabhorn Graduate Institute, Bangkok, 10210, Thailand
| | - Amy Huang
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Yuzhu Wang
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Thalida Em Arpawong
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Eileen M Crimmins
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Penglong Wang
- The Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Xianbang Sun
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - Chunyu Liu
- The Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
- Boston University's and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA
| | - Daniel Levy
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
- Boston University's and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA
| | - Kelvin Yen
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - Giselle M Petzinger
- Department of Neurology, University of Southern California, Los Angeles, CA, USA
| | - Nicholas A Graham
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Michael W Jakowec
- Department of Neurology, University of Southern California, Los Angeles, CA, USA
- Department of Biokinesiology and Physical Therapy, The George and MaryLou Boone Center for Parkinson's Disease Research, University of Southern California, Los Angeles, CA, USA
| | - Pinchas Cohen
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
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10
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Ellis RJ, Marquine MJ, Kaul M, Fields JA, Schlachetzki JCM. Mechanisms underlying HIV-associated cognitive impairment and emerging therapies for its management. Nat Rev Neurol 2023; 19:668-687. [PMID: 37816937 PMCID: PMC11052664 DOI: 10.1038/s41582-023-00879-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/07/2023] [Indexed: 10/12/2023]
Abstract
People living with HIV are affected by the chronic consequences of neurocognitive impairment (NCI) despite antiretroviral therapies that suppress viral replication, improve health and extend life. Furthermore, viral suppression does not eliminate the virus, and remaining infected cells may continue to produce viral proteins that trigger neurodegeneration. Comorbidities such as diabetes mellitus are likely to contribute substantially to CNS injury in people living with HIV, and some components of antiretroviral therapy exert undesirable side effects on the nervous system. No treatment for HIV-associated NCI has been approved by the European Medicines Agency or the US Food and Drug Administration. Historically, roadblocks to developing effective treatments have included a limited understanding of the pathophysiology of HIV-associated NCI and heterogeneity in its clinical manifestations. This heterogeneity might reflect multiple underlying causes that differ among individuals, rather than a single unifying neuropathogenesis. Despite these complexities, accelerating discoveries in HIV neuropathogenesis are yielding potentially druggable targets, including excessive immune activation, metabolic alterations culminating in mitochondrial dysfunction, dysregulation of metal ion homeostasis and lysosomal function, and microbiome alterations. In addition to drug treatments, we also highlight the importance of non-pharmacological interventions. By revisiting mechanisms implicated in NCI and potential interventions addressing these mechanisms, we hope to supply reasons for optimism in people living with HIV affected by NCI and their care providers.
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Affiliation(s)
- Ronald J Ellis
- Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
| | - María J Marquine
- Department of Medicine, Duke University, Durham, NC, USA
- Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
| | - Marcus Kaul
- School of Medicine, Division of Biomedical Sciences, University of California Riverside, Riverside, CA, USA
| | - Jerel Adam Fields
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
| | - Johannes C M Schlachetzki
- Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
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11
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Neilson LE, Quinn JF, Lim MM. Screening and Targeting Risk Factors for Prodromal Synucleinopathy: Taking Steps toward a Prescriptive Multi-modal Framework. Aging Dis 2023; 14:1243-1263. [PMID: 37307836 PMCID: PMC10389816 DOI: 10.14336/ad.2022.1024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 10/24/2022] [Indexed: 06/14/2023] Open
Abstract
As the prevalence of Parkinson's disease (PD) grows, so too does the population at-risk of developing PD, those in the so-called prodromal period. This period can span from those experiencing subtle motor deficits yet not meeting full diagnostic criteria or those with physiologic markers of disease alone. Several disease-modifying therapies have failed to show a neuroprotective effect. A common criticism is that neurodegeneration, even in the early motor stages, has advanced too far for neuro-restoration-based interventions to be effective. Therefore, identifying this early population is essential. Once identified, these patients could then potentially benefit from sweeping lifestyle modifications to alter their disease trajectory. Herein, we review the literature on risk factors for, and prodromal symptoms of, PD with an emphasis on ones which may be modifiable in the earliest possible stages. We propose a process for identifying this population and speculate on some strategies which may modulate disease trajectory. Ultimately, this proposal warrants prospective studies.
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Affiliation(s)
- Lee E Neilson
- Department of Neurology, Veterans Affairs Portland Healthcare System, Portland, OR 97239, USA.
- Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA
| | - Joseph F Quinn
- Department of Neurology, Veterans Affairs Portland Healthcare System, Portland, OR 97239, USA.
- Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA
| | - Miranda M Lim
- Department of Neurology, Veterans Affairs Portland Healthcare System, Portland, OR 97239, USA.
- Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA
- Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR 97239, USA.
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, OR 97239, USA.
- Oregon Institute of Occupational Health Sciences, Oregon Health and Science University, Portland, OR 97239, USA.
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12
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Hernández CL. Mitochondrial DNA in Human Diversity and Health: From the Golden Age to the Omics Era. Genes (Basel) 2023; 14:1534. [PMID: 37628587 PMCID: PMC10453943 DOI: 10.3390/genes14081534] [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: 06/19/2023] [Revised: 07/21/2023] [Accepted: 07/24/2023] [Indexed: 08/27/2023] Open
Abstract
Mitochondrial DNA (mtDNA) is a small fraction of our hereditary material. However, this molecule has had an overwhelming presence in scientific research for decades until the arrival of high-throughput studies. Several appealing properties justify the application of mtDNA to understand how human populations are-from a genetic perspective-and how individuals exhibit phenotypes of biomedical importance. Here, I review the basics of mitochondrial studies with a focus on the dawn of the field, analysis methods and the connection between two sides of mitochondrial genetics: anthropological and biomedical. The particularities of mtDNA, with respect to inheritance pattern, evolutionary rate and dependence on the nuclear genome, explain the challenges of associating mtDNA composition and diseases. Finally, I consider the relevance of this single locus in the context of omics research. The present work may serve as a tribute to a tool that has provided important insights into the past and present of humankind.
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Affiliation(s)
- Candela L Hernández
- Department of Biodiversity, Ecology and Evolution, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain
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13
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Ju WK, Perkins GA, Kim KY, Bastola T, Choi WY, Choi SH. Glaucomatous optic neuropathy: Mitochondrial dynamics, dysfunction and protection in retinal ganglion cells. Prog Retin Eye Res 2023; 95:101136. [PMID: 36400670 DOI: 10.1016/j.preteyeres.2022.101136] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/04/2022] [Accepted: 11/03/2022] [Indexed: 11/18/2022]
Abstract
Glaucoma is a leading cause of irreversible blindness worldwide and is characterized by a slow, progressive, and multifactorial degeneration of retinal ganglion cells (RGCs) and their axons, resulting in vision loss. Despite its high prevalence in individuals 60 years of age and older, the causing factors contributing to glaucoma progression are currently not well characterized. Intraocular pressure (IOP) is the only proven treatable risk factor. However, lowering IOP is insufficient for preventing disease progression. One of the significant interests in glaucoma pathogenesis is understanding the structural and functional impairment of mitochondria in RGCs and their axons and synapses. Glaucomatous risk factors such as IOP elevation, aging, genetic variation, neuroinflammation, neurotrophic factor deprivation, and vascular dysregulation, are potential inducers for mitochondrial dysfunction in glaucoma. Because oxidative phosphorylation stress-mediated mitochondrial dysfunction is associated with structural and functional impairment of mitochondria in glaucomatous RGCs, understanding the underlying mechanisms and relationship between structural and functional alterations in mitochondria would be beneficial to developing mitochondria-related neuroprotection in RGCs and their axons and synapses against glaucomatous neurodegeneration. Here, we review the current studies focusing on mitochondrial dynamics-based structural and functional alterations in the mitochondria of glaucomatous RGCs and therapeutic strategies to protect RGCs against glaucomatous neurodegeneration.
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Affiliation(s)
- Won-Kyu Ju
- Hamilton Glaucoma Center and Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego, La Jolla, CA, 92093, USA.
| | - Guy A Perkins
- National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093, USA
| | - Keun-Young Kim
- National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093, USA
| | - Tonking Bastola
- Hamilton Glaucoma Center and Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego, La Jolla, CA, 92093, USA
| | - Woo-Young Choi
- Hamilton Glaucoma Center and Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego, La Jolla, CA, 92093, USA; Department of Plastic Surgery, College of Medicine, Chosun University, Gwang-ju, South Korea
| | - Soo-Ho Choi
- Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA
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14
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Smullen M, Olson MN, Murray LF, Suresh M, Yan G, Dawes P, Barton NJ, Mason JN, Zhang Y, Fernandez-Fontaine AA, Church GM, Mastroeni D, Wang Q, Lim ET, Chan Y, Readhead B. Modeling of mitochondrial genetic polymorphisms reveals induction of heteroplasmy by pleiotropic disease locus 10398A>G. Sci Rep 2023; 13:10405. [PMID: 37369829 DOI: 10.1038/s41598-023-37541-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 06/23/2023] [Indexed: 06/29/2023] Open
Abstract
Mitochondrial (MT) dysfunction has been associated with several neurodegenerative diseases including Alzheimer's disease (AD). While MT-copy number differences have been implicated in AD, the effect of MT heteroplasmy on AD has not been well characterized. Here, we analyzed over 1800 whole genome sequencing data from four AD cohorts in seven different tissue types to determine the extent of MT heteroplasmy present. While MT heteroplasmy was present throughout the entire MT genome for blood samples, we detected MT heteroplasmy only within the MT control region for brain samples. We observed that an MT variant 10398A>G (rs2853826) was significantly associated with overall MT heteroplasmy in brain tissue while also being linked with the largest number of distinct disease phenotypes of all annotated MT variants in MitoMap. Using gene-expression data from our brain samples, our modeling discovered several gene networks involved in mitochondrial respiratory chain and Complex I function associated with 10398A>G. The variant was also found to be an expression quantitative trait loci (eQTL) for the gene MT-ND3. We further characterized the effect of 10398A>G by phenotyping a population of lymphoblastoid cell-lines (LCLs) with and without the variant allele. Examination of RNA sequence data from these LCLs reveal that 10398A>G was an eQTL for MT-ND4. We also observed in LCLs that 10398A>G was significantly associated with overall MT heteroplasmy within the MT control region, confirming the initial findings observed in post-mortem brain tissue. These results provide novel evidence linking MT SNPs with MT heteroplasmy and open novel avenues for the investigation of pathomechanisms that are driven by this pleiotropic disease associated loci.
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Affiliation(s)
- Molly Smullen
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - Meagan N Olson
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - Liam F Murray
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - Madhusoodhanan Suresh
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - Guang Yan
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - Pepper Dawes
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - Nathaniel J Barton
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - Jivanna N Mason
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - Yucheng Zhang
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - Aria A Fernandez-Fontaine
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - George M Church
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA
| | - Diego Mastroeni
- ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, 85281, USA
| | - Qi Wang
- ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, 85281, USA
| | - Elaine T Lim
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA
| | - Yingleong Chan
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
- Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
- NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
| | - Benjamin Readhead
- ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, 85281, USA.
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15
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Lorca R, Aparicio A, Gómez J, Álvarez-Velasco R, Pascual I, Avanzas P, González-Urbistondo F, Alen A, Vázquez-Coto D, González-Fernández M, García-Lago C, Cuesta-Llavona E, Morís C, Coto E. Mitochondrial Heteroplasmy as a Marker for Premature Coronary Artery Disease: Analysis of the Poly-C Tract of the Control Region Sequence. J Clin Med 2023; 12:jcm12062133. [PMID: 36983136 PMCID: PMC10053235 DOI: 10.3390/jcm12062133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/26/2023] [Accepted: 03/06/2023] [Indexed: 03/11/2023] Open
Abstract
Mitochondrial DNA (mtDNA) differs from the nuclear genome in many aspects: a maternal inheritance pattern; being more prone to acquire somatic de novo mutations, accumulative with age; and the possible coexistence of different mtDNA alleles (heteroplasmy). Mitochondria are key cellular organelles responsible for energy production and involved in complex mechanisms, including atherosclerosis. In this scenario, we aimed to evaluate mtDNA variants that could be associated with premature cardiovascular disease. We evaluated 188 consecutive patients presenting with premature myocardial infarction with ST elevation (STEMI) confirmed by coronary angiogram. mtDNA polymorphisms and clinical data were evaluated and compared with 271 individuals from the same population (control group). Tobacco consumption (80.85% vs. 21.21%, p < 0.01) and dyslipidemia (38.83% vs. 28.41%, p = 0.02) were significantly more frequent among STEMI patients. Moreover, C16223T mtDNA mutation and poly-C heteroplasmy were significantly more frequent among premature STEMI male patients than in controls. The OR associated C16223T mtDNA with the increased presence of cardiovascular risk factors. Our data suggest that mtDNA 16223T and heteroplasmy may be associated with unstable premature atherosclerosis disease in men. Moreover, the presence of cardiovascular risk factors (CVRFs) was associated with C16223T mtDNA, with a cumulative effect. Protective mitochondrial pathways are potential therapeutic targets. Preventing exposure to the damaging mechanisms associated with CVRFs is of utmost importance.
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Affiliation(s)
- Rebeca Lorca
- Área del Corazón, Hospital Universitario Central Asturias, 33011 Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias, ISPA, 33011 Oviedo, Spain
- Departamento de Morfología y Biología Celular, Universidad de Oviedo, 33003 Oviedo, Spain
- Unidad de Cardiopatías Familiares, Área del Corazón y Departamento de Genética Molecular, Hospital Universitario Central Asturias, 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORs), 28029 Madrid, Spain
| | - Andrea Aparicio
- Área del Corazón, Hospital Universitario Central Asturias, 33011 Oviedo, Spain
| | - Juan Gómez
- Instituto de Investigación Sanitaria del Principado de Asturias, ISPA, 33011 Oviedo, Spain
- Unidad de Cardiopatías Familiares, Área del Corazón y Departamento de Genética Molecular, Hospital Universitario Central Asturias, 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORs), 28029 Madrid, Spain
- CIBER-Enfermedades Respiratorias, 28029 Madrid, Spain
- Laboratorio de Genética, Hospital Universitario Central Asturias, 33011 Oviedo, Spain
- Correspondence:
| | - Rut Álvarez-Velasco
- Área del Corazón, Hospital Universitario Central Asturias, 33011 Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias, ISPA, 33011 Oviedo, Spain
| | - Isaac Pascual
- Área del Corazón, Hospital Universitario Central Asturias, 33011 Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias, ISPA, 33011 Oviedo, Spain
- Departamento de Medicina, Universidad de Oviedo, 33003 Oviedo, Spain
| | - Pablo Avanzas
- Área del Corazón, Hospital Universitario Central Asturias, 33011 Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias, ISPA, 33011 Oviedo, Spain
- Departamento de Medicina, Universidad de Oviedo, 33003 Oviedo, Spain
- CIBER-Enfermedades Cardiovasculares, 28029 Madrid, Spain
| | | | - Alberto Alen
- Área del Corazón, Hospital Universitario Central Asturias, 33011 Oviedo, Spain
| | - Daniel Vázquez-Coto
- Laboratorio de Genética, Hospital Universitario Central Asturias, 33011 Oviedo, Spain
| | | | - Claudia García-Lago
- Laboratorio de Genética, Hospital Universitario Central Asturias, 33011 Oviedo, Spain
| | - Elías Cuesta-Llavona
- Instituto de Investigación Sanitaria del Principado de Asturias, ISPA, 33011 Oviedo, Spain
- Laboratorio de Genética, Hospital Universitario Central Asturias, 33011 Oviedo, Spain
| | - César Morís
- Área del Corazón, Hospital Universitario Central Asturias, 33011 Oviedo, Spain
- Instituto de Investigación Sanitaria del Principado de Asturias, ISPA, 33011 Oviedo, Spain
- Unidad de Cardiopatías Familiares, Área del Corazón y Departamento de Genética Molecular, Hospital Universitario Central Asturias, 33011 Oviedo, Spain
- Departamento de Medicina, Universidad de Oviedo, 33003 Oviedo, Spain
| | - Eliecer Coto
- Instituto de Investigación Sanitaria del Principado de Asturias, ISPA, 33011 Oviedo, Spain
- Unidad de Cardiopatías Familiares, Área del Corazón y Departamento de Genética Molecular, Hospital Universitario Central Asturias, 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORs), 28029 Madrid, Spain
- Laboratorio de Genética, Hospital Universitario Central Asturias, 33011 Oviedo, Spain
- Departamento de Medicina, Universidad de Oviedo, 33003 Oviedo, Spain
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16
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Monge-Ochoa B, Montoro L, Montoya J, Ruiz-Pesini E, López-Pérez MJ, de Castro F, Díez-Sánchez C. m.4216 T > C polymorphism in JT cluster determines a lower pregnancy rate in response to controlled ovarian stimulation treatment. J Assist Reprod Genet 2023; 40:671-682. [PMID: 36701026 PMCID: PMC10033795 DOI: 10.1007/s10815-023-02721-2] [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: 02/14/2022] [Accepted: 01/10/2023] [Indexed: 01/27/2023] Open
Abstract
PURPOSE To analyze the influence of Caucasian mitochondrial haplogroups on controlled ovarian stimulation outcome (COS), embryo (E), and pregnancy success. METHODS In a Caucasian population (n = 517) undergoing COS, mitochondrial haplogroups and physiological parameters were determined. Patients were classified, according to Bologna criteria, as good (>3)/poor ≤3) responder, on dependence of recruited oocytes (RO), and in pregnancy/non-pregnancy groups. Haplogroups were determined by sequencing mitochondrial hypervariable sequence I and confirmed by polymerase chain reaction (PCR), followed by restriction fragment length polymorphisms (RFLP). RESULTS The rank of total dose of FSH (TD FSH) was similar in all clusters/haplogroups, except in JT, which is narrower (950-3,650 IU), particularly in T (1,350-3,650 IU). The statistical analysis showed higher RO and E in JT when compared to U, although it was only Uk which accumulated significantly in pregnancy respect to JT. Pearson's correlations between TD FSH and RO showed negative statistical significance in all population (P = 0.001), H (P = 0.03), JT (P = 0.01), and T (P = 0.03). The percentage of contribution of TD FSH on RO was almost nine times in the JT cluster as compared to all population one. CONCLUSIONS JT cluster shows a different influence of TD FSH on RO. JT cluster shows higher RO and E than U, but it is Uk which exhibits a significant higher pregnancy rate than JT. The negative influence of the JT cluster on pregnancy success strongly suggests that the m.4216 T > C polymorphism could be responsible.
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Affiliation(s)
- Belén Monge-Ochoa
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain
| | - Luis Montoro
- Unidad de Reproducción Asistida, Hospital Universitario Príncipe de Asturias, Universidad Complutense de Madrid, Alcalá de Henares, Madrid, Spain
| | - Julio Montoya
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Madrid, Spain
- Instituto de Investigación Sanitaria (IIS) de Aragón, Zaragoza, Spain
| | - Eduardo Ruiz-Pesini
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Madrid, Spain
- Instituto de Investigación Sanitaria (IIS) de Aragón, Zaragoza, Spain
| | - Manuel J López-Pérez
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain
| | - Francisco de Castro
- Unidad de Reproducción Asistida, Hospital Universitario Príncipe de Asturias, Universidad Complutense de Madrid, Alcalá de Henares, Madrid, Spain
| | - Carmen Díez-Sánchez
- Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
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Cosemans C, Wang C, Martens DS, Janssen BG, Vanpoucke C, Lefebvre W, Smeets K, Nawrot TS, Plusquin M. In Utero Exposure to Air Pollutants and Mitochondrial Heteroplasmy in Neonates. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2023; 57:350-359. [PMID: 36516295 DOI: 10.1021/acs.est.2c02556] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Mitochondria are sensitive to oxidative stress, which can be caused by traffic-related air pollution. Placental mitochondrial DNA (mtDNA) mutations have been previously linked with air pollution. However, the relationship between prenatal air pollution and cord-blood mtDNA mutations has been poorly understood. Therefore, we hypothesized that prenatal particulate matter (PM2.5) and NO2 exposures are associated with cord-blood mtDNA heteroplasmy. As part of the ENVIRONAGE cohort, 200 mother-newborn pairs were recruited. Cord-blood mitochondrial single-nucleotide polymorphisms were identified by whole mitochondrial genome sequencing, and heteroplasmy levels were evaluated based on the variant allele frequency (VAF). Outdoor PM2.5 and NO2 concentrations were determined by a high-resolution spatial-temporal interpolation method based on the maternal residential address. Distributed lag linear models were used to determine sensitive time windows for the association between NO2 exposure and cord-blood mtDNA heteroplasmy. A 5 μg/m3 increment in NO2 was linked with MT-D-Loop16311T>C heteroplasmy from gestational weeks 17-25. MT-CYTB14766C>T was negatively associated with NO2 exposure in mid pregnancy, from weeks 14-17, and positively associated in late pregnancy, from weeks 31-36. No significant associations were observed with prenatal PM2.5 exposure. This is the first study to show that prenatal NO2 exposure is associated with cord-blood mitochondrial mutations and suggests two critical windows of exposure in mid-to-late pregnancy.
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Affiliation(s)
- Charlotte Cosemans
- Centre for Environmental Sciences, Hasselt University, 3590 Diepenbeek, Belgium
| | - Congrong Wang
- Centre for Environmental Sciences, Hasselt University, 3590 Diepenbeek, Belgium
| | - Dries S Martens
- Centre for Environmental Sciences, Hasselt University, 3590 Diepenbeek, Belgium
| | - Bram G Janssen
- Centre for Environmental Sciences, Hasselt University, 3590 Diepenbeek, Belgium
| | - Charlotte Vanpoucke
- Belgian Interregional Environment Agency, IRCEL-CELINE, 1000 Brussels, Belgium
| | - Wouter Lefebvre
- Flemish Institute for Technological Research, VITO, 2400 Mol, Belgium
| | - Karen Smeets
- 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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18
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Mitochondrial DNA Repair in Neurodegenerative Diseases and Ageing. Int J Mol Sci 2022; 23:ijms231911391. [PMID: 36232693 PMCID: PMC9569545 DOI: 10.3390/ijms231911391] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 09/20/2022] [Accepted: 09/21/2022] [Indexed: 11/17/2022] Open
Abstract
Mitochondria are the only organelles, along with the nucleus, that have their own DNA. Mitochondrial DNA (mtDNA) is a double-stranded circular molecule of ~16.5 kbp that can exist in multiple copies within the organelle. Both strands are translated and encode for 22 tRNAs, 2 rRNAs, and 13 proteins. mtDNA molecules are anchored to the inner mitochondrial membrane and, in association with proteins, form a structure called nucleoid, which exerts a structural and protective function. Indeed, mitochondria have evolved mechanisms necessary to protect their DNA from chemical and physical lesions such as DNA repair pathways similar to those present in the nucleus. However, there are mitochondria-specific mechanisms such as rapid mtDNA turnover, fission, fusion, and mitophagy. Nevertheless, mtDNA mutations may be abundant in somatic tissue due mainly to the proximity of the mtDNA to the oxidative phosphorylation (OXPHOS) system and, consequently, to the reactive oxygen species (ROS) formed during ATP production. In this review, we summarise the most common types of mtDNA lesions and mitochondria repair mechanisms. The second part of the review focuses on the physiological role of mtDNA damage in ageing and the effect of mtDNA mutations in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. Considering the central role of mitochondria in maintaining cellular homeostasis, the analysis of mitochondrial function is a central point for developing personalised medicine.
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19
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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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20
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Xu Q, Sun P, Feng C, Chen Q, Sun X, Chen Y, Tian G. Varying Clinical Phenotypes of Mitochondrial DNA T12811C Mutation: A Case Series Report. Front Med (Lausanne) 2022; 9:912103. [PMID: 35860740 PMCID: PMC9291510 DOI: 10.3389/fmed.2022.912103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 06/13/2022] [Indexed: 11/18/2022] Open
Abstract
The T12811C mitochondrial DNA (mtDNA) mutation has been reported in Leber hereditary optic neuropathy (LHON) previously, with vision loss as the main manifestation. The involvement of other organ systems, including the central and peripheral nervous system, heart, and extraocular muscles, has not been well described. This case series report investigated four patients with T12811C mtDNA mutation, verified through a next generation sequencing. Two male patients presented with bilateral subacute visual decrease combined with involvement of multiple organ systems: leukoencephalopathy, hypertrophic cardiomyopathy, neurosensory deafness, spinal cord lesion and peripheral neuropathies. Two female patients presented with progressive ptosis and ophthalmoplegia, one of whom also manifested optic atrophy. This study found out that patients harboring T12811C mtDNA mutation manifested not only as vision loss, but also as a multi-system disorder affecting the nervous system, heart, and extraocular muscles.
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Affiliation(s)
- Qingdan Xu
- Department of Ophthalmology, Eye and ENT Hospital, Fudan University, Shanghai, China
| | - Ping Sun
- Department of Ophthalmology, Eye and ENT Hospital, Fudan University, Shanghai, China
| | - Chaoyi Feng
- NHC Key Laboratory of Myopia, Chinese Academy of Medical Sciences, and Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China
| | - Qian Chen
- NHC Key Laboratory of Myopia, Chinese Academy of Medical Sciences, and Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China
| | - Xinghuai Sun
- Department of Ophthalmology, Eye and ENT Hospital, Fudan University, Shanghai, China
- NHC Key Laboratory of Myopia, Chinese Academy of Medical Sciences, and Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China
- State Key Laboratory of Medical Neurobiology, Institute of Brain Science, Fudan University, Shanghai, China
| | - Yuhong Chen
- Department of Ophthalmology, Eye and ENT Hospital, Fudan University, Shanghai, China
- NHC Key Laboratory of Myopia, Chinese Academy of Medical Sciences, and Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China
- *Correspondence: Yuhong Chen,
| | - Guohong Tian
- Department of Ophthalmology, Eye and ENT Hospital, Fudan University, Shanghai, China
- NHC Key Laboratory of Myopia, Chinese Academy of Medical Sciences, and Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China
- Guohong Tian,
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21
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Abstract
Abstract
Mitochondria, the cell powerhouse, are membrane-bound organelles present in the cytoplasm of almost all the eukaryotic cells. Their main function is to generate energy in the form of adenosine triphosphate (ATP). In addition, mitochondria store calcium for the cell signaling activities, generate heat, harbor pathways of intermediate metabolism and mediate cell growth and death. Primary mitochondrial diseases (MDs) form a clinically as well as genetically heterogeneous group of inherited disorders that result from the mitochondrial energetic metabolism malfunctions. The lifetime risk of the MDs development is estimated at 1:1470 of newborns, which makes them one of the most recurrent groups of inherited disorders with an important burden for society.
MDs are progressive with wide range of symptoms of variable severity that can emerge congenitally or anytime during the life. MD can be caused by mutations in the mitochondrial DNA (mtDNA) or nuclear DNA genes. Mutations inducing impairment of mitochondrial function have been found in more than 400 genes. Furthermore, more than 1200 nuclear genes, which could play a role in the MDs’ genetic etiology, are involved in the mitochondrial activities. However, the knowledge regarding the mechanism of the mitochondrial pathogenicity appears to be most essential for the development of effective patient’s treatment suffering from the mitochondrial disease. This is an overview update focused on the mitochondrial biology and the mitochondrial diseases associated genes.
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22
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Amor H, Hammadeh ME. A Systematic Review of the Impact of Mitochondrial Variations on Male Infertility. Genes (Basel) 2022; 13:genes13071182. [PMID: 35885965 PMCID: PMC9325252 DOI: 10.3390/genes13071182] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/24/2022] [Accepted: 06/28/2022] [Indexed: 02/01/2023] Open
Abstract
According to current estimates, infertility affects one in four couples trying to conceive. Primary or secondary infertility can be due either to both partners or only to the man or the woman. Up to 15% of infertility cases in men can be attributed to genetic factors that can lead to irreversible partial or complete spermatogenic arrest. The increased use of assisted reproductive technology (ART) has provided not only insights into the causes of male infertility but also afforded a diagnostic tool to detect and manage this condition among couples. Genes control a variety of physiological attributes, such as the hypothalamic–pituitary–gonadal axis, development, and germ cell differentiation. In the era of ART, it is important to understand the genetic basis of infertility so as to provide the most tailored therapy and counseling to couples. Genetic factors involved in male infertility can be chromosome abnormalities or single-gene disorders, mitochondrial DNA (mtDNA) mutations, Y-chromosome deletions, multifactorial disorders, imprinting disorders, or endocrine disorders of genetic origin. In this review, we discuss the role of mitochondria and the mitochondrial genome as an indicator of sperm quality and fertility.
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23
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Al-Kafaji G, Alharbi MA, Alkandari H, Salem AH, Bakhiet M. Analysis of the entire mitochondrial genome reveals Leber's hereditary optic neuropathy mitochondrial DNA mutations in an Arab cohort with multiple sclerosis. Sci Rep 2022; 12:11099. [PMID: 35773337 PMCID: PMC9246974 DOI: 10.1038/s41598-022-15385-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 06/23/2022] [Indexed: 11/25/2022] Open
Abstract
Several mitochondrial DNA (mtDNA) mutations of Leber's hereditary optic neuropathy (LHON) have been reported in patients with multiple sclerosis (MS) from different ethnicities. To further study the involvement of LHON mtDNA mutations in MS in the Arab population, we analyzed sequencing data of the entire mitochondrial genome from 47 unrelated Saudi individuals, 23 patients with relapse-remitting MS (RRMS) and 24 healthy controls. Ten LHON mutations/variants were detected in the patients but were absent in the controls. Of them, the common primary pathogenic mutation m.14484T>C and the rare mutation m.10237T>C were found in one patient, whereas the rare mutation m.9101T>C was found in another patient. The remaining were secondary single nucleotide variants (SNVs) found either in synergy with the primary/rare mutations or individually in other patients. Patients carrying LHON variants also exhibited distinct mtDNA variants throughout the mitochondrial genome, eight were previously reported in patients with LHON. Moreover, five other LHON-related SNVs differed significantly in their prevalence among patients and controls (P < 0.05). This study, the first to investigate LHON mtDNA mutations/variants in a Saudi cohort may suggest a role of these mutations/variants in the pathogenesis or genetic predisposition to MS, a possibility which needs to be explored further in a large-scale.
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Affiliation(s)
- Ghada Al-Kafaji
- Department of Molecular Medicine and Al-Jawhara Centre for Molecular Medicine, Genetics, and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain. .,Department of molecular Medicine and Al-Jawhara Centre for Molecular Medicine, Genetics and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Salmaniya Avenue, Building 293, Road 2904, Block 329, Manama, Kingdom of Bahrain.
| | - Maram A Alharbi
- College of Forensic Sciences, Naif Arab University for Security Sciences, Riyadh, Kingdom of Saudi Arabia
| | - Hasan Alkandari
- Department of Molecular Medicine and Al-Jawhara Centre for Molecular Medicine, Genetics, and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain
| | - Abdel Halim Salem
- Department of Anatomy, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain
| | - Moiz Bakhiet
- Department of Molecular Medicine and Al-Jawhara Centre for Molecular Medicine, Genetics, and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain
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24
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Gao XY, Yang T, Gu Y, Sun XH. Mitochondrial Dysfunction in Parkinson’s Disease: From Mechanistic Insights to Therapy. Front Aging Neurosci 2022; 14:885500. [PMID: 35795234 PMCID: PMC9250984 DOI: 10.3389/fnagi.2022.885500] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 05/30/2022] [Indexed: 12/02/2022] Open
Abstract
Parkinson’s disease (PD) is one of the most common neurodegenerative movement disorders worldwide. There are currently no cures or preventative treatments for PD. Emerging evidence indicates that mitochondrial dysfunction is closely associated with pathogenesis of sporadic and familial PD. Because dopaminergic neurons have high energy demand, cells affected by PD exhibit mitochondrial dysfunction that promotes the disease-defining the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The mitochondrion has a particularly important role as the cellular “powerhouse” of dopaminergic neurons. Therefore, mitochondria have become a promising therapeutic target for PD treatments. This review aims to describe mitochondrial dysfunction in the pathology of PD, outline the genes associated with familial PD and the factors related to sporadic PD, summarize current knowledge on mitochondrial quality control in PD, and give an overview of therapeutic strategies for targeting mitochondria in neuroprotective interventions in PD.
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Affiliation(s)
- Xiao-Yan Gao
- Department of Neurology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
- Science Experiment Center, China Medical University, Shenyang, China
| | - Tuo Yang
- Department of Neurology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Ying Gu
- Department of Neurology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Xiao-Hong Sun
- Department of Neurology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
- Science Experiment Center, China Medical University, Shenyang, China
- *Correspondence: Xiao-Hong Sun,
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25
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Thiankhaw K, Chattipakorn K, Chattipakorn SC, Chattipakorn N. Roles of humanin and derivatives on the pathology of neurodegenerative diseases and cognition. Biochim Biophys Acta Gen Subj 2022; 1866:130097. [DOI: 10.1016/j.bbagen.2022.130097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/13/2022] [Accepted: 01/20/2022] [Indexed: 10/19/2022]
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26
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Flønes IH, Tzoulis C. Mitochondrial Respiratory Chain Dysfunction—A Hallmark Pathology of Idiopathic Parkinson’s Disease? Front Cell Dev Biol 2022; 10:874596. [PMID: 35433702 PMCID: PMC9010539 DOI: 10.3389/fcell.2022.874596] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 03/10/2022] [Indexed: 12/21/2022] Open
Abstract
Parkinson’s disease (PD) is the most common age-dependent neurodegenerative synucleinopathy. Loss of dopaminergic neurons of the substantia nigra pars compacta, together with region- and cell-specific aggregations of α-synuclein are considered main pathological hallmarks of PD, but its etiopathogenesis remains largely unknown. Mitochondrial dysfunction, in particular quantitative and/or functional deficiencies of the mitochondrial respiratory chain (MRC), has been associated with the disease. However, after decades of research in this field, the pervasiveness and anatomical extent of MRC dysfunction in PD remain largely unknown. Moreover, it is not known whether the observed MRC defects are pathogenic, compensatory responses, or secondary epiphenomena. In this perspective, we give an overview of current evidence for MRC dysfunction in PD, highlight pertinent knowledge gaps, and propose potential strategies for future research.
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Affiliation(s)
- Irene H. Flønes
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway
- K.G Jebsen Center for Translational Research in Parkinson’s Disease, University of Bergen, Bergen, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Charalampos Tzoulis
- Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway
- K.G Jebsen Center for Translational Research in Parkinson’s Disease, University of Bergen, Bergen, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- *Correspondence: Charalampos Tzoulis,
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27
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Tzeng I. Role of mitochondria DNA A10398G polymorphism on development of Parkinson's disease: A PRISMA-compliant meta-analysis. J Clin Lab Anal 2022; 36:e24274. [PMID: 35146807 PMCID: PMC8906025 DOI: 10.1002/jcla.24274] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 01/24/2022] [Accepted: 01/25/2022] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Parkinson's disease (PD) is characterized by memory loss and multiple cognitive disorders caused primarily by neurodegeneration. However, the preventative effects of the mitochondrial A10398G DNA polymorphism remain controversial. This meta-analysis comprehensively assessed evidence on the influence of the mitochondrial DNA A10398G variant on PD development. METHODS The PubMed, EMBASE, EBSCO, Springer Link, and Web of Science databases were searched from inception to May 31, 2020. We used a pooled model with random effects to explore the effect of A10398G on the development of PD. Stata MP version 14.0 was used to calculate the odds ratios and 95% confidence intervals (CIs) from the eligible studies to assess the impact of mitochondrial DNA A10398G on PD development. RESULTS The overall survey of the populations showed no significant association between mitochondrial DNA A10398G polymorphism (G allele compared to A allele) and PD (odds ratio = 0.85, 95% CI = 0.70-1.04, p = 0.111); however, a significant association between the mutation and PD was observed in the Caucasian population (odds ratio = 0.71, 95% CI = 0.58-0.87, p = 0.001). A neutral effect was observed in the Asian population (odds ratio = 1.10, 95% CI = 0.94-1.28, p = 0.242). CONCLUSIONS The results of this meta-analysis showed the potential protective effect of the mitochondrial DNA A10398G polymorphism on the risk of developing PD in the Caucasian population. Studies with better designs and larger samples with intensive work are required to validate these results.
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Affiliation(s)
- I‐Shiang Tzeng
- Department of ResearchTaipei Tzu Chi HospitalBuddhist Tzu Chi Medical FoundationNew Taipei CityTaiwan
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28
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Fonseca Cabral G, Schaan AP, Cavalcante GC, Sena-dos-Santos C, de Souza TP, Souza Port’s NM, dos Santos Pinheiro JA, Ribeiro-dos-Santos Â, Vidal AF. Nuclear and Mitochondrial Genome, Epigenome and Gut Microbiome: Emerging Molecular Biomarkers for Parkinson's Disease. Int J Mol Sci 2021; 22:9839. [PMID: 34576000 PMCID: PMC8471599 DOI: 10.3390/ijms22189839] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 06/23/2021] [Accepted: 06/28/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Parkinson's disease (PD) is currently the second most common neurodegenerative disorder, burdening about 10 million elderly individuals worldwide. The multifactorial nature of PD poses a difficult obstacle for understanding the mechanisms involved in its onset and progression. Currently, diagnosis depends on the appearance of clinical signs, some of which are shared among various neurologic disorders, hindering early diagnosis. There are no effective tools to prevent PD onset, detect the disease in early stages or accurately report the risk of disease progression. Hence, there is an increasing demand for biomarkers that may identify disease onset and progression, as treatment-based medicine may not be the best approach for PD. Over the last few decades, the search for molecular markers to predict susceptibility, aid in accurate diagnosis and evaluate the progress of PD have intensified, but strategies aimed to improve individualized patient care have not yet been established. CONCLUSIONS Genomic variation, regulation by epigenomic mechanisms, as well as the influence of the host gut microbiome seem to have a crucial role in the onset and progress of PD, thus are considered potential biomarkers. As such, the human nuclear and mitochondrial genome, epigenome, and the host gut microbiome might be the key elements to the rise of personalized medicine for PD patients.
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Affiliation(s)
- Gleyce Fonseca Cabral
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, R. Augusto Correa, Belém 66075-110, Brazil; (G.F.C.); (A.P.S.); (G.C.C.); (C.S.-d.-S.); (T.P.d.S.); (J.A.d.S.P.)
| | - Ana Paula Schaan
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, R. Augusto Correa, Belém 66075-110, Brazil; (G.F.C.); (A.P.S.); (G.C.C.); (C.S.-d.-S.); (T.P.d.S.); (J.A.d.S.P.)
| | - Giovanna C. Cavalcante
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, R. Augusto Correa, Belém 66075-110, Brazil; (G.F.C.); (A.P.S.); (G.C.C.); (C.S.-d.-S.); (T.P.d.S.); (J.A.d.S.P.)
| | - Camille Sena-dos-Santos
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, R. Augusto Correa, Belém 66075-110, Brazil; (G.F.C.); (A.P.S.); (G.C.C.); (C.S.-d.-S.); (T.P.d.S.); (J.A.d.S.P.)
| | - Tatiane Piedade de Souza
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, R. Augusto Correa, Belém 66075-110, Brazil; (G.F.C.); (A.P.S.); (G.C.C.); (C.S.-d.-S.); (T.P.d.S.); (J.A.d.S.P.)
| | - Natacha M. Souza Port’s
- Laboratório de Neurofarmacologia Molecular, Universidade de São Paulo, São Paulo 05508-000, Brazil;
| | - Jhully Azevedo dos Santos Pinheiro
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, R. Augusto Correa, Belém 66075-110, Brazil; (G.F.C.); (A.P.S.); (G.C.C.); (C.S.-d.-S.); (T.P.d.S.); (J.A.d.S.P.)
| | - Ândrea Ribeiro-dos-Santos
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, R. Augusto Correa, Belém 66075-110, Brazil; (G.F.C.); (A.P.S.); (G.C.C.); (C.S.-d.-S.); (T.P.d.S.); (J.A.d.S.P.)
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará–R. dos Mundurucus, Belém 66073-000, Brazil
- Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Pará, R. Augusto Correa, Belém 66075-110, Brazil
| | - Amanda F. Vidal
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, R. Augusto Correa, Belém 66075-110, Brazil; (G.F.C.); (A.P.S.); (G.C.C.); (C.S.-d.-S.); (T.P.d.S.); (J.A.d.S.P.)
- Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Pará, R. Augusto Correa, Belém 66075-110, Brazil
- ITVDS—Instituto Tecnológico Vale Desenvolvimento Sustentável–R. Boaventura da Silva, Belém 66055-090, Brazil
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29
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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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30
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Nathanson SD, Detmar M, Padera TP, Yates LR, Welch DR, Beadnell TC, Scheid AD, Wrenn ED, Cheung K. Mechanisms of breast cancer metastasis. Clin Exp Metastasis 2021; 39:117-137. [PMID: 33950409 PMCID: PMC8568733 DOI: 10.1007/s10585-021-10090-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 03/20/2021] [Indexed: 02/06/2023]
Abstract
Invasive breast cancer tends to metastasize to lymph nodes and systemic sites. The management of metastasis has evolved by focusing on controlling the growth of the disease in the breast/chest wall, and at metastatic sites, initially by surgery alone, then by a combination of surgery with radiation, and later by adding systemic treatments in the form of chemotherapy, hormone manipulation, targeted therapy, immunotherapy and other treatments aimed at inhibiting the proliferation of cancer cells. It would be valuable for us to know how breast cancer metastasizes; such knowledge would likely encourage the development of therapies that focus on mechanisms of metastasis and might even allow us to avoid toxic therapies that are currently used for this disease. For example, if we had a drug that targeted a gene that is critical for metastasis, we might even be able to cure a vast majority of patients with breast cancer. By bringing together scientists with expertise in molecular aspects of breast cancer metastasis, and those with expertise in the mechanical aspects of metastasis, this paper probes interesting aspects of the metastasis cascade, further enlightening us in our efforts to improve the outcome from breast cancer treatments.
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Affiliation(s)
- S David Nathanson
- Department of Surgery, Henry Ford Cancer Institute, 2799 W Grand Boulevard, Detroit, MI, USA.
| | - Michael Detmar
- Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland
| | - Timothy P Padera
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Danny R Welch
- Department of Cancer Biology, University of Kansas Medical Center and University of Kansas Cancer Center, Kansas City, KS, USA
| | - Thomas C Beadnell
- Department of Cancer Biology, University of Kansas Medical Center and University of Kansas Cancer Center, Kansas City, KS, USA
| | - Adam D Scheid
- Department of Cancer Biology, University of Kansas Medical Center and University of Kansas Cancer Center, Kansas City, KS, USA
| | - Emma D Wrenn
- Translational Research Program, Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA
| | - Kevin Cheung
- Translational Research Program, Public Health Sciences and Human Biology Divisions, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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31
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González MDM, Santos C, Alarcón C, Ramos A, Cos M, Catalano G, Acebes JJ, Aluja MP. Mitochondrial DNA haplogroups J and T increase the risk of glioma. Mitochondrion 2021; 58:95-101. [PMID: 33675980 DOI: 10.1016/j.mito.2021.02.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 01/29/2021] [Accepted: 02/18/2021] [Indexed: 12/21/2022]
Abstract
The presence of different sets of mitochondrial polymorphisms generated by the accumulation of mutations in different maternal lineages has allowed differentiating mitochondrial haplogroups in human populations. These polymorphisms, in turn, may have effects at the phenotypic level, considering a possible contribution of these germinal mutations to the development of certain diseases such as cancer. The main goal of the present study is to establish a possible association between mitochondrial haplogroups and the risk of suffering glioma. Blood samples were obtained from 32 patients from Catalonia (Spain) diagnosed with different grades of glioma (II, III and IV), according to the World Health Organization. The mitochondrial genome was amplified and sequenced using MiSeq 2000 (Illumina). The HaploGrep tool implemented in mtDNA-Server v.1.0.5 was used for the identification of mitochondrial haplogroups. Data obtained in the present study was further pooled with data from previous European studies including glioma patients from Galicia (Spain) and Italy. Results for the Catalonian samples showed an association between individuals with haplogroup J and the increased risk of suffering glioma, with a significant increase of the frequency of individuals with this haplogroup (25%) regarding the general population (7%). Combining different sets of patients with European origin, it appears that individuals with haplogroups J and T have a significantly higher risk of suffering glioma (p < 0.001; OR: 2.407 and p = 0.007; OR: 1.82, respectively). This is the first study that establishes an association between different mitochondrial haplogroups and the risk of suffering glioma, highlighting the role of mitochondrial variants in this disease.
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Affiliation(s)
- María Del Mar González
- Unitat d'Antropologia Biològica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain; GREAB - Research Group in Biological Anthropology, Generalitat de Catalunya, Spain
| | - Cristina Santos
- Unitat d'Antropologia Biològica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain; GREAB - Research Group in Biological Anthropology, Generalitat de Catalunya, Spain
| | - Carlos Alarcón
- Servicio de Neurocirugía, Hospital Universitari Mútua Terrassa, Terrassa, Barcelona, Spain; Servicio de Neurocirugía, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain
| | - Amanda Ramos
- Unitat d'Antropologia Biològica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain; GREAB - Research Group in Biological Anthropology, Generalitat de Catalunya, Spain
| | - Mònica Cos
- Sección de Neurorradiología, Institut de Diagnòstic per la Imatge, Centre Bellvitge, Hospitalet de Llobregat, Barcelona, Spain
| | - Giulio Catalano
- Unitat d'Antropologia Biològica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain; Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche, Università degli Studi di Palermo, Palermo, Italy
| | - Juan José Acebes
- Servicio de Neurocirugía, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain
| | - Maria Pilar Aluja
- Unitat d'Antropologia Biològica, Departament de Biologia Animal, Biologia Vegetal i Ecologia, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain; GREAB - Research Group in Biological Anthropology, Generalitat de Catalunya, Spain
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32
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Lechuga-Vieco AV, Justo-Méndez R, Enríquez JA. Not all mitochondrial DNAs are made equal and the nucleus knows it. IUBMB Life 2020; 73:511-529. [PMID: 33369015 PMCID: PMC7985871 DOI: 10.1002/iub.2434] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 12/06/2020] [Accepted: 12/09/2020] [Indexed: 12/13/2022]
Abstract
The oxidative phosphorylation (OXPHOS) system is the only structure in animal cells with components encoded by two genomes, maternally transmitted mitochondrial DNA (mtDNA), and biparentally transmitted nuclear DNA (nDNA). MtDNA‐encoded genes have to physically assemble with their counterparts encoded in the nucleus to build together the functional respiratory complexes. Therefore, structural and functional matching requirements between the protein subunits of these molecular complexes are rigorous. The crosstalk between nDNA and mtDNA needs to overcome some challenges, as the nuclear‐encoded factors have to be imported into the mitochondria in a correct quantity and match the high number of organelles and genomes per mitochondria that encode and synthesize their own components locally. The cell is able to sense the mito‐nuclear match through changes in the activity of the OXPHOS system, modulation of the mitochondrial biogenesis, or reactive oxygen species production. This implies that a complex signaling cascade should optimize OXPHOS performance to the cellular‐specific requirements, which will depend on cell type, environmental conditions, and life stage. Therefore, the mitochondria would function as a cellular metabolic information hub integrating critical information that would feedback the nucleus for it to respond accordingly. Here, we review the current understanding of the complex interaction between mtDNA and nDNA.
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Affiliation(s)
- Ana Victoria Lechuga-Vieco
- Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.,MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Raquel Justo-Méndez
- Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
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33
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Mitochondrial Dysfunction in Parkinson's Disease: Focus on Mitochondrial DNA. Biomedicines 2020; 8:biomedicines8120591. [PMID: 33321831 PMCID: PMC7763033 DOI: 10.3390/biomedicines8120591] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/05/2020] [Accepted: 12/08/2020] [Indexed: 12/14/2022] Open
Abstract
Mitochondria, the energy stations of the cell, are the only extranuclear organelles, containing their own (mitochondrial) DNA (mtDNA) and the protein synthesizing machinery. The location of mtDNA in close proximity to the oxidative phosphorylation system of the inner mitochondrial membrane, the main source of reactive oxygen species (ROS), is an important factor responsible for its much higher mutation rate than nuclear DNA. Being more vulnerable to damage than nuclear DNA, mtDNA accumulates mutations, crucial for the development of mitochondrial dysfunction playing a key role in the pathogenesis of various diseases. Good evidence exists that some mtDNA mutations are associated with increased risk of Parkinson’s disease (PD), the movement disorder resulted from the degenerative loss of dopaminergic neurons of substantia nigra. Although their direct impact on mitochondrial function/dysfunction needs further investigation, results of various studies performed using cells isolated from PD patients or their mitochondria (cybrids) suggest their functional importance. Studies involving mtDNA mutator mice also demonstrated the importance of mtDNA deletions, which could also originate from abnormalities induced by mutations in nuclear encoded proteins needed for mtDNA replication (e.g., polymerase γ). However, proteomic studies revealed only a few mitochondrial proteins encoded by mtDNA which were downregulated in various PD models. This suggests nuclear suppression of the mitochondrial defects, which obviously involve cross-talk between nuclear and mitochondrial genomes for maintenance of mitochondrial functioning.
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34
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Ito H, Kurokawa H, Matsui H. Mitochondrial reactive oxygen species and heme, non-heme iron metabolism. Arch Biochem Biophys 2020; 700:108695. [PMID: 33232715 DOI: 10.1016/j.abb.2020.108695] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 11/17/2020] [Accepted: 11/18/2020] [Indexed: 12/13/2022]
Abstract
Mitochondria are one of the most important organelles for eukaryotes, including humans, to produce energy. In the energy-producing process, mitochondria constantly generate reactive oxygen species as a by-product of electrons leaking out from the electron transport chain react with oxygen. The active oxygen, in turn, plays pivotal roles in mediating several signalings, including those that are implicated in the development of some diseases such as neurodegenerative disease, cardiovascular disease, and carcinogenesis. This signaling, derived from mitochondrial reactive oxygen species, also affects intracellular iron homeostasis by regulating the expression of transporters. Heme iron is incorporated into cells through HCP1, and non-heme iron is transported by DMT1 in absorptive cells. Intracellular iron is exported by ferroportin and bound with transferrin. In most types of cell including erythrocyte, transferrin-bound iron is incorporated through transferrin-transferrin receptor system. We previously reported that the expression of HCP1 and DMT1 was upregulated in cancer cells and that overexpression of manganese superoxide dismutase, which is a mitochondrial-specific superoxide dismutase, downregulated the expression. These findings indicate that mitochondrial reactive oxygen species is associated with iron-related oxidative reactions. Recently, a mitochondria-specific iron transporter, mitoferrin, was identified, and the relationships among mitochondria, iron transportation, and diseases have been increasingly clarified.
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Affiliation(s)
- Hiromu Ito
- Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan; Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Hiromi Kurokawa
- Algae Biomass research and development, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Hirofumi Matsui
- Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan; Algae Biomass research and development, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
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35
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Tasdogan A, McFadden DG, Mishra P. Mitochondrial DNA Haplotypes as Genetic Modifiers of Cancer. Trends Cancer 2020; 6:1044-1058. [PMID: 32980320 DOI: 10.1016/j.trecan.2020.08.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 08/05/2020] [Accepted: 08/18/2020] [Indexed: 02/06/2023]
Abstract
Mitochondria play an essential role in cellular metabolism, generation of reactive oxygen species (ROS), and the initiation of apoptosis. These properties enable mitochondria to be crucial integrators in the pathways of tumorigenesis. An open question is to what extent variation in the mitochondrial genome (mtDNA) contributes to the biological heterogeneity observed in human tumors. In this review, we summarize our current understanding of the role of mtDNA genetics in relation to human cancers.
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Affiliation(s)
- Alpaslan Tasdogan
- Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - David G McFadden
- Department of Internal Medicine, Department of Biochemistry, Simmons Comprehensive Cancer Center, Division of Endocrinology, Program in Molecular Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Prashant Mishra
- Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics, Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
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36
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Brown JA, Sammy MJ, Ballinger SW. An evolutionary, or "Mitocentric" perspective on cellular function and disease. Redox Biol 2020; 36:101568. [PMID: 32512469 PMCID: PMC7281786 DOI: 10.1016/j.redox.2020.101568] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 05/01/2020] [Accepted: 05/05/2020] [Indexed: 12/11/2022] Open
Abstract
The incidence of common, metabolic diseases (e.g. obesity, cardiovascular disease, diabetes) with complex genetic etiology has been steadily increasing nationally and globally. While identification of a genetic model that explains susceptibility and risk for these diseases has been pursued over several decades, no clear paradigm has yet been found to disentangle the genetic basis of polygenic/complex disease development. Since the evolution of the eukaryotic cell involved a symbiotic interaction between the antecedents of the mitochondrion and nucleus (which itself is a genetic hybrid), we suggest that this history provides a rational basis for investigating whether genetic interaction and co-evolution of these genomes still exists. We propose that both mitochondrial and Mendelian, or "mito-Mendelian" genetics play a significant role in cell function, and thus disease risk. This paradigm contemplates the natural variation and co-evolution of both mitochondrial and nuclear DNA backgrounds on multiple mitochondrial functions that are discussed herein, including energy production, cell signaling and immune response, which collectively can influence disease development. At the nexus of these processes is the economy of mitochondrial metabolism, programmed by both mitochondrial and nuclear genomes.
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Affiliation(s)
- Jamelle A Brown
- Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Melissa J Sammy
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Scott W Ballinger
- Department of Pathology, Division of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
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37
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Karakaidos P, Rampias T. Mitonuclear Interactions in the Maintenance of Mitochondrial Integrity. Life (Basel) 2020; 10:life10090173. [PMID: 32878185 PMCID: PMC7555762 DOI: 10.3390/life10090173] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 08/28/2020] [Indexed: 12/27/2022] Open
Abstract
In eukaryotic cells, mitochondria originated in an α-proteobacterial endosymbiont. Although these organelles harbor their own genome, the large majority of genes, originally encoded in the endosymbiont, were either lost or transferred to the nucleus. As a consequence, mitochondria have become semi-autonomous and most of their processes require the import of nuclear-encoded components to be functional. Therefore, the mitochondrial-specific translation has evolved to be coordinated by mitonuclear interactions to respond to the energetic demands of the cell, acquiring unique and mosaic features. However, mitochondrial-DNA-encoded genes are essential for the assembly of the respiratory chain complexes. Impaired mitochondrial function due to oxidative damage and mutations has been associated with numerous human pathologies, the aging process, and cancer. In this review, we highlight the unique features of mitochondrial protein synthesis and provide a comprehensive insight into the mitonuclear crosstalk and its co-evolution, as well as the vulnerabilities of the animal mitochondrial genome.
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38
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Vianello C, Cocetta V, Caicci F, Boldrin F, Montopoli M, Martinuzzi A, Carelli V, Giacomello M. Interaction Between Mitochondrial DNA Variants and Mitochondria/Endoplasmic Reticulum Contact Sites: A Perspective Review. DNA Cell Biol 2020; 39:1431-1443. [PMID: 32598172 DOI: 10.1089/dna.2020.5614] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Mitochondria contain their own genome, mitochondrial DNA (mtDNA), essential to support their fundamental intracellular role in ATP production and other key metabolic and homeostatic pathways. Mitochondria are highly dynamic organelles that communicate with all the other cellular compartments, through sites of high physical proximity. Among all, their crosstalk with the endoplasmic reticulum (ER) appears particularly important as its derangement is tightly implicated with several human disorders. Population-specific mtDNA variants clustered in defining the haplogroups have been shown to exacerbate or mitigate these pathological conditions. The exact mechanisms of the mtDNA background-modifying effect are not completely clear and a possible explanation is the outcome of mitochondrial efficiency on retrograde signaling to the nucleus. However, the possibility that different haplogroups shape the proximity and crosstalk between mitochondria and the ER has never been proposed neither investigated. In this study, we pose and discuss this question and provide preliminary data to answer it. Besides, we also address the possibility that single, disease-causing mtDNA point mutations may act also by reshaping organelle communication. Overall, this perspective review provides a theoretical platform for future studies on the interaction between mtDNA variants and organelle contact sites.
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Affiliation(s)
| | - Veronica Cocetta
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | | | | | - Monica Montopoli
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.,VIMM-Veneto Institute of Molecular Medicine, Padova, Italy
| | - Andrea Martinuzzi
- Department of Neurorehabilitation, IRCCS "E. Medea" Scientific Institute, Conegliano Research Center, Treviso, Italy
| | - Valerio Carelli
- Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.,IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Italy
| | - Marta Giacomello
- Department of Biology, University of Padova, Padova, Italy.,Department of Biomedical Sciences, University of Padova, Padova, Italy
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Xiao F, Li M, Wang J, Liu J, Li J, Fang H, Lyu J, Shen L. Association between mitochondrial DNA haplogroup variation and coronary artery disease. Nutr Metab Cardiovasc Dis 2020; 30:960-966. [PMID: 32402592 DOI: 10.1016/j.numecd.2020.03.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 03/01/2020] [Accepted: 03/10/2020] [Indexed: 11/30/2022]
Abstract
BACKGROUND AND AIMS Mitochondrial DNA (mtDNA) haplogroups have been associated with the development of coronary artery disease (CAD) in European populations. However, the specific mtDNA haplogroups associated with CAD have not been investigated in Chinese populations. METHODS AND RESULTS Here, we carried out a case-control study including 1036 and 481 CAD patients and 973 and 511 geographically matched asymptomatic control subjects in southern and northern China, respectively. After adjusting for age and gender, our results indicated that mtDNA haplogroups are not associated with the occurrence of CAD and its subcategories, acute coronary syndromes and stable coronary heart disease, in both southern and northern Chinese populations. By focusing on the southern Chinese population, we further revealed that mtDNA haplogroups are not associated with CAD severity. Type 2 diabetes (T2D) and hypertension are two key driving factors for the development of CAD, nonetheless, we found that the frequencies of the 12 studied mtDNA haplogroups did not differ between patients with and without T2D or hypertension. CONCLUSION mtDNA haplogroups are not associated with the occurrence of CAD or its subcategories in Chinese populations. Other factors such as environment and nuclear genetic background may contribute to the occurrence of CAD.
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Affiliation(s)
- Fangyi Xiao
- Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Meinan Li
- 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
| | - Junyi 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
| | - Jiangtao Liu
- Department of Orthopedics Surgery, Ningbo HwaMei Hospital, University of Chinese Academy of Science, Ningbo, Zhejiang, China
| | - Jin Li
- 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
| | - 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
| | - 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; College of Laboratory Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China.
| | - Lijun Shen
- Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, Zhejiang, China; 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.
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40
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Mehrpour S, Rodrigues CR, Ferreira RC, Briones MRDS, Oliveira ASB. Hardy-Weinberg Equilibrium in different mitochondrial haplogroups of four genes associated with neuroprotection and neurodegeneration. ARQUIVOS DE NEURO-PSIQUIATRIA 2020; 78:269-276. [PMID: 32490968 DOI: 10.1590/0004-282x20200002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 12/09/2019] [Indexed: 11/21/2022]
Abstract
BACKGROUND Malfunctioning or damaged mitochondria result in altered energy metabolism, redox equilibrium, and cellular dynamics and is a central point in the pathogenesis of neurological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic Lateral Sclerosis. Therefore, it is of utmost importance to identify mitochondrial genetic susceptibility markers for neurodegenerative diseases. Potential markers include the respiratory chain enzymes Riboflavin kinase (RFK), Flavin adenine dinucleotide synthetase (FAD), Succinate dehydrogenase B subunit (SDHB), and Cytochrome C1 (CYC1). These enzymes are associated with neuroprotection and neurodegeneration. OBJECTIVE To test if variants in genes RFK, FAD, SDHB and CYC1 deviate from Hardy-Weinberg Equilibrium (HWE) in different human mitochondrial haplogroups. METHODS Sequence variants in genes RFK, FAD, SDHB and CYC1 of 2,504 non-affected individuals of the 1,000 genomes project were used for mitochondrial haplogroup assessment and HWE calculations in different mitochondrial haplogroups. RESULTS We show that RFK variants deviate from HWE in haplogroups G, H, L, V and W, variants of FAD in haplogroups B, J, L, U, and C, variants of SDHB in relation to the C, W, and A and CYC1 variants in B, L, U, D, and T. HWE deviation indicates action of selective pressures and genetic drift. CONCLUSIONS HWE deviation of particular variants in relation to global populational HWE, could be, at least in part, associated with the differential susceptibility of specific populations and ethnicities to neurodegenerative diseases. Our data might contribute to the epidemiology and diagnostic/prognostic methods for neurodegenerative diseases.
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Affiliation(s)
- Sheida Mehrpour
- Departamento de Neurologia e Neurocirurgia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Camila Ronqui Rodrigues
- Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Renata Carmona Ferreira
- Departamento de Neurologia e Neurocirurgia, Universidade Federal de São Paulo, São Paulo, SP, Brazil.,Bridges Genomics, São Paulo SP, Brazil
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41
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Monzio Compagnoni G, Di Fonzo A, Corti S, Comi GP, Bresolin N, Masliah E. The Role of Mitochondria in Neurodegenerative Diseases: the Lesson from Alzheimer's Disease and Parkinson's Disease. Mol Neurobiol 2020; 57:2959-2980. [PMID: 32445085 DOI: 10.1007/s12035-020-01926-1] [Citation(s) in RCA: 225] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 04/22/2020] [Indexed: 12/15/2022]
Abstract
Although the pathogenesis of neurodegenerative diseases is still widely unclear, various mechanisms have been proposed and several pieces of evidence are supportive for an important role of mitochondrial dysfunction. The present review provides a comprehensive and up-to-date overview about the role of mitochondria in the two most common neurodegenerative disorders: Alzheimer's disease (AD) and Parkinson's disease (PD). Mitochondrial involvement in AD is supported by clinical features like reduced glucose and oxygen brain metabolism and by numerous microscopic and molecular findings, including altered mitochondrial morphology, impaired respiratory chain function, and altered mitochondrial DNA. Furthermore, amyloid pathology and mitochondrial dysfunction seem to be bi-directionally correlated. Mitochondria have an even more remarkable role in PD. Several hints show that respiratory chain activity, in particular complex I, is impaired in the disease. Mitochondrial DNA alterations, involving deletions, point mutations, depletion, and altered maintenance, have been described. Mutations in genes directly implicated in mitochondrial functioning (like Parkin and PINK1) are responsible for rare genetic forms of the disease. A close connection between alpha-synuclein accumulation and mitochondrial dysfunction has been observed. Finally, mitochondria are involved also in atypical parkinsonisms, in particular multiple system atrophy. The available knowledge is still not sufficient to clearly state whether mitochondrial dysfunction plays a primary role in the very initial stages of these diseases or is secondary to other phenomena. However, the presented data strongly support the hypothesis that whatever the initial cause of neurodegeneration is, mitochondrial impairment has a critical role in maintaining and fostering the neurodegenerative process.
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Affiliation(s)
- Giacomo Monzio Compagnoni
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. .,Department of Neurology, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy. .,Department of Neurology, Khurana Laboratory, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
| | - Alessio Di Fonzo
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Stefania Corti
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Neuroscience Section, Dino Ferrari Center, University of Milan, Milan, Italy
| | - Giacomo P Comi
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Neuroscience Section, Dino Ferrari Center, University of Milan, Milan, Italy
| | - Nereo Bresolin
- IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Neuroscience Section, Dino Ferrari Center, University of Milan, Milan, Italy
| | - Eliezer Masliah
- Division of Neuroscience and Laboratory of Neurogenetics, National Institute on Aging, National Institute of Health, Bethesda, MD, USA
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Sukhorukov VS, Voronkova AS, Litvinova NA, Baranich TI, Illarioshkin SN. The Role of Mitochondrial DNA Individuality in the Pathogenesis of Parkinson’s Disease. RUSS J GENET+ 2020. [DOI: 10.1134/s1022795420040146] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Martín-Jiménez R, Lurette O, Hebert-Chatelain E. Damage in Mitochondrial DNA Associated with Parkinson's Disease. DNA Cell Biol 2020; 39:1421-1430. [PMID: 32397749 DOI: 10.1089/dna.2020.5398] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Mitochondria are the only organelles that contain their own genetic material (mtDNA). Mitochondria are involved in several key physiological functions, including ATP production, Ca2+ homeostasis, and metabolism of neurotransmitters. Since these organelles perform crucial processes to maintain neuronal homeostasis, mitochondrial dysfunctions can lead to various neurodegenerative diseases. Several mitochondrial proteins involved in ATP production are encoded by mtDNA. Thus, any mtDNA alteration can ultimately lead to mitochondrial dysfunction and cell death. Accumulation of mutations, deletions, and rearrangements in mtDNA has been observed in animal models and patients suffering from Parkinson's disease (PD). Also, specific inherited variations associated with mtDNA genetic groups (known as mtDNA haplogroups) are associated with lower or higher risk of developing PD. Consequently, mtDNA alterations should now be considered important hallmarks of this neurodegenerative disease. This review provides an update about the role of mtDNA alterations in the physiopathology of PD.
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Affiliation(s)
- Rebeca Martín-Jiménez
- Department of Biology and Université de Moncton, Moncton, Canada
- Canada Research Chair in Mitochondrial Signaling and Physiopathology, Université de Moncton, Moncton, Canada
| | - Olivier Lurette
- Department of Biology and Université de Moncton, Moncton, Canada
- Canada Research Chair in Mitochondrial Signaling and Physiopathology, Université de Moncton, Moncton, Canada
| | - Etienne Hebert-Chatelain
- Department of Biology and Université de Moncton, Moncton, Canada
- Canada Research Chair in Mitochondrial Signaling and Physiopathology, Université de Moncton, Moncton, Canada
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44
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Costa G, Sisalli MJ, Simola N, Della Notte S, Casu MA, Serra M, Pinna A, Feliciello A, Annunziato L, Scorziello A, Morelli M. Gender Differences in Neurodegeneration, Neuroinflammation and Na +-Ca 2+ Exchangers in the Female A53T Transgenic Mouse Model of Parkinson's Disease. Front Aging Neurosci 2020; 12:118. [PMID: 32477098 PMCID: PMC7232579 DOI: 10.3389/fnagi.2020.00118] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 04/08/2020] [Indexed: 12/20/2022] Open
Abstract
Twelve-month-old male mice expressing the human A53T variant of α-synuclein (A53T) develop dopamine neuron degeneration, neuroinflammation, and motor deficits, along with dysfunctions of the mitochondrial Na+-Ca2+ exchanger (NCX) isoforms 1 (NCX1) and 3 (NCX3) in the nigrostriatal system. Since gender is thought to play a role in the etiology of Parkinson's disease (PD), we characterized neurochemical and behavioral alterations in 12-month-old female A53T transgenic mice. We investigated the presence of dopaminergic degeneration, astrogliosis and microgliosis using immunohistochemistry for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule-1 (IBA-1) in both the substantia nigra pars compacta (SNc) and striatum. In the same regions, we also evaluated the co-localization of NCX1 in cells positive for IBA-1 and the co-localization of NCX3 in TH-positive neurons and fibers. Furthermore, in both male and female mice, we performed motor (beam walking and pole tests) and memory [novel object recognition (NOR) and spontaneous alternation] tasks, together with tests to evaluate peripheral deficits (olfactory and stool collection tests). Female A53T transgenic mice displayed degeneration of nigral dopaminergic neurons, but neither microgliosis nor astrogliosis in the SNc and striatum. Moreover, female A53T transgenic mice displayed co-localization between NCX1 and IBA-1 positive cells in the striatum but not SNc, whereas NCX3 did not co-localize with either TH-positive terminals or neuronal bodies in the nigrostriatal system. Furthermore, female A53T transgenic mice showed increased crossing time in the beam walking test, but no impairments in the pole or memory tests, and in tests that evaluated peripheral deficits, whereas male A53T transgenic mice displayed motor, memory and peripheral deficits. Immunohistochemical and behavioral results obtained here in the female mice differ from those previously observed in males, and suggest a dissimilar influence of NCX1 and NCX3 on dopaminergic function in female and male A53T transgenic mice, strengthening the validity of these mice as a model for studying the etiological factors of PD.
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Affiliation(s)
- Giulia Costa
- Department of Biomedical Sciences, Section of Neuroscience, University of Cagliari, Cagliari, Italy
| | - Maria Jose Sisalli
- Department of Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy
| | - Nicola Simola
- Department of Biomedical Sciences, Section of Neuroscience, University of Cagliari, Cagliari, Italy.,National Institute of Neuroscience (INN), University of Cagliari, Cagliari, Italy
| | - Salvatore Della Notte
- Department of Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy
| | - Maria Antonietta Casu
- National Research Council of Italy, Institute of Translational Pharmacology, UOS of Cagliari, Scientific and Technological Park of Sardinia POLARIS, Pula, Italy
| | - Marcello Serra
- Department of Biomedical Sciences, Section of Neuroscience, University of Cagliari, Cagliari, Italy
| | - Annalisa Pinna
- National Research Council of Italy, Neuroscience Institute, Cagliari, Italy
| | - Antonio Feliciello
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy
| | - Lucio Annunziato
- SDN Research Institute Diagnostics and Nuclear (IRCCS SDN), Naples, Italy
| | - Antonella Scorziello
- Department of Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy
| | - Micaela Morelli
- Department of Biomedical Sciences, Section of Neuroscience, University of Cagliari, Cagliari, Italy.,National Institute of Neuroscience (INN), University of Cagliari, Cagliari, Italy.,National Research Council of Italy, Neuroscience Institute, Cagliari, Italy
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45
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Biocomplexity and Fractality in the Search of Biomarkers of Aging and Pathology: Mitochondrial DNA Profiling of Parkinson's Disease. Int J Mol Sci 2020; 21:ijms21051758. [PMID: 32143500 PMCID: PMC7084552 DOI: 10.3390/ijms21051758] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 02/26/2020] [Accepted: 03/01/2020] [Indexed: 12/18/2022] Open
Abstract
Increasing evidence implicates mitochondrial dysfunction in the etiology of Parkinson's disease (PD). Mitochondrial DNA (mtDNA) mutations are considered a possible cause and this mechanism might be shared with the aging process and with other age-related neurodegenerative disorders such as Alzheimer's disease (AD). We have recently proposed a computerized method for mutated mtDNA characterization able to discriminate between AD and aging. The present study deals with mtDNA mutation-based profiling of PD. Peripheral blood mtDNA sequences from late-onset PD patients and age-matched controls were analyzed and compared to the revised Cambridge Reference Sequence (rCRS). The chaos game representation (CGR) method, modified to visualize heteroplasmic mutations, was used to display fractal properties of mtDNA sequences and fractal lacunarity analysis was applied to quantitatively characterize PD based on mtDNA mutations. Parameter β, from the hyperbola model function of our lacunarity method, was statistically different between PD and control groups when comparing mtDNA sequence frames corresponding to GenBank np 5713-9713. Our original method, based on CGR and lacunarity analysis, represents a useful tool to analyze mtDNA mutations. Lacunarity parameter β is able to characterize individual mutation profile of mitochondrial genome and could represent a promising index to discriminate between PD and aging.
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46
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Braganza A, Annarapu GK, Shiva S. Blood-based bioenergetics: An emerging translational and clinical tool. Mol Aspects Med 2020; 71:100835. [PMID: 31864667 PMCID: PMC7031032 DOI: 10.1016/j.mam.2019.100835] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 11/27/2019] [Accepted: 12/11/2019] [Indexed: 12/16/2022]
Abstract
Accumulating studies demonstrate that mitochondrial genetics and function are central to determining the susceptibility to, and prognosis of numerous diseases across all organ systems. Despite this recognition, mitochondrial function remains poorly characterized in humans primarily due to the invasiveness of obtaining viable tissue for mitochondrial studies. Recent studies have begun to test the hypothesis that circulating blood cells, which can be obtained by minimally invasive methodology, can be utilized as a biomarker of systemic bioenergetic function in human populations. Here we present the available methodologies for assessing blood cell bioenergetics and review studies that have applied these techniques to healthy and disease populations. We focus on the validation of this methodology in healthy subjects, as well as studies testing whether blood cell bioenergetics are altered in disease, correlate with clinical parameters, and compare with other methodology for assessing human mitochondrial function. Finally, we present the challenges and goals for the development of this emerging approach into a tool for translational research and personalized medicine.
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Affiliation(s)
- Andrea Braganza
- Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Pittsburgh, PA, USA
| | - Gowtham K Annarapu
- Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Pittsburgh, PA, USA
| | - Sruti Shiva
- Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Pittsburgh, PA, USA; Department of Pharmacology & Chemical Biology, Pittsburgh, PA, USA; Center for Metabolism and Mitochondrial Medicine (C3M), University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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47
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Environmental factors modulated ancient mitochondrial DNA variability and the prevalence of rheumatic diseases in the Basque Country. Sci Rep 2019; 9:20380. [PMID: 31892727 PMCID: PMC6938509 DOI: 10.1038/s41598-019-56921-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 12/17/2019] [Indexed: 11/09/2022] Open
Abstract
Among the factors that would explain the distribution of mitochondrial lineages in Europe, climate and diseases may have played an important role. A possible explanation lies in the nature of the mitochondrion, in which the energy generation process produces reactive oxygen species that may influence the development of different diseases. The present study is focused on the medieval necropolis of San Miguel de Ereñozar (13th-16th centuries, Basque Country), whose inhabitants presented a high prevalence of rheumatic diseases and lived during the Little Ice Age (LIA). Our results indicate a close relationship between rheumatic diseases and mitochondrial haplogroup H, and specifically between spondyloarthropathies and sub-haplogroup H2. One possible explanation may be the climate change that took place in the LIA that favoured those haplogroups that were more energy-efficient, such as haplogroup H, to endure lower temperatures and food shortage. However, it had a biological trade-off: the increased risk of developing rheumatic diseases.
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48
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Fields JA, Swinton MK, Carson A, Soontornniyomkij B, Lindsay C, Han MM, Frizzi K, Sambhwani S, Murphy A, Achim CL, Ellis RJ, Calcutt NA. Tenofovir disoproxil fumarate induces peripheral neuropathy and alters inflammation and mitochondrial biogenesis in the brains of mice. Sci Rep 2019; 9:17158. [PMID: 31748578 PMCID: PMC6868155 DOI: 10.1038/s41598-019-53466-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 11/01/2019] [Indexed: 01/08/2023] Open
Abstract
Mounting evidence suggests that antiretroviral therapy (ART) drugs may contribute to the prevalence of HIV-associated neurological dysfunction. The HIV envelope glycoprotein (gp120) is neurotoxic and has been linked to alterations in mitochondrial function and increased inflammatory gene expression, which are common neuropathological findings in HIV+ cases on ART with neurological disorders. Tenofovir disproxil fumarate (TDF) has been shown to affect neurogenesis in brains of mice and mitochondria in neurons. In this study, we hypothesized that TDF contributes to neurotoxicity by modulating mitochondrial biogenesis and inflammatory pathways. TDF administered to wild-type (wt) and GFAP-gp120 transgenic (tg) mice caused peripheral neuropathy, as indicated by nerve conduction slowing and thermal hyperalgesia. Conversely TDF protected gp120-tg mice from cognitive dysfunction. In the brains of wt and gp120-tg mice, TDF decreased expression of mitochondrial transcription factor A (TFAM). However, double immunolabelling revealed that TFAM was reduced in neurons and increased in astroglia in the hippocampi of TDF-treated wt and gp120-tg mice. TDF also increased expression of GFAP and decreased expression of IBA1 in the wt and gp120-tg mice. TDF increased tumor necrosis factor (TNF) α in wt mice. However, TDF reduced interleukin (IL) 1β and TNFα mRNA in gp120-tg mouse brains. Primary human astroglia were exposed to increasing doses of TDF for 24 hours and then analyzed for mitochondrial alterations and inflammatory gene expression. In astroglia, TDF caused a dose-dependent increase in oxygen consumption rate, extracellular acidification rate and spare respiratory capacity, changes consistent with increased metabolism. TDF also reduced IL-1β-mediated increases in IL-1β and TNFα mRNA. These data demonstrate that TDF causes peripheral neuropathy in mice and alterations in inflammatory signaling and mitochondrial activity in the brain.
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Affiliation(s)
- Jerel Adam Fields
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
| | - Mary K Swinton
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
| | - Aliyah Carson
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
| | | | - Charmaine Lindsay
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
| | - May Madi Han
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
| | - Katie Frizzi
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
| | - Shrey Sambhwani
- Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
| | - Anne Murphy
- Department of Pharmacology, University of California San Diego, La Jolla, CA, USA
| | - Cristian L Achim
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
| | - Ronald J Ellis
- Department of Neurosciences, University of California San Diego, La Jolla, CA, USA
| | - Nigel A Calcutt
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
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49
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Shi Q, Luan Q, Wang X, Cai Y. Correlation study on mtDNA polymorphisms as potential risk factors in aggressive periodontitis by NGS. Oral Dis 2019; 26:401-408. [PMID: 31715075 DOI: 10.1111/odi.13231] [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: 04/16/2019] [Revised: 10/11/2019] [Accepted: 11/06/2019] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Using next-generation sequencing (NGS) to determine whether aggressive periodontitis is associated with specific mitochondrial polymorphisms. MATERIALS AND METHODS A total of 165 unrelated Han Chinese were enrolled in the study. We analyzed the mitochondrial DNA (mtDNA) in 97 patients with aggressive periodontitis and 68 healthy controls by NGS. The mitochondrial DNA was L-PCR-amplified and subsequently sequenced by an Illumina Genome Analyzer (NGS). Chi-square tests were used to assess the differences between the two groups. In cases of significant difference, multivariate logistic regression models were further used to analyze the association between mtDNA polymorphisms and aggressive periodontitis. RESULTS Significant association was observed between aggressive periodontitis and eight mitochondrial polymorphisms: "8860G-10400C" (OR = 2.828, p = .002), "8701A" (OR = 2.308, p = .005), "12705C-10398A" (OR = 2.683, p = .002), "9540C" (OR = 3.838, p = .001) and "10873T-15043G" (OR = 4.375, p = .001). CONCLUSIONS The pathogenesis of aggressive periodontitis is complicated, and its heredity is not well characterized. Our study was the first to use next-generation sequencing and found that 8860G-10400C, 8701A, 12705C-10398A, 9540C, and 10873T-15043G are associated with aggressive periodontitis in the Han Chinese population.
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Affiliation(s)
- Qiao Shi
- Department of Periodontology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, China
| | - Qingxian Luan
- Department of Periodontology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, China
| | - Xiaoxuan Wang
- Department of Periodontology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, China
| | - Yu Cai
- Department of Periodontology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, China.,Central Laboratory, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Peking University School and Hospital of Stomatology, Beijing, China
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50
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Müller-Nedebock AC, Brennan RR, Venter M, Pienaar IS, van der Westhuizen FH, Elson JL, Ross OA, Bardien S. The unresolved role of mitochondrial DNA in Parkinson's disease: An overview of published studies, their limitations, and future prospects. Neurochem Int 2019; 129:104495. [PMID: 31233840 PMCID: PMC6702091 DOI: 10.1016/j.neuint.2019.104495] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 05/27/2019] [Accepted: 06/21/2019] [Indexed: 12/21/2022]
Abstract
Parkinson's disease (PD), a progressive neurodegenerative disorder, has long been associated with mitochondrial dysfunction in both sporadic and familial forms of the disease. Mitochondria are crucial for maintaining cellular homeostasis, and their dysfunction is detrimental to dopaminergic neurons. These neurons are highly dependent on mitochondrial adenosine triphosphate (ATP) and degenerate in PD. Mitochondria contain their own genomes (mtDNA). The role of mtDNA has been investigated in PD on the premise that it encodes vital components of the ATP-generating oxidative phosphorylation (OXPHOS) complexes and accumulates somatic variation with age. However, the association between mtDNA variation and PD remains controversial. Herein, we provide an overview of previously published studies on the role of inherited as well as somatic (acquired) mtDNA changes in PD including point mutations, deletions and depletion. We outline limitations of previous investigations and the difficulties associated with studying mtDNA, which have left its role unresolved in the context of PD. Lastly, we highlight the potential for further research in this field and provide suggestions for future studies. Overall, the mitochondrial genome is indispensable for proper cellular function and its contribution to PD requires further, more extensive investigation.
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Affiliation(s)
- Amica C Müller-Nedebock
- Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa
| | | | - Marianne Venter
- Human Metabolomics, North-West University, Potchefstroom, South Africa
| | - Ilse S Pienaar
- School of Life Sciences, University of Sussex, Falmer, BN1 9PH, United Kingdom; Centre for Neuroinflammation and Neurodegeneration, Imperial College London, London, United Kingdom
| | | | - Joanna L Elson
- Human Metabolomics, North-West University, Potchefstroom, South Africa; Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom
| | - Owen A Ross
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, USA; School of Medicine and Medical Science, University College Dublin, Dublin, Ireland
| | - Soraya Bardien
- Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa.
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