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Subasinghe K, Barber R, Phillips N. miRNA mediated mitochondrial function and gene regulation associated with Alzheimer's disease. FRONTIERS IN AGING 2025; 6:1582812. [PMID: 40433169 PMCID: PMC12106540 DOI: 10.3389/fragi.2025.1582812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Accepted: 05/02/2025] [Indexed: 05/29/2025]
Abstract
MicroRNAs (miRNAs) are small non-coding RNA molecules that are known to regulate gene expression in their target locations thereby contributing to epigenetic mechanisms associated with disease pathologies. Dysregulation of miRNA activity has been implicated in the pathology of Alzheimer's disease (AD), offering insights into potential biomarkers for early diagnosis and therapeutic targets. Mitochondrial dysfunction and its associated effects (such as oxidative stress) can be seen in early-onset AD. This review critically examines recent findings on mitochondrial-associated miRNAs-including miR-34a, miR-140, miR-455-3p, and miR-1273g-3p-highlighting their roles in mitochondrial bioenergetics, oxidative stress, and synaptic function. We discuss the therapeutic potential of targeting specific miRNAs to restore mitochondrial health and explore their utility as early biomarkers for AD diagnosis. A better understanding of miRNA-mediated mitochondrial regulation may open new avenues for early intervention in AD.
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Affiliation(s)
- Kumudu Subasinghe
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Robert Barber
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX, United States
- Department of Family Health, University of North Texas Health Science Center, Fort Worth, TX, United States
- Institute for Translational Research, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Nicole Phillips
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX, United States
- Institute for Translational Research, University of North Texas Health Science Center, Fort Worth, TX, United States
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Petracci I, Bellini S, Goljanek-Whysall K, Quinlan LR, Fiszer A, Cakmak A, Njume CM, Borroni B, Ghidoni R. Exploring the Role of microRNAs as Blood Biomarkers in Alzheimer's Disease and Frontotemporal Dementia. Int J Mol Sci 2025; 26:3399. [PMID: 40244285 PMCID: PMC11989394 DOI: 10.3390/ijms26073399] [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: 02/20/2025] [Revised: 03/28/2025] [Accepted: 04/02/2025] [Indexed: 04/18/2025] Open
Abstract
Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the most common forms of dementia globally. AD is characterized by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated tau in the brain, leading to progressive memory loss and cognitive decline, significantly impairing daily life. In contrast, FTD is marked by selective degeneration of the frontal and/or temporal lobes, typically resulting in profound changes in personality and social behavior, speech disorders, and psychiatric symptoms. Numerous studies have found microRNAs (miRNAs)-small, non-coding RNA molecules that regulate gene expression post-transcriptionally-to be dysregulated in AD and FTD. As a result, miRNAs have emerged as promising novel biomarkers for these diseases. This review examines the current understanding of miRNAs in AD and FTD, emphasizing their potential as accessible, noninvasive biomarkers for diagnosing these prevalent neurodegenerative disorders.
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Affiliation(s)
- Irene Petracci
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy; (I.P.); (S.B.); (B.B.)
| | - Sonia Bellini
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy; (I.P.); (S.B.); (B.B.)
| | - Katarzyna Goljanek-Whysall
- Discipline of Physiology, School of Medicine, University of Galway, H91 TH33 Galway, Ireland (L.R.Q.)
- Institute of Life Course and Medical Sciences (ILCAMS), University of Liverpool, L7 8TX Liverpool, UK
- Galway RNA Research Cluster, University of Galway, H91 TK33 Galway, Ireland
| | - Leo R. Quinlan
- Discipline of Physiology, School of Medicine, University of Galway, H91 TH33 Galway, Ireland (L.R.Q.)
| | - Agnieszka Fiszer
- Department of Medical Biotechnology, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland;
| | - Ali Cakmak
- Department of Computer Engineering, Ayazaga Campus, Istanbul Technical University, Reşitpaşa, Sarıyer, 34467 Istanbul, Turkey; (A.C.); (C.M.N.)
| | - Cyrille Mesue Njume
- Department of Computer Engineering, Ayazaga Campus, Istanbul Technical University, Reşitpaşa, Sarıyer, 34467 Istanbul, Turkey; (A.C.); (C.M.N.)
| | - Barbara Borroni
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy; (I.P.); (S.B.); (B.B.)
- Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy
| | - Roberta Ghidoni
- Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy; (I.P.); (S.B.); (B.B.)
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Zhao Z, Wang S, Wang K, Ji X, Chen D, Shen Q, Yu Y, Cui S, Wang J, Chen Z, Tang G. Transcriptome analysis of liver and ileum reveals potential regulation of long non-coding RNA in pigs with divergent feed efficiency. Anim Biosci 2025; 38:588-599. [PMID: 39483020 PMCID: PMC11917451 DOI: 10.5713/ab.24.0434] [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: 06/25/2024] [Revised: 08/23/2024] [Accepted: 09/18/2024] [Indexed: 11/03/2024] Open
Abstract
OBJECTIVE Long non-coding RNA (LncRNA) plays a significant role in regulating feed efficiency. This study aims to explore the key lncRNAs, associated genes, and pathways in pigs with extreme feed efficiencies. METHODS We screened pigs with extremely high and low residual feed intake through a 12-week animal growth trial and then conducted transcriptome analysis on their liver and ileum tissues. We analyzed the differential expressed lncRNAs, microRNAs (miRNAs), and messenger RNAs through target gene prediction and functional analysis. And we identified key lncRNAs and their potential regulatory genes associated with feed efficiency through the construction of competitive endogenous RNA network. RESULTS Differentially expressed lncRNAs were pinpointed in the liver, revealing 23 crucial target genes primarily associated with guanosine triphosphate metabolism and glycolipid biosynthesis. In the ileum, a screening identified 92 pivotal target genes, mainly linked to lipid and small molecule metabolism. Moreover, LOC106504303 and LOC102160805 emerged as potentially significant lncRNAs respectively, playing roles in mitochondrial oxidative phosphorylation in the liver, and lipid and cholesterol metabolism in the ileum. CONCLUSION The lncRNAs regulate energy metabolism and biosynthesis in the liver, and the digestive absorption capacity in the small intestine, affecting the feed efficiency of pigs.
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Affiliation(s)
- Zhenjian Zhao
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130,
China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130,
China
| | - Shujie Wang
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130,
China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130,
China
| | - Kai Wang
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130,
China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130,
China
| | - Xiang Ji
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130,
China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130,
China
| | - Dong Chen
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130,
China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130,
China
| | - Qi Shen
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130,
China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130,
China
| | - Yang Yu
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130,
China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130,
China
| | - Shendi Cui
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130,
China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130,
China
| | - Junge Wang
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130,
China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130,
China
| | - Ziyang Chen
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130,
China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130,
China
| | - Guoqing Tang
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130,
China
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130,
China
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Yashooa RK, Duranti E, Conconi D, Lavitrano M, Mustafa SA, Villa C. Mitochondrial microRNAs: Key Drivers in Unraveling Neurodegenerative Diseases. Int J Mol Sci 2025; 26:626. [PMID: 39859339 PMCID: PMC11766038 DOI: 10.3390/ijms26020626] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/07/2025] [Accepted: 01/12/2025] [Indexed: 01/27/2025] Open
Abstract
MicroRNAs (miRNAs) are a class of small non-coding RNAs (ncRNAs) crucial for regulating gene expression at the post-transcriptional level. Recent evidence has shown that miRNAs are also found in mitochondria, organelles that produce energy in the cell. These mitochondrial miRNAs, also known as mitomiRs, are essential for regulating mitochondrial function and metabolism. MitomiRs can originate from the nucleus, following traditional miRNA biogenesis pathways, or potentially from mitochondrial DNA, allowing them to directly affect gene expression and cellular energy dynamics within the mitochondrion. While miRNAs have been extensively investigated, the function and involvement of mitomiRs in the development of neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis remain to be elucidated. This review aims to discuss findings on the role of mitomiRs in such diseases and their potential as therapeutic targets, as well as to highlight future research directions.
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Affiliation(s)
- Raya Kh. Yashooa
- Department of Biology, College of Education for Pure Science, University of Al-Hamdaniya, Mosul 41002, Iraq;
| | - Elisa Duranti
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (E.D.); (D.C.); (M.L.)
| | - Donatella Conconi
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (E.D.); (D.C.); (M.L.)
| | - Marialuisa Lavitrano
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (E.D.); (D.C.); (M.L.)
| | - Suhad A. Mustafa
- General Directorate of Scientific Research Center, Salahaddin University-Erbil, Kurdistan Region, Erbil 44001, Iraq;
| | - Chiara Villa
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy; (E.D.); (D.C.); (M.L.)
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5
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Patranabis S. Recent Advances in the miRNA-Mediated Regulation of Neuronal Differentiation and Death. Neuromolecular Med 2024; 26:52. [PMID: 39648193 DOI: 10.1007/s12017-024-08820-2] [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: 10/23/2024] [Accepted: 11/25/2024] [Indexed: 12/10/2024]
Abstract
The review aims to focus on the role of miRNA in gene regulation, related to differentiation and apoptosis of neurons, focusing on the array of miRNAs involved in the processes. miRNAs are a known class of small regulatory RNAs, which in association with RNA processing bodies, play major roles in different cellular events, such as neurogenesis and neuronal differentiation. miRNAs function in controlling neuronal events by targeting different important molecules of cellular signalling. The post-translational modification of Ago2 is crucial in modulating the neurons' miRNA-mediated regulation. Thus, understanding the crosstalk between cellular signalling and miRNA activity affecting neuronal events is very important to decipher novel targets and related signalling pathways, involved in neuronal survival and neurodegeneration.
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6
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Larose A, Miller CCJ, Mórotz GM. The lemur tail kinase family in neuronal function and disfunction in neurodegenerative diseases. Cell Mol Life Sci 2024; 81:447. [PMID: 39520508 PMCID: PMC11550312 DOI: 10.1007/s00018-024-05480-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 09/12/2024] [Accepted: 10/12/2024] [Indexed: 11/16/2024]
Abstract
The complex neuronal architecture and the long distance of synapses from the cell body require precisely orchestrated axonal and dendritic transport processes to support key neuronal functions including synaptic signalling, learning and memory formation. Protein phosphorylation is a major regulator of both intracellular transport and synaptic functions. Some kinases and phosphatases such as cyclin dependent kinase-5 (cdk5)/p35, glycogen synthase kinase-3β (GSK3β) and protein phosphatase-1 (PP1) are strongly involved in these processes. A primary pathological hallmark of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis/frontotemporal dementia, is synaptic degeneration together with disrupted intracellular transport. One attractive possibility is that alterations to key kinases and phosphatases may underlie both synaptic and axonal transport damages. The brain enriched lemur tail kinases (LMTKs, formerly known as lemur tyrosine kinases) are involved in intracellular transport and synaptic functions, and are also centrally placed in cdk5/p35, GSK3β and PP1 signalling pathways. Loss of LMTKs is documented in major neurodegenerative diseases and thus can contribute to pathological defects in these disorders. However, whilst function of their signalling partners became clearer in modulating both synaptic signalling and axonal transport progress has only recently been made around LMTKs. In this review, we describe this progress with a special focus on intracellular transport, synaptic functions and neurodegenerative diseases.
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Affiliation(s)
- Angelique Larose
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4, Budapest, H-1089, Hungary
- Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary
| | - Christopher C J Miller
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane Camberwell, London, SE5 9RX, UK.
| | - Gábor M Mórotz
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4, Budapest, H-1089, Hungary.
- Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary.
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7
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Peng L, Zhang Z, Li Q, Song Z, Yan C, Ling H. Unveiling the multifaceted pathogenesis and therapeutic drugs of Alzheimer's disease: A comprehensive review. Heliyon 2024; 10:e39217. [PMID: 39629139 PMCID: PMC11612466 DOI: 10.1016/j.heliyon.2024.e39217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 08/02/2024] [Accepted: 10/09/2024] [Indexed: 12/07/2024] Open
Abstract
Alzheimer's disease (AD) is a severe neurodegenerative disorder characterized by the accumulation of β-amyloid (Aβ) plaques and tau phosphorylation-induced neurofibrillary tangles. This review comprehensively summarizes AD pathogenesis and related factors, drawing on a wealth of authoritative reports and research findings. Specifically, we delve into the intricate mechanisms underlying AD pathology, including Aβ deposition, tau protein phosphorylation, cholinergic dysfunction, neuroinflammation, mitochondrial oxidative stress, ferroptosis, imbalance in the gut microbiota, and microRNA dysregulation. We also explored the effects of these factors on the brain, including synaptic damage and cognitive impairment. Moreover, our review highlights the associations between the pathogenesis of AD and inflammatory cytokines in the peripheral blood and cerebrospinal fluid, dysbiosis of the gut microbiota, and changes in microRNA expression. Overall, we provided a systematic and illustrative overview of the pathogenesis and therapeutic drugs for AD, offering help in the prevention and treatment of this condition.
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Affiliation(s)
- Liting Peng
- Department of Physiology, Hengyang Medical School, University of South China, Hengyang, 421000, Hunan, China
| | - Zhiming Zhang
- Department of Anesthesiology, The First People's Hospital of Chenzhou, The Chenzhou Affiliated Hospital, Hengyang Medical School, University of South China, Chenzhou, 423000, Hunan, China
| | - Qi Li
- Department of Physiology, Hengyang Medical School, University of South China, Hengyang, 421000, Hunan, China
| | - Zhenjiang Song
- Department of Physiology, Hengyang Medical School, University of South China, Hengyang, 421000, Hunan, China
| | - Canqun Yan
- The Health Management Center, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Hongyan Ling
- Department of Physiology, Hengyang Medical School, University of South China, Hengyang, 421000, Hunan, China
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Abed S, Ebrahimi A, Fattahi F, Kouchakali G, Shekari-Khaniani M, Mansoori-Derakhshan S. The Role of Non-Coding RNAs in Mitochondrial Dysfunction of Alzheimer's Disease. J Mol Neurosci 2024; 74:100. [PMID: 39466447 DOI: 10.1007/s12031-024-02262-y] [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: 07/11/2024] [Accepted: 08/25/2024] [Indexed: 10/30/2024]
Abstract
Although brain amyloid-β (Aβ) peptide buildup is the main cause of Alzheimer's disease (AD), mitochondrial abnormalities can also contribute to the illness's development, as either a primary or secondary factor, as programmed cell death and efficient energy generation depend on the proper operation of mitochondria. As a result, non-coding RNAs (ncRNAs) may play a crucial role in ensuring that nuclear genes related to mitochondria and mitochondrial genes function normally. Interestingly, a significant number of recent studies have focused on the impact of ncRNAs on the expression of nucleus and mitochondrial genes. Additionally, researchers have proposed some intriguing therapeutic approaches to treat and reduce the severity of AD by adjusting the levels of these ncRNAs. The goal of this work was to consolidate the existing knowledge in this field of study by systematically investigating ncRNAs, with a particular emphasis on microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and small nucleolar RNAs (snoRNAs). Therefore, the impact and processes by which ncRNAs govern mitochondrial activity in the onset and progression of AD are thoroughly reviewed in this article. Collectively, the effects of ncRNAs on physiological and molecular mechanisms associated with mitochondrial abnormalities that exacerbate AD are thoroughly reviewed in the current research, while also emphasizing the relationship between disturbed mitophagy in AD and ncRNAs.
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Affiliation(s)
- Samin Abed
- Department of Genetics, Tabriz University of Medical University, Tabriz, Iran
| | - Amir Ebrahimi
- Department of Genetics, Tabriz University of Medical University, Tabriz, Iran
| | - Fatemeh Fattahi
- Department of Genetics, Tabriz University of Medical University, Tabriz, Iran
| | - Ghazal Kouchakali
- Department of Genetics, Tabriz University of Medical University, Tabriz, Iran
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Jusic A, Erpapazoglou Z, Dalgaard LT, Lakkisto P, de Gonzalo-Calvo D, Benczik B, Ágg B, Ferdinandy P, Fiedorowicz K, Schroen B, Lazou A, Devaux Y, on behalf of EU-CardioRNA COST Action CA17129, AtheroNET COST Action CA21153. Guidelines for mitochondrial RNA analysis. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102262. [PMID: 39091381 PMCID: PMC11292373 DOI: 10.1016/j.omtn.2024.102262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 08/04/2024]
Abstract
Mitochondria are the energy-producing organelles of mammalian cells with critical involvement in metabolism and signaling. Studying their regulation in pathological conditions may lead to the discovery of novel drugs to treat, for instance, cardiovascular or neurological diseases, which affect high-energy-consuming cells such as cardiomyocytes, hepatocytes, or neurons. Mitochondria possess both protein-coding and noncoding RNAs, such as microRNAs, long noncoding RNAs, circular RNAs, and piwi-interacting RNAs, encoded by the mitochondria or the nuclear genome. Mitochondrial RNAs are involved in anterograde-retrograde communication between the nucleus and mitochondria and play an important role in physiological and pathological conditions. Despite accumulating evidence on the presence and biogenesis of mitochondrial RNAs, their study continues to pose significant challenges. Currently, there are no standardized protocols and guidelines to conduct deep functional characterization and expression profiling of mitochondrial RNAs. To overcome major obstacles in this emerging field, the EU-CardioRNA and AtheroNET COST Action networks summarize currently available techniques and emphasize critical points that may constitute sources of variability and explain discrepancies between published results. Standardized methods and adherence to guidelines to quantify and study mitochondrial RNAs in normal and disease states will improve research outputs, their reproducibility, and translation potential to clinical application.
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Affiliation(s)
- Amela Jusic
- HAYA Therapeutics SA, Route De La Corniche 6, SuperLab Suisse - Batiment Serine, 1066 Epalinges, Switzerland
- Cardiovascular Research Unit, Department of Precision Health, Luxembourg Institute of Health, 1445 Strassen, Luxembourg
| | - Zoi Erpapazoglou
- Ιnstitute for Fundamental Biomedical Research, B.S.R.C. “Alexander Fleming”, Vari, 16672 Athens, Greece
| | - Louise Torp Dalgaard
- Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark
| | - Päivi Lakkisto
- Minerva Foundation Institute for Medical Research, 00290 Helsinki, Finland
- Department of Clinical Chemistry, University of Helsinki and Helsinki University Hospital, 00014 Helsinki, Finland
| | - David de Gonzalo-Calvo
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, 25198 Lleida, Spain
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, 28029 Madrid, Spain
| | - Bettina Benczik
- Cardiometabolic and HUN-REN-SU System Pharmacology Research Group, Center for Pharmacology and Drug Research & Development, Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary
- Pharmahungary Group, 6722 Szeged, Hungary
| | - Bence Ágg
- Cardiometabolic and HUN-REN-SU System Pharmacology Research Group, Center for Pharmacology and Drug Research & Development, Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary
- Pharmahungary Group, 6722 Szeged, Hungary
| | - Péter Ferdinandy
- Cardiometabolic and HUN-REN-SU System Pharmacology Research Group, Center for Pharmacology and Drug Research & Development, Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary
- Pharmahungary Group, 6722 Szeged, Hungary
| | | | - Blanche Schroen
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, ER 6229 Maastricht, the Netherlands
| | - Antigone Lazou
- School of Biology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Yvan Devaux
- Cardiovascular Research Unit, Department of Precision Health, Luxembourg Institute of Health, 1445 Strassen, Luxembourg
| | - on behalf of EU-CardioRNA COST Action CA17129
- HAYA Therapeutics SA, Route De La Corniche 6, SuperLab Suisse - Batiment Serine, 1066 Epalinges, Switzerland
- Cardiovascular Research Unit, Department of Precision Health, Luxembourg Institute of Health, 1445 Strassen, Luxembourg
- Ιnstitute for Fundamental Biomedical Research, B.S.R.C. “Alexander Fleming”, Vari, 16672 Athens, Greece
- Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark
- Minerva Foundation Institute for Medical Research, 00290 Helsinki, Finland
- Department of Clinical Chemistry, University of Helsinki and Helsinki University Hospital, 00014 Helsinki, Finland
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, 25198 Lleida, Spain
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, 28029 Madrid, Spain
- Cardiometabolic and HUN-REN-SU System Pharmacology Research Group, Center for Pharmacology and Drug Research & Development, Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary
- Pharmahungary Group, 6722 Szeged, Hungary
- NanoBioMedical Centre, Adam Mickiewicz University in Poznan, 61614 Poznan, Poland
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, ER 6229 Maastricht, the Netherlands
- School of Biology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - AtheroNET COST Action CA21153
- HAYA Therapeutics SA, Route De La Corniche 6, SuperLab Suisse - Batiment Serine, 1066 Epalinges, Switzerland
- Cardiovascular Research Unit, Department of Precision Health, Luxembourg Institute of Health, 1445 Strassen, Luxembourg
- Ιnstitute for Fundamental Biomedical Research, B.S.R.C. “Alexander Fleming”, Vari, 16672 Athens, Greece
- Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark
- Minerva Foundation Institute for Medical Research, 00290 Helsinki, Finland
- Department of Clinical Chemistry, University of Helsinki and Helsinki University Hospital, 00014 Helsinki, Finland
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, 25198 Lleida, Spain
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, 28029 Madrid, Spain
- Cardiometabolic and HUN-REN-SU System Pharmacology Research Group, Center for Pharmacology and Drug Research & Development, Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary
- Pharmahungary Group, 6722 Szeged, Hungary
- NanoBioMedical Centre, Adam Mickiewicz University in Poznan, 61614 Poznan, Poland
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, ER 6229 Maastricht, the Netherlands
- School of Biology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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10
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Li YB, Fu Q, Guo M, Du Y, Chen Y, Cheng Y. MicroRNAs: pioneering regulators in Alzheimer's disease pathogenesis, diagnosis, and therapy. Transl Psychiatry 2024; 14:367. [PMID: 39256358 PMCID: PMC11387755 DOI: 10.1038/s41398-024-03075-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 08/21/2024] [Accepted: 08/27/2024] [Indexed: 09/12/2024] Open
Abstract
This article delves into Alzheimer's disease (AD), a prevalent neurodegenerative condition primarily affecting the elderly. It is characterized by progressive memory and cognitive impairments, severely disrupting daily life. Recent research highlights the potential involvement of microRNAs in the pathogenesis of AD. MicroRNAs (MiRNAs), short non-coding RNAs comprising 20-24 nucleotides, significantly influence gene regulation by hindering translation or promoting degradation of target genes. This review explores the role of specific miRNAs in AD progression, focusing on their impact on β-amyloid (Aβ) peptide accumulation, intracellular aggregation of hyperphosphorylated tau proteins, mitochondrial dysfunction, neuroinflammation, oxidative stress, and the expression of the APOE4 gene. Our insights contribute to understanding AD's pathology, offering new avenues for identifying diagnostic markers and developing novel therapeutic targets.
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Affiliation(s)
- Yao-Bo Li
- Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing, China
| | - Qiang Fu
- Institute of National Security, Minzu University of China, Beijing, China
| | - Mei Guo
- Key Laboratory of Ethnomedicine of Ministry of Education, School of Pharmacy, Minzu University of China, Beijing, China
| | - Yang Du
- Institute of National Security, Minzu University of China, Beijing, China
| | - Yuewen Chen
- Chinese Academy of Sciences Key Laboratory of Brain Connectome and Manipulation, Shenzhen Key Laboratory of Translational Research for Brain Diseases, The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China.
- Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, Shenzhen, China.
| | - Yong Cheng
- Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing, China.
- Institute of National Security, Minzu University of China, Beijing, China.
- Key Laboratory of Ethnomedicine of Ministry of Education, School of Pharmacy, Minzu University of China, Beijing, China.
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11
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Rezq S, Huffman AM, Basnet J, Alsemeh AE, do Carmo JM, Yanes Cardozo LL, Romero DG. MicroRNA-21 modulates brown adipose tissue adipogenesis and thermogenesis in a mouse model of polycystic ovary syndrome. Biol Sex Differ 2024; 15:53. [PMID: 38987854 PMCID: PMC11238487 DOI: 10.1186/s13293-024-00630-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 06/26/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND Polycystic ovary syndrome (PCOS), the most common endocrine disorder in premenopausal women, is associated with increased obesity, hyperandrogenism, and altered brown adipose tissue (BAT) thermogenesis. MicroRNAs play critical functions in brown adipocyte differentiation and maintenance. We aim to study the role of microRNA-21 (miR-21) in altered energy homeostasis and BAT thermogenesis in a PCOS mouse model of peripubertal androgen exposure. METHODS Three-week-old miR-21 knockout (miR21KO) or wild-type (WT) female mice were treated with dihydrotestosterone (DHT) or vehicle for 90 days. Body composition was determined by EchoMRI. Energy expenditure (EE), oxygen consumption (VO2), carbon dioxide production (VCO2), and respiratory exchange ratio (RER) were measured by indirect calorimetry. Androgen receptor (AR), and markers of adipogenesis, de novo lipogenesis, angiogenesis, extracellular matrix remodeling, and thermogenesis were quantified by RT-qPCR and/or Western-blot. RESULTS MiR-21 ablation attenuated DHT-mediated increase in body weight while having no effect on fat or BAT mass. MiR-21 ablation attenuated DHT-mediated BAT AR upregulation. MiR-21 ablation did not alter EE; however, miR21KO DHT-treated mice have reduced VO2, VCO2, and RER. MiR-21 ablation reversed DHT-mediated decrease in food intake and increase in sleep time. MiR-21 ablation decreased some adipogenesis (Adipoq, Pparγ, and Cebpβ) and extracellular matrix remodeling (Mmp-9 and Timp-1) markers expression in DHT-treated mice. MiR-21 ablation abolished DHT-mediated increases in thermogenesis markers Cpt1a and Cpt1b, while decreasing CIDE-A expression. CONCLUSIONS Our findings suggest that BAT miR-21 may play a role in regulating DHT-mediated thermogenic dysfunction in PCOS. Modulation of BAT miR-21 levels could be a novel therapeutic approach for the treatment of PCOS-associated metabolic derangements.
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Affiliation(s)
- Samar Rezq
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA.
- Women's Health Research Center, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA.
- Cardiovascular-Renal Research Center, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA.
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA.
| | - Alexandra M Huffman
- Women's Health Research Center, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA
- Cardiovascular-Renal Research Center, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA
| | - Jelina Basnet
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA
- Women's Health Research Center, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA
- Cardiovascular-Renal Research Center, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA
| | - Amira E Alsemeh
- Department of Anatomy, Histology, and Embryology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Jussara M do Carmo
- Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA
- Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA
| | - Licy L Yanes Cardozo
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA
- Department of Medicine, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA
- Women's Health Research Center, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA
- Cardiovascular-Renal Research Center, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA
| | - Damian G Romero
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA.
- Women's Health Research Center, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA.
- Cardiovascular-Renal Research Center, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA.
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA.
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Cortes S, Farhat E, Talarico G, Mennigen JA. The dynamic transcriptomic response of the goldfish brain under chronic hypoxia. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART D, GENOMICS & PROTEOMICS 2024; 50:101233. [PMID: 38608489 DOI: 10.1016/j.cbd.2024.101233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 03/26/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024]
Abstract
Oxygen is essential to fuel aerobic metabolism. Some species evolved mechanisms to tolerate periods of severe hypoxia and even anoxia in their environment. Among them, goldfish (Carassius auratus) are unique, in that they do not enter a comatose state under severely hypoxic conditions. There is thus significant interest in the field of comparative physiology to uncover the mechanistic basis underlying hypoxia tolerance in goldfish, with a particular focus on the brain. Taking advantage of the recently published and annotated goldfish genome, we profile the transcriptomic response of the goldfish brain under normoxic (21 kPa oxygen saturation) and, following gradual reduction, constant hypoxic conditions after 1 and 4 weeks (2.1 kPa oxygen saturation). In addition to analyzing differentially expressed protein-coding genes and enriched pathways, we also profile differentially expressed microRNAs (miRs). Using in silico approaches, we identify possible miR-mRNA relationships. Differentially expressed transcripts compared to normoxia were either common to both timepoints of hypoxia exposure (n = 174 mRNAs; n = 6 miRs), or exclusive to 1-week (n = 441 mRNAs; n = 23 miRs) or 4-week hypoxia exposure (n = 491 mRNAs; n = 34 miRs). Under chronic hypoxia, an increasing number of transcripts, including those of paralogous genes, was downregulated over time, suggesting a decrease in transcription. GO-terms related to the vascular system, oxidative stress, stress signalling, oxidoreductase activity, nucleotide- and intermediary metabolism, and mRNA posttranscriptional regulation were found to be enriched under chronic hypoxia. Known 'hypoxamiRs', such as miR-210-3p/5p, and miRs such as miR-29b-3p likely contribute to posttranscriptional regulation of these pathways under chronic hypoxia in the goldfish brain.
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Affiliation(s)
- S Cortes
- Department of Biology, University of Ottawa, K1N6N5 20 Marie Curie, Ottawa, ON, Canada; Laboratorio de Oncogenómica, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico
| | - E Farhat
- Department of Biology, University of Ottawa, K1N6N5 20 Marie Curie, Ottawa, ON, Canada; Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0371 Oslo, Norway
| | - Ggm Talarico
- Department of Biology, University of Ottawa, K1N6N5 20 Marie Curie, Ottawa, ON, Canada
| | - J A Mennigen
- Department of Biology, University of Ottawa, K1N6N5 20 Marie Curie, Ottawa, ON, Canada.
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13
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Kelley CM, Maloney B, Beck JS, Ginsberg SD, Liang W, Lahiri DK, Mufson EJ, Counts SE. Micro-RNA profiles of pathology and resilience in posterior cingulate cortex of cognitively intact elders. Brain Commun 2024; 6:fcae082. [PMID: 38572270 PMCID: PMC10988646 DOI: 10.1093/braincomms/fcae082] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 12/22/2023] [Accepted: 03/05/2024] [Indexed: 04/05/2024] Open
Abstract
The posterior cingulate cortex (PCC) is a key hub of the default mode network underlying autobiographical memory retrieval, which falters early in the progression of Alzheimer's disease (AD). We recently performed RNA sequencing of post-mortem PCC tissue samples from 26 elderly Rush Religious Orders Study participants who came to autopsy with an ante-mortem diagnosis of no cognitive impairment but who collectively displayed a range of Braak I-IV neurofibrillary tangle stages. Notably, cognitively unimpaired subjects displaying high Braak stages may represent cognitive resilience to AD pathology. Transcriptomic data revealed elevated synaptic and ATP-related gene expression in Braak Stages III/IV compared with Stages I/II, suggesting these pathways may be related to PCC resilience. We also mined expression profiles for small non-coding micro-RNAs (miRNAs), which regulate mRNA stability and may represent an underexplored potential mechanism of resilience through the fine-tuning of gene expression within complex cellular networks. Twelve miRNAs were identified as differentially expressed between Braak Stages I/II and III/IV. However, the extent to which the levels of all identified miRNAs were associated with subject demographics, neuropsychological test performance and/or neuropathological diagnostic criteria within this cohort was not explored. Here, we report that a total of 667 miRNAs are significantly associated (rho > 0.38, P < 0.05) with subject variables. There were significant positive correlations between miRNA expression levels and age, perceptual orientation and perceptual speed. By contrast, higher miRNA levels correlated negatively with semantic and episodic memory. Higher expression of 15 miRNAs associated with lower Braak Stages I-II and 47 miRNAs were associated with higher Braak Stages III-IV, suggesting additional mechanistic influences of PCC miRNA expression with resilience. Pathway analysis showed enrichment for miRNAs operating in pathways related to lysine degradation and fatty acid synthesis and metabolism. Finally, we demonstrated that the 12 resilience-related miRNAs differentially expressed in Braak Stages I/II versus Braak Stages III/IV were predicted to regulate mRNAs related to amyloid processing, tau and inflammation. In summary, we demonstrate a dynamic state wherein differential PCC miRNA levels are associated with cognitive performance and post-mortem neuropathological AD diagnostic criteria in cognitively intact elders. We posit these relationships may inform miRNA transcriptional alterations within the PCC relevant to potential early protective (resilience) or pathogenic (pre-clinical or prodromal) responses to disease pathogenesis and thus may be therapeutic targets.
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Affiliation(s)
- Christy M Kelley
- Department of Translational Neuroscience and Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Bryan Maloney
- Departments of Psychiatry and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - John S Beck
- Departments of Translational Neuroscience and Family Medicine, Michigan State University College of Human Medicine, Grand Rapids, MI 49503, USA
| | - Stephen D Ginsberg
- Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA
- Departments of Psychiatry, Neuroscience & Physiology, and the NYU Neuroscience Institute, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Winnie Liang
- Translational Genomics Research Institute, Phoenix, AZ 85004, USA
| | - Debomoy K Lahiri
- Departments of Psychiatry and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Elliott J Mufson
- Department of Translational Neuroscience and Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ 85013, USA
| | - Scott E Counts
- Departments of Translational Neuroscience and Family Medicine, Michigan State University College of Human Medicine, Grand Rapids, MI 49503, USA
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14
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Kaur S, Verma H, Kaur S, Gangwar P, Yadav A, Yadav B, Rao R, Dhiman M, Mantha AK. Understanding the multifaceted role of miRNAs in Alzheimer's disease pathology. Metab Brain Dis 2024; 39:217-237. [PMID: 37505443 DOI: 10.1007/s11011-023-01265-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 07/16/2023] [Indexed: 07/29/2023]
Abstract
Small non-coding RNAs (miRNAs) regulate gene expression by binding to mRNA and mediating its degradation or inhibiting translation. Since miRNAs can regulate the expression of several genes, they have multiple roles to play in biological processes and human diseases. The majority of miRNAs are known to be expressed in the brain and are involved in synaptic functions, thus marking their presence and role in major neurodegenerative disorders, including Alzheimer's disease (AD). In AD, amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) are known to be the major hallmarks. The clearance of Aβ and tau is known to be associated with miRNA dysregulation. In addition, the β-site APP cleaving enzyme (BACE 1), which cleaves APP to form Aβ, is also found to be regulated by miRNAs, thus directly affecting Aβ accumulation. Growing evidences suggest that neuroinflammation can be an initial event in AD pathology, and miRNAs have been linked with the regulation of neuroinflammation. Inflammatory disorders have also been associated with AD pathology, and exosomes associated with miRNAs are known to regulate brain inflammation, suggesting for the role of systemic miRNAs in AD pathology. Several miRNAs have been related in AD, years before the clinical symptoms appear, most of which are associated with regulating the cell cycle, immune system, stress responses, cellular senescence, nerve growth factor (NGF) signaling, and synaptic regulation. Phytochemicals, especially polyphenols, alter the expression of various miRNAs by binding to miRNAs or binding to the transcriptional activators of miRNAs, thus control/alter various metabolic pathways. Awing to the sundry biological processes being regulated by miRNAs in the brain and regulation of expression of miRNAs via phytochemicals, miRNAs and the regulatory bioactive phytochemicals can serve as therapeutic agents in the treatment and management of AD.
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Affiliation(s)
- Sharanjot Kaur
- Department of Microbiology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India
| | - Harkomal Verma
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO - Ghudda, Bathinda, 151 401, Punjab, India
| | - Sukhchain Kaur
- Department of Microbiology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India
| | - Prabhakar Gangwar
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO - Ghudda, Bathinda, 151 401, Punjab, India
| | - Anuradha Yadav
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO - Ghudda, Bathinda, 151 401, Punjab, India
| | - Bharti Yadav
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO - Ghudda, Bathinda, 151 401, Punjab, India
| | - Rashmi Rao
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO - Ghudda, Bathinda, 151 401, Punjab, India
| | - Monisha Dhiman
- Department of Microbiology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India
| | - Anil Kumar Mantha
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO - Ghudda, Bathinda, 151 401, Punjab, India.
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15
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Huang Y, Driedonks TAP, Cheng L, Turchinovich A, Pletnikova O, Redding-Ochoa J, Troncoso JC, Hill AF, Mahairaki V, Zheng L, Witwer KW. Small RNA Profiles of Brain Tissue-Derived Extracellular Vesicles in Alzheimer's Disease. J Alzheimers Dis 2024; 99:S235-S248. [PMID: 37781809 DOI: 10.3233/jad-230872] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
Background Extracellular vesicles (EVs) and non-coding RNAs (ncRNAs) are emerging contributors to Alzheimer's disease (AD) pathophysiology. Differential abundance of ncRNAs carried by EVs may provide valuable insights into underlying disease mechanisms. Brain tissue-derived EVs (bdEVs) are particularly relevant, as they may offer valuable insights about the tissue of origin. However, there is limited research on diverse ncRNA species in bdEVs in AD. Objective This study explored whether the non-coding RNA composition of EVs isolated from post-mortem brain tissue is related to AD pathogenesis. Methods bdEVs from age-matched late-stage AD patients (n = 23) and controls (n = 10) that had been separated and characterized in our previous study were used for RNA extraction, small RNA sequencing, and qPCR verification. Results Significant differences of non-coding RNAs between AD and controls were found, especially for miRNAs and tRNAs. AD pathology-related miRNA and tRNA differences of bdEVs partially matched expression differences in source brain tissues. AD pathology had a more prominent association than biological sex with bdEV miRNA and tRNA components in late-stage AD brains. Conclusions Our study provides further evidence that EV non-coding RNAs from human brain tissue, including but not limited to miRNAs, may be altered and contribute to AD pathogenesis.
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Affiliation(s)
- Yiyao Huang
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Tom A P Driedonks
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lesley Cheng
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Australia
| | - Andrey Turchinovich
- Division of Cancer Genome Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Heidelberg Biolabs GmbH, Heidelberg, Germany
| | - Olga Pletnikova
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Javier Redding-Ochoa
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Juan C Troncoso
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Andrew F Hill
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Australia
- Institute of Health and Sport, Victoria University, Melbourne, Australia
| | - Vasiliki Mahairaki
- Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lei Zheng
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Kenneth W Witwer
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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16
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UENO YUJI. Mechanism of Post-stroke Axonal Outgrowth and Functional Recovery. JUNTENDO IJI ZASSHI = JUNTENDO MEDICAL JOURNAL 2023; 69:364-369. [PMID: 38845728 PMCID: PMC10984353 DOI: 10.14789/jmj.jmj23-0025-r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 08/21/2023] [Indexed: 06/09/2024]
Abstract
Axonal outgrowth after stroke plays an important role in tissue repair and is critical for functional recovery. In the peri-infarct area of a rat middle cerebral artery occlusion model, we found that the axons and dendrites that had fallen off in the acute phase of stroke (7 days) were regenerated in the chronic phase of stroke (56 days). In vitro, we showed that phosphatase tensin homolog deleted on chromosome 10/Akt/Glycogen synthase kinase 3β signaling is implicated in postischemic axonal regeneration. In a rat model of chronic cerebral hypoperfusion, oral administration of L-carnitine induced axonal and oligodendrocyte regeneration in the cerebral white matter, resulting in myelin thickening, and it improved cognitive impairment in rats with chronic cerebral ischemia. Recently, it has been shown that exosomes enhanced functional recovery after stroke. Exosome treatment has less tumorigenicity, does not occlude the microvascular system, has low immunogenicity, and does not require a host immune response compared to conventional cell therapy. Several studies demonstrated specific microRNA in exosomes, which regulated signaling pathways related to neurogenesis after stroke. Collectively, there are various mechanisms of axonal regeneration and functional recovery after stroke, and it is expected that new therapeutic agents for stroke with the aim of axonal regeneration will be developed and used in real-world clinical practice in the future.
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Affiliation(s)
- YUJI UENO
- Corresponding author: Yuji Ueno, Department of Neurology, University of Yamanashi, 1110 Shimokato, Chuo-city, Yamanashi 409-3898, Japan, TEL/FAX: +81-55-273-9896 E-mail: ,
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17
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Altounian M, Bellon A, Mann F. Neuronal miR-17-5p contributes to interhemispheric cortical connectivity defects induced by prenatal alcohol exposure. Cell Rep 2023; 42:113020. [PMID: 37610874 DOI: 10.1016/j.celrep.2023.113020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 06/30/2023] [Accepted: 08/08/2023] [Indexed: 08/25/2023] Open
Abstract
Structural and functional deficits in brain connectivity are reported in patients with fetal alcohol spectrum disorders (FASDs), but whether and how prenatal alcohol exposure (PAE) affects axonal development of neurons and disrupts wiring between brain regions is unknown. Here, we develop a mouse model of moderate alcohol exposure during prenatal brain wiring to study the effects of PAE on corpus callosum (CC) development. PAE induces aberrant navigation of interhemispheric CC axons that persists even after exposure ends, leading to ectopic termination in the contralateral cortex. The neuronal miR-17-5p and its target ephrin type A receptor 4 (EphA4) mediate the effect of alcohol on the contralateral targeting of CC axons. Thus, altered microRNA-mediated regulation of axonal guidance may have implications for interhemispheric cortical connectivity and associated behaviors in FASD.
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Affiliation(s)
| | - Anaïs Bellon
- Aix Marseille University, INSERM, INMED, Marseille, France
| | - Fanny Mann
- Aix Marseille University, CNRS, IBDM, Marseille, France.
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18
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Prasad Panda S, Kesharwani A. Micronutrients/miRs/ATP networking in mitochondria: Clinical intervention with ferroptosis, cuproptosis, and calcium burden. Mitochondrion 2023; 71:1-16. [PMID: 37172668 DOI: 10.1016/j.mito.2023.05.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 04/12/2023] [Accepted: 05/07/2023] [Indexed: 05/15/2023]
Abstract
The mitochondrial electron transport chain (mtETC) requires mainly coenzyme Q10 (CoQ10), copper (Cu2+), calcium (Ca2+), and iron (Fe2+) ions for efficient ATP production. According to cross-sectional research, up to 50% of patients with micronutrient imbalances have been linked to oxidative stress, mitochondrial dysfunction, reduced ATP production, and the prognosis of various diseases. The condition of ferroptosis, which is caused by the downregulation of CoQ10 and the activation of non-coding micro RNAs (miRs), is strongly linked to free radical accumulation, cancer, and neurodegenerative diseases. The entry of micronutrients into the mitochondrial matrix depends upon the higher threshold level of mitochondrial membrane potential (ΔΨm), and high cytosolic micronutrients. The elevated micronutrient in the mitochondrial matrix causes the utilization of all ATP, leading to a drop in ATP levels. Mitochondrial calcium uniporter (MCU) and Na+/Ca2+ exchanger (NCX) play a major role in Ca2+ influx in the mitochondrial matrix. The mitochondrial Ca2+ overload is regulated by specific miRs such as miR1, miR7, miR25, miR145, miR138, and miR214, thereby reducing apoptosis and improving ATP production. Cuproptosis is primarily brought on by increased Cu+ build-up and mitochondrial proteotoxic stress, mediated by ferredoxin-1 (FDX1) and long non-coding RNAs. Cu importers (SLC31A1) and exporters (ATP7B) influence intracellular Cu2+ levels to control cuproptosis. According to literature reviews, very few randomized micronutrient interventions have been carried out, despite the identification of a high prevalence of micronutrient deficiencies. In this review, we concentrated on essential micronutrients and specific miRs associated with ATP production that balance oxidative stress in mitochondria.
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Affiliation(s)
- Siva Prasad Panda
- Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India.
| | - Adarsh Kesharwani
- Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India.
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19
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Saikia BJ, Bhardwaj J, Paul S, Sharma S, Neog A, Paul SR, Binukumar BK. Understanding the Roles and Regulation of Mitochondrial microRNAs (MitomiRs) in Neurodegenerative Diseases: Current Status and Advances. Mech Ageing Dev 2023:111838. [PMID: 37329989 DOI: 10.1016/j.mad.2023.111838] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 06/13/2023] [Accepted: 06/13/2023] [Indexed: 06/19/2023]
Abstract
MicroRNAs (miRNA) are a class of small non-coding RNA, roughly 21 - 22 nucleotides in length, which are master gene regulators. These miRNAs bind to the mRNA's 3' - untranslated region and regulate post-transcriptional gene regulation, thereby influencing various physiological and cellular processes. Another class of miRNAs known as mitochondrial miRNA (MitomiRs) has been found to either originate from the mitochondrial genome or be translocated directly into the mitochondria. Although the role of nuclear DNA encoded miRNA in the progression of various neurological diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, etc. is well known, accumulating evidence suggests the possible role of deregulated mitomiRs in the progression of various neurodegenerative diseases with unknown mechanism. We have attempted to outline the current state of mitomiRs role in controlling mitochondrial gene expression and function through this review, paying particular attention to their contribution to neurological processes, their etiology, and their potential therapeutic use.
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Affiliation(s)
- Bhaskar Jyoti Saikia
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Juhi Bhardwaj
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Sangita Paul
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Srishti Sharma
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Anindita Neog
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007
| | - Swaraj Ranjan Paul
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007
| | - B K Binukumar
- CSIR Institute of Genomics and Integrative Biology, Mall Road, New Delhi - 110007; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India.
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20
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Kobayashi A, Takeiwa T, Ikeda K, Inoue S. Roles of Noncoding RNAs in Regulation of Mitochondrial Electron Transport Chain and Oxidative Phosphorylation. Int J Mol Sci 2023; 24:9414. [PMID: 37298366 PMCID: PMC10253563 DOI: 10.3390/ijms24119414] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 05/23/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
The mitochondrial electron transport chain (ETC) plays an essential role in energy production by inducing oxidative phosphorylation (OXPHOS) to drive numerous biochemical processes in eukaryotic cells. Disorders of ETC and OXPHOS systems are associated with mitochondria- and metabolism-related diseases, including cancers; thus, a comprehensive understanding of the regulatory mechanisms of ETC and OXPHOS systems is required. Recent studies have indicated that noncoding RNAs (ncRNAs) play key roles in mitochondrial functions; in particular, some ncRNAs have been shown to modulate ETC and OXPHOS systems. In this review, we introduce the emerging roles of ncRNAs, including microRNAs (miRNAs), transfer-RNA-derived fragments (tRFs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), in the mitochondrial ETC and OXPHOS regulation.
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Affiliation(s)
- Ami Kobayashi
- Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, 60 Fenwood Rd., Boston, MA 02115, USA;
- Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Itabashi-ku, Tokyo 173-0015, Japan;
| | - Toshihiko Takeiwa
- Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Itabashi-ku, Tokyo 173-0015, Japan;
| | - Kazuhiro Ikeda
- Division of Systems Medicine & Gene Therapy, Saitama Medical University, Hidaka 350-1241, Japan;
| | - Satoshi Inoue
- Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Itabashi-ku, Tokyo 173-0015, Japan;
- Division of Systems Medicine & Gene Therapy, Saitama Medical University, Hidaka 350-1241, Japan;
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21
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Piol D, Robberechts T, Da Cruz S. Lost in local translation: TDP-43 and FUS in axonal/neuromuscular junction maintenance and dysregulation in amyotrophic lateral sclerosis. Neuron 2023; 111:1355-1380. [PMID: 36963381 DOI: 10.1016/j.neuron.2023.02.028] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/21/2022] [Accepted: 02/16/2023] [Indexed: 03/26/2023]
Abstract
Key early features of amyotrophic lateral sclerosis (ALS) are denervation of neuromuscular junctions and axonal degeneration. Motor neuron homeostasis relies on local translation through controlled regulation of axonal mRNA localization, transport, and stability. Yet the composition of the local transcriptome, translatome (mRNAs locally translated), and proteome during health and disease remains largely unexplored. This review covers recent discoveries on axonal translation as a critical mechanism for neuronal maintenance/survival. We focus on two RNA binding proteins, transactive response DNA binding protein-43 (TDP-43) and fused in sarcoma (FUS), whose mutations cause ALS and frontotemporal dementia (FTD). Emerging evidence points to their essential role in the maintenance of axons and synapses, including mRNA localization, transport, and local translation, and whose dysfunction may contribute to ALS. Finally, we describe recent advances in omics-based approaches mapping compartment-specific local RNA and protein compositions, which will be invaluable to elucidate fundamental local processes and identify key targets for therapy development.
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Affiliation(s)
- Diana Piol
- VIB-KU Leuven Center for Brain and Disease Research, Department of Neurosciences, KU Leuven, Leuven Brain Institute, Leuven, Belgium
| | - Tessa Robberechts
- VIB-KU Leuven Center for Brain and Disease Research, Department of Neurosciences, KU Leuven, Leuven Brain Institute, Leuven, Belgium
| | - Sandrine Da Cruz
- VIB-KU Leuven Center for Brain and Disease Research, Department of Neurosciences, KU Leuven, Leuven Brain Institute, Leuven, Belgium.
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22
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Corbett RJ, Ford LM, Raney NE, Grabowski JM, Ernst CW. Pig fetal skeletal muscle development is associated with genome-wide DNA hypomethylation and corresponding alterations in transcript and microRNA expression. Genome 2023; 66:68-79. [PMID: 36876850 DOI: 10.1139/gen-2022-0008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2023]
Abstract
Fetal myogenesis represents a critical period of porcine skeletal muscle development and requires coordinated expression of thousands of genes. Epigenetic mechanisms, including DNA methylation, drive transcriptional regulation during development; however, these processes are understudied in developing porcine tissues. We performed bisulfite sequencing to assess DNA methylation in pig longissimus dorsi muscle at 41- and 70-days gestation (dg), as well as RNA- and small RNA-sequencing to identify coordinated changes in methylation and expression between myogenic stages. We identified 45 739 differentially methylated regions (DMRs) between stages, and the majority (N = 34 232) were hypomethylated at 70 versus 41 dg. Integration of methylation and transcriptomic data revealed strong associations between differential gene methylation and expression. Differential miRNA methylation was significantly negatively correlated with abundance, and dynamic expression of assayed miRNAs persisted postnatally. Motif analysis revealed significant enrichment of myogenic regulatory factor motifs among hypomethylated regions, suggesting that DNA hypomethylation may function to increase accessibility of muscle-specific transcription factors. We show that developmental DMRs are enriched for GWAS SNPs for muscle- and meat-related traits, demonstrating the potential for epigenetic processes to influence phenotypic diversity. Our results enhance understanding of DNA methylation dynamics of porcine myogenesis and reveal putative cis-regulatory elements governed by epigenetic processes.
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Affiliation(s)
- R J Corbett
- Genetics & Genome Sciences Graduate Program, Michigan State University, East Lansing, MI 48824, USA
| | - L M Ford
- Genetics & Genome Sciences Graduate Program, Michigan State University, East Lansing, MI 48824, USA
| | - N E Raney
- Department of Animal Science, Michigan State University, East Lansing, MI 48824, USA
| | - J M Grabowski
- Department of Animal Science, Michigan State University, East Lansing, MI 48824, USA
| | - C W Ernst
- Department of Animal Science, Michigan State University, East Lansing, MI 48824, USA
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23
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Hyttinen JMT, Blasiak J, Kaarniranta K. Non-Coding RNAs Regulating Mitochondrial Functions and the Oxidative Stress Response as Putative Targets against Age-Related Macular Degeneration (AMD). Int J Mol Sci 2023; 24:ijms24032636. [PMID: 36768958 PMCID: PMC9917342 DOI: 10.3390/ijms24032636] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 01/23/2023] [Accepted: 01/23/2023] [Indexed: 01/31/2023] Open
Abstract
Age-related macular degeneration (AMD) is an ever-increasing, insidious disease which reduces the quality of life of millions of elderly people around the world. AMD is characterised by damage to the retinal pigment epithelium (RPE) in the macula region of the retina. The origins of this multi-factorial disease are complex and still not fully understood. Oxidative stress and mitochondrial imbalance in the RPE are believed to be important factors in the development of AMD. In this review, the regulation of the mitochondrial function and antioxidant stress response by non-coding RNAs (ncRNAs), newly emerged epigenetic factors, is discussed. These molecules include microRNAs, long non-coding RNAs, and circular non-coding RNAs. They act mainly as mRNA suppressors, controllers of other ncRNAs, or by interacting with proteins. We include here examples of these RNA molecules which affect various mitochondrial processes and antioxidant signaling of the cell. As a future prospect, the possibility to manipulate these ncRNAs to strengthen mitochondrial and antioxidant response functions is discussed. Non-coding RNAs could be used as potential diagnostic markers for AMD, and in the future, also as therapeutic targets, either by suppressing or increasing their expression. In addition to AMD, it is possible that non-coding RNAs could be regulators in other oxidative stress-related degenerative diseases.
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Affiliation(s)
- Juha M. T. Hyttinen
- Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
- Correspondence:
| | - Janusz Blasiak
- Department of Molecular Genetics, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
| | - Kai Kaarniranta
- Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
- Department of Ophthalmology, Kuopio University Hospital, P.O. Box 100, FI-70029 Kuopio, Finland
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24
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Gambardella J, Fiordelisi A, Sorriento D, Cerasuolo F, Buonaiuto A, Avvisato R, Pisani A, Varzideh F, Riccio E, Santulli G, Iaccarino G. Mitochondrial microRNAs Are Dysregulated in Patients with Fabry Disease. J Pharmacol Exp Ther 2023; 384:72-78. [PMID: 35764328 PMCID: PMC9827504 DOI: 10.1124/jpet.122.001250] [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] [Received: 04/02/2022] [Revised: 05/20/2022] [Accepted: 05/25/2022] [Indexed: 01/13/2023] Open
Abstract
Fabry disease (FD) is a lysosomal storage disorder caused by mutations in the gene for α-galactosidase A, inducing a progressive accumulation of globotriaosylceramide (GB3) and its metabolites in different organs and tissues. GB3 deposition does not fully explain the clinical manifestations of FD, and other pathogenetic mechanisms have been proposed, requiring the identification of new biomarkers for monitoring FD patients. Emerging evidence suggests the involvement of mitochondrial alterations in FD. Here, we propose mitochondrial-related microRNAs (miRs) as potential biomarkers of mitochondrial involvement in FD. Indeed, we demonstate that miRs regulating different aspects of mitochondrial homeostasis including expression and assembly of respiratory chain, mitogenesis, antioxidant capacity, and apoptosis are consistently dysregulated in FD patients. Our data unveil a novel noncoding RNA signature of FD patients, indicating mitochondrial-related miRs as new potential pathogenic players and biomarkers in FD. SIGNIFICANCE STATEMENT: This study demonstrates for the first time that a specific signature of circulating mitochondrial miRs (mitomiRs) is dysregulated in FD patients. MitomiRs regulating fundamental aspects of mitochondrial homeostasis and fitness, including expression and assembly of the respiratory chain, mitogenesis, antioxidant capacity, and apoptosis are significantly dysregulated in FD patients. Taken together, these new findings introduce mitomiRs as unprecedented biomarkers of FD and point at mitochondrial dysfunction as a novel potential mechanistic target for therapeutic approaches.
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Affiliation(s)
- Jessica Gambardella
- Department of Advanced Biomedical Sciences (J.G., A.F., D.S., F.C., A.B., R.A., G.I.); Interdepartmental Center of Research on Hypertension and Related Conditions (J.G., G.I.), and Department of Public Health (A.P., E.R.); Federico II University, Naples, Italy; and Departments of Medicine (Cardiology) and Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Institute for Neuroimmunology and Inflammation, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Einstein-Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York City, New York (J.G., F.V., G.S.)
| | - Antonella Fiordelisi
- Department of Advanced Biomedical Sciences (J.G., A.F., D.S., F.C., A.B., R.A., G.I.); Interdepartmental Center of Research on Hypertension and Related Conditions (J.G., G.I.), and Department of Public Health (A.P., E.R.); Federico II University, Naples, Italy; and Departments of Medicine (Cardiology) and Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Institute for Neuroimmunology and Inflammation, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Einstein-Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York City, New York (J.G., F.V., G.S.)
| | - Daniela Sorriento
- Department of Advanced Biomedical Sciences (J.G., A.F., D.S., F.C., A.B., R.A., G.I.); Interdepartmental Center of Research on Hypertension and Related Conditions (J.G., G.I.), and Department of Public Health (A.P., E.R.); Federico II University, Naples, Italy; and Departments of Medicine (Cardiology) and Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Institute for Neuroimmunology and Inflammation, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Einstein-Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York City, New York (J.G., F.V., G.S.)
| | - Federica Cerasuolo
- Department of Advanced Biomedical Sciences (J.G., A.F., D.S., F.C., A.B., R.A., G.I.); Interdepartmental Center of Research on Hypertension and Related Conditions (J.G., G.I.), and Department of Public Health (A.P., E.R.); Federico II University, Naples, Italy; and Departments of Medicine (Cardiology) and Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Institute for Neuroimmunology and Inflammation, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Einstein-Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York City, New York (J.G., F.V., G.S.)
| | - Antonietta Buonaiuto
- Department of Advanced Biomedical Sciences (J.G., A.F., D.S., F.C., A.B., R.A., G.I.); Interdepartmental Center of Research on Hypertension and Related Conditions (J.G., G.I.), and Department of Public Health (A.P., E.R.); Federico II University, Naples, Italy; and Departments of Medicine (Cardiology) and Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Institute for Neuroimmunology and Inflammation, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Einstein-Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York City, New York (J.G., F.V., G.S.)
| | - Roberta Avvisato
- Department of Advanced Biomedical Sciences (J.G., A.F., D.S., F.C., A.B., R.A., G.I.); Interdepartmental Center of Research on Hypertension and Related Conditions (J.G., G.I.), and Department of Public Health (A.P., E.R.); Federico II University, Naples, Italy; and Departments of Medicine (Cardiology) and Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Institute for Neuroimmunology and Inflammation, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Einstein-Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York City, New York (J.G., F.V., G.S.)
| | - Antonio Pisani
- Department of Advanced Biomedical Sciences (J.G., A.F., D.S., F.C., A.B., R.A., G.I.); Interdepartmental Center of Research on Hypertension and Related Conditions (J.G., G.I.), and Department of Public Health (A.P., E.R.); Federico II University, Naples, Italy; and Departments of Medicine (Cardiology) and Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Institute for Neuroimmunology and Inflammation, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Einstein-Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York City, New York (J.G., F.V., G.S.)
| | - Fahimeh Varzideh
- Department of Advanced Biomedical Sciences (J.G., A.F., D.S., F.C., A.B., R.A., G.I.); Interdepartmental Center of Research on Hypertension and Related Conditions (J.G., G.I.), and Department of Public Health (A.P., E.R.); Federico II University, Naples, Italy; and Departments of Medicine (Cardiology) and Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Institute for Neuroimmunology and Inflammation, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Einstein-Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York City, New York (J.G., F.V., G.S.)
| | - Eleonora Riccio
- Department of Advanced Biomedical Sciences (J.G., A.F., D.S., F.C., A.B., R.A., G.I.); Interdepartmental Center of Research on Hypertension and Related Conditions (J.G., G.I.), and Department of Public Health (A.P., E.R.); Federico II University, Naples, Italy; and Departments of Medicine (Cardiology) and Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Institute for Neuroimmunology and Inflammation, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Einstein-Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York City, New York (J.G., F.V., G.S.)
| | - Gaetano Santulli
- Department of Advanced Biomedical Sciences (J.G., A.F., D.S., F.C., A.B., R.A., G.I.); Interdepartmental Center of Research on Hypertension and Related Conditions (J.G., G.I.), and Department of Public Health (A.P., E.R.); Federico II University, Naples, Italy; and Departments of Medicine (Cardiology) and Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Institute for Neuroimmunology and Inflammation, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Einstein-Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York City, New York (J.G., F.V., G.S.)
| | - Guido Iaccarino
- Department of Advanced Biomedical Sciences (J.G., A.F., D.S., F.C., A.B., R.A., G.I.); Interdepartmental Center of Research on Hypertension and Related Conditions (J.G., G.I.), and Department of Public Health (A.P., E.R.); Federico II University, Naples, Italy; and Departments of Medicine (Cardiology) and Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Institute for Neuroimmunology and Inflammation, Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Einstein-Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York City, New York (J.G., F.V., G.S.)
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25
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Hou L, Xing N, Yue Z, Wu J, Wang F, Guo Z. Dicer induced reactive oxygen species inhibit hepatocellular carcinoma through interacting with cytochrome c oxidase. BIOTECHNOL BIOTEC EQ 2022. [DOI: 10.1080/13102818.2022.2082318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Affiliation(s)
- Lin Hou
- Department of Endocrine and Metabolic Disease, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P. R. China
| | - Na Xing
- Department of Endocrine and Metabolic Disease, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P. R. China
| | - Zhao Yue
- Department of Gastroenterology and Hepatology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P. R. China
| | - Jianhua Wu
- Animal Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P. R. China
| | - Fujun Wang
- Department of Endocrine and Metabolic Disease, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P. R. China
| | - Zhanjun Guo
- Department of Immunology and Rheumatology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P. R. China
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26
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Exosomal MicroRNA-Based Predictive Model for Preclinical Alzheimer's Disease: A Multicenter Study. Biol Psychiatry 2022; 92:44-53. [PMID: 35221095 DOI: 10.1016/j.biopsych.2021.12.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 12/07/2021] [Accepted: 12/09/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND Exosomal microRNAs (miRNAs) have been demonstrated to be biomarkers of Alzheimer's disease (AD). However, whether exosomal miRNAs can predict AD at the asymptomatic stage remains unclear. METHODS This study is a multicenter study with four independent datasets to verify the capacity of exosomal miRNAs to identify preclinical AD. Subjects were recruited from a Beijing center in the pilot study (dataset 1: subjects with AD, n = 20; control subjects, n = 20), from other centers across China (dataset 2: subjects with AD, n = 95; control subjects, n = 93), a longitudinal cohort (dataset 3: subjects with preclinical AD, n = 101; control subjects, n = 102), and a confirmation study on familial AD (dataset 4: mutation carriers, n = 56; nonmutation carriers, n = 57). RESULTS A panel of miRNAs was changed in subjects with AD and can detect preclinical AD 5 to 7 years before the onset of cognitive impairment (areas under the curve = 0.85-0.88). CONCLUSIONS Exosomal miRNAs can be effective biomarkers for predicting AD 5 to 7 years prior to cognitive impairment onset.
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27
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Gestational Exercise Increases Male Offspring's Maximal Workload Capacity Early in Life. Int J Mol Sci 2022; 23:ijms23073916. [PMID: 35409278 PMCID: PMC8999565 DOI: 10.3390/ijms23073916] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 02/04/2023] Open
Abstract
Mothers’ antenatal strategies to improve the intrauterine environment can positively decrease pregnancy-derived intercurrences. By challenging the mother–fetus unit, gestational exercise (GE) favorably modulates deleterious stimuli, such as high-fat, high-sucrose (HFHS) diet-induced adverse consequences for offspring. We aimed to analyze whether GE alters maternal HFHS-consumption effects on male offspring’s maximal workload performance (MWP) and in some skeletal muscle (the soleus—SOL and the tibialis anterior—TA) biomarkers associated with mitochondrial biogenesis and oxidative fitness. Infant male Sprague-Dawley rats were divided into experimental groups according to mothers’ dietary and/or exercise conditions: offspring of sedentary control diet-fed or HFHS-fed mothers (C–S or HFHS–S, respectively) and of exercised HFHS-fed mothers (HFHS–E). Although maternal HFHS did not significantly alter MWP, offspring from GE dams exhibited increased MWP. Lower SOL AMPk levels in HFHS–S were reverted by GE. SOL PGC-1α, OXPHOS C-I and C-IV subunits remained unaltered by maternal diet, although increased in HFHS–E offspring. Additionally, GE prevented maternal diet-related SOL miR-378a overexpression, while upregulated miR-34a expression. Decreased TA C-IV subunit expression in HFHS–S was reverted in HFHS–E, concomitantly with the downregulation of miR-338. In conclusion, GE in HFHS-fed dams increases the offspring’s MWP, which seems to be associated with the intrauterine modulation of SM mitochondrial density and functional markers.
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28
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Liu S, Fan M, Zheng Q, Hao S, Yang L, Xia Q, Qi C, Ge J. MicroRNAs in Alzheimer's disease: Potential diagnostic markers and therapeutic targets. Biomed Pharmacother 2022; 148:112681. [PMID: 35177290 DOI: 10.1016/j.biopha.2022.112681] [Citation(s) in RCA: 107] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/26/2022] [Accepted: 01/31/2022] [Indexed: 12/13/2022] Open
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease, with cognitive decline as the primary clinical feature. According to epidemiological statistics, 50 million people worldwide are currently affected by Alzheimer's disease. Although new drugs such as aducanumab have been approved for use in the treatment of AD, none of them have reversed the progression of AD. MicroRNAs (miRNAs) are small molecule RNAs that exert their biological functions by regulating the expression of intracellular proteins, and differential abundance and varieties are found between the central and peripheral tissues of AD patients and healthy controls. This article will summarise the changes of miRNAs in the AD process, and the potential role of diagnostic markers and therapeutic targets in AD will be explored.
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Affiliation(s)
- Sen Liu
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China; Anhui Provincial Laboratory of Inflammatory and Immunity Disease, Anhui Institute of Innovative Drugs, Hefei, China
| | - Min Fan
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China; Anhui Provincial Laboratory of Inflammatory and Immunity Disease, Anhui Institute of Innovative Drugs, Hefei, China
| | - Qiang Zheng
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China; Anhui Provincial Laboratory of Inflammatory and Immunity Disease, Anhui Institute of Innovative Drugs, Hefei, China
| | - Shengwei Hao
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China; Anhui Provincial Laboratory of Inflammatory and Immunity Disease, Anhui Institute of Innovative Drugs, Hefei, China
| | - Longjun Yang
- Chaohu Clinical Medical College, Anhui Medical University, Hefei, China
| | - Qingrong Xia
- Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, China
| | - Congcong Qi
- Department of Laboratory Animal Science, Fudan University, Shanghai, China.
| | - Jinfang Ge
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China; Anhui Provincial Laboratory of Inflammatory and Immunity Disease, Anhui Institute of Innovative Drugs, Hefei, China.
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29
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Tsamou M, Carpi D, Pistollato F, Roggen EL. Sporadic Alzheimer's Disease- and Neurotoxicity-Related microRNAs Affecting Key Events of Tau-Driven Adverse Outcome Pathway Toward Memory Loss. J Alzheimers Dis 2022; 86:1427-1457. [PMID: 35213375 DOI: 10.3233/jad-215434] [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] [Indexed: 12/13/2022]
Abstract
BACKGROUND A complex network of aging-related homeostatic pathways that are sensitive to further deterioration in the presence of genetic, systemic, and environmental risk factors, and lifestyle, is implicated in the pathogenesis of progressive neurodegenerative diseases, such as sporadic (late-onset) Alzheimer's disease (sAD). OBJECTIVE Since sAD pathology and neurotoxicity share microRNAs (miRs) regulating common as well as overlapping pathological processes, environmental neurotoxic compounds are hypothesized to exert a risk for sAD initiation and progression. METHODS Literature search for miRs associated with human sAD and environmental neurotoxic compounds was conducted. Functional miR analysis using PathDip was performed to create miR-target interaction networks. RESULTS The identified miRs were successfully linked to the hypothetical starting point and key events of the earlier proposed tau-driven adverse outcome pathway toward memory loss. Functional miR analysis confirmed most of the findings retrieved from literature and revealed some interesting findings. The analysis identified 40 miRs involved in both sAD and neurotoxicity that dysregulated processes governing the plausible adverse outcome pathway for memory loss. CONCLUSION Creating miR-target interaction networks related to pathological processes involved in sAD initiation and progression, and environmental chemical-induced neurotoxicity, respectively, provided overlapping miR-target interaction networks. This overlap offered an opportunity to create an alternative picture of the mechanisms underlying sAD initiation and early progression. Looking at initiation and progression of sAD from this new angle may open for new biomarkers and novel drug targets for sAD before the appearance of the first clinical symptoms.
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Affiliation(s)
- Maria Tsamou
- ToxGenSolutions (TGS), Maastricht, The Netherlands
| | - Donatella Carpi
- European Commission, Joint Research Centre (JRC), Ispra VA, Italy
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Emerging Roles of Non-Coding RNAs in the Feed Efficiency of Livestock Species. Genes (Basel) 2022; 13:genes13020297. [PMID: 35205343 PMCID: PMC8872339 DOI: 10.3390/genes13020297] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/27/2022] [Accepted: 01/31/2022] [Indexed: 01/27/2023] Open
Abstract
A global population of already more than seven billion people has led to an increased demand for food and water, and especially the demand for meat. Moreover, the cost of feed used in animal production has also increased dramatically, which requires animal breeders to find alternatives to reduce feed consumption. Understanding the biology underlying feed efficiency (FE) allows for a better selection of feed-efficient animals. Non-coding RNAs (ncRNAs), especially micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs), play important roles in the regulation of bio-logical processes and disease development. The functions of ncRNAs in the biology of FE have emerged as they participate in the regulation of many genes and pathways related to the major FE indicators, such as residual feed intake and feed conversion ratio. This review provides the state of the art studies related to the ncRNAs associated with FE in livestock species. The contribution of ncRNAs to FE in the liver, muscle, and adipose tissues were summarized. The research gap of the function of ncRNAs in key processes for improved FE, such as the nutrition, heat stress, and gut–brain axis, was examined. Finally, the potential uses of ncRNAs for the improvement of FE were discussed.
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31
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Koppers M, Holt CE. Receptor-Ribosome Coupling: A Link Between Extrinsic Signals and mRNA Translation in Neuronal Compartments. Annu Rev Neurosci 2022; 45:41-61. [DOI: 10.1146/annurev-neuro-083021-110015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Axons receive extracellular signals that help to guide growth and synapse formation during development and to maintain neuronal function and survival during maturity. These signals relay information via cell surface receptors that can initiate local intracellular signaling at the site of binding, including local messenger RNA (mRNA) translation. Direct coupling of translational machinery to receptors provides an attractive way to activate this local mRNA translation and change the local proteome with high spatiotemporal resolution. Here, we first discuss the increasing evidence that different external stimuli trigger translation of specific subsets of mRNAs in axons via receptors and thus play a prominent role in various processes in both developing and mature neurons. We then discuss the receptor-mediated molecular mechanisms that regulate local mRNA translational with a focus on direct receptor-ribosome coupling. We advance the idea that receptor-ribosome coupling provides several advantages over other translational regulation mechanisms and is a common mechanism in cell communication. Expected final online publication date for the Annual Review of Neuroscience, Volume 45 is July 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Max Koppers
- Department of Biology, Division of Cell Biology, Neurobiology and Biophysics, Utrecht University, Utrecht, The Netherlands
| | - Christine E. Holt
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
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32
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Gowda P, Reddy PH, Kumar S. Deregulated mitochondrial microRNAs in Alzheimer's disease: Focus on synapse and mitochondria. Ageing Res Rev 2022; 73:101529. [PMID: 34813976 PMCID: PMC8692431 DOI: 10.1016/j.arr.2021.101529] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 10/17/2021] [Accepted: 11/16/2021] [Indexed: 01/03/2023]
Abstract
Alzheimer's disease (AD) is the most common cause of dementia and is currently one of the biggest public health concerns in the world. Mitochondrial dysfunction in neurons is one of the major hallmarks of AD. Emerging evidence suggests that mitochondrial miRNAs potentially play important roles in the mitochondrial dysfunctions, focusing on synapse in AD progression. In this meta-analysis paper, a comprehensive literature review was conducted to identify and discuss the (1) role of mitochondrial miRNAs that regulate mitochondrial and synaptic functions; (2) the role of various factors such as mitochondrial dynamics, biogenesis, calcium signaling, biological sex, and aging on synapse and mitochondrial function; (3) how synapse damage and mitochondrial dysfunctions contribute to AD; (4) the structure and function of synapse and mitochondria in the disease process; (5) latest research developments in synapse and mitochondria in healthy and disease states; and (6) therapeutic strategies that improve synaptic and mitochondrial functions in AD. Specifically, we discussed how differences in the expression of mitochondrial miRNAs affect ATP production, oxidative stress, mitophagy, bioenergetics, mitochondrial dynamics, synaptic activity, synaptic plasticity, neurotransmission, and synaptotoxicity in neurons observed during AD. However, more research is needed to confirm the locations and roles of individual mitochondrial miRNAs in the development of AD.
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Affiliation(s)
- Prashanth Gowda
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Neuroscience & Pharmacology, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Neurology, Departments of School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Neuroscience & Pharmacology, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Neurology, Departments of School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Department of Speech, Language and Hearing Sciences, School Health Professions, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
| | - Subodh Kumar
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
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33
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Tai Y, Chen J, Tao Z, Ren J. Non-coding RNAs: New players in mitophagy and neurodegeneration. Neurochem Int 2021; 152:105253. [PMID: 34864089 DOI: 10.1016/j.neuint.2021.105253] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 11/14/2021] [Accepted: 11/29/2021] [Indexed: 10/19/2022]
Abstract
Mitophagy controls mitochondrial quality to maintain cellular homeostasis, while aberrations in this process are responsible for neurodegenerative diseases. Mitophagy is initiated through the recruitment of autophagosomes in a ubiquitin-dependent or ubiquitin-independent manner under different stress conditions. Although the detailed molecular mechanisms of how mitophagy processes influence neurodegeneration remain largely uncharacterized, there is mounting evidence indicating that non-coding RNAs (ncRNAs), a variety of endogenous regulators, including microRNAs and long non-coding RNAs, extensively participate in mitophagy processes and play pivotal roles in the aging process and neurodegenerative diseases. Here, we reviewed the major mitophagy pathways modulated by some classical and newly found ncRNAs and summarized the diverse mechanisms in a regulatory network. We also discussed the generalizability of ncRNAs in the development of common neurodegenerative diseases related to proteotoxicity and the importance of mitophagy in the pathogenesis of these diseases. In summary, we propose that ncRNAs act as linkers between mitophagy and neurodegeneration, showing the potential therapeutic application of mitophagy regulation mediated by ncRNAs in neurodegenerative diseases.
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Affiliation(s)
- Yusi Tai
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
| | - Jing Chen
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Zhouteng Tao
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
| | - Jin Ren
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
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34
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Li L, Yu J, Ji SJ. Axonal mRNA localization and translation: local events with broad roles. Cell Mol Life Sci 2021; 78:7379-7395. [PMID: 34698881 PMCID: PMC11072051 DOI: 10.1007/s00018-021-03995-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 09/17/2021] [Accepted: 10/14/2021] [Indexed: 12/19/2022]
Abstract
Messenger RNA (mRNA) can be transported and targeted to different subcellular compartments and locally translated. Local translation is an evolutionally conserved mechanism that in mammals, provides an important tool to exquisitely regulate the subcellular proteome in different cell types, including neurons. Local translation in axons is involved in processes such as neuronal development, function, plasticity, and diseases. Here, we summarize the current progress on axonal mRNA transport and translation. We focus on the regulatory mechanisms governing how mRNAs are transported to axons and how they are locally translated in axons. We discuss the roles of axonally synthesized proteins, which either function locally in axons, or are retrogradely trafficked back to soma to achieve neuron-wide gene regulation. We also examine local translation in neurological diseases. Finally, we give a critical perspective on the remaining questions that could be answered to uncover the fundamental rules governing local translation, and discuss how this could lead to new therapeutic targets for neurological diseases.
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Affiliation(s)
- Lichao Li
- School of Life Sciences, Department of Biology, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Brain Research Center, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China
| | - Jun Yu
- School of Life Sciences, Department of Biology, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Brain Research Center, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China
| | - Sheng-Jian Ji
- School of Life Sciences, Department of Biology, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Brain Research Center, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China.
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35
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Duroux-Richard I, Apparailly F, Khoury M. Mitochondrial MicroRNAs Contribute to Macrophage Immune Functions Including Differentiation, Polarization, and Activation. Front Physiol 2021; 12:738140. [PMID: 34803730 PMCID: PMC8595120 DOI: 10.3389/fphys.2021.738140] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 09/22/2021] [Indexed: 12/22/2022] Open
Abstract
A subset of microRNA (miRNA) has been shown to play an important role in mitochondrial (mt) functions and are named MitomiR. They are present within or associated with mitochondria. Most of the mitochondrial miRNAs originate from the nucleus, while a very limited number is encoded by mtDNA. Moreover, the miRNA machinery including the Dicer and Argonaute has also been detected within mitochondria. Recent, literature has established a close relationship between miRNAs and inflammation. Indeed, specific miRNA signatures are associated with macrophage differentiation, polarization and functions. Nevertheless, the regulation of macrophage inflammatory pathways governed specifically by MitomiR and their implication in immune-mediated inflammatory disorders remain poorly studied. Here, we propose a hypothesis in which MitomiR play a key role in triggering macrophage differentiation and modulating their downstream activation and immune functions. We sustain this proposition by bioinformatic data obtained from either the human monocytic THP1 cell line or the purified mitochondrial fraction of PMA-induced human macrophages. Interestingly, 22% of the 754 assayed miRNAs were detected in the mitochondrial fraction and are either exclusively or highly enriched cellular miRNA. Furthermore, the in silico analysis performed in this study, identified a specific MitomiR signature associated with macrophage differentiation that was correlated with gene targets within the mitochondria genome or with mitochondrial pathways. Overall, our hypothesis and data suggest a previously unrecognized link between MitomiR and macrophage function and fate. We also suggest that the MitomiR-dependent control could be further enhanced through the transfer of mitochondria from donor to target cells, as a new strategy for MitomiR delivery.
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Affiliation(s)
| | - Florence Apparailly
- IRMB, INSERM, Université de Montpellier, CHU Montpellier, Montpellier, France.,Clinical Department for Osteoarticular Diseases, University Hospital of Montpellier, Montpellier, France
| | - Maroun Khoury
- Laboratory of Nano-Regenerative Medicine, Faculty of Medicine, Universidad de Los Andes, Santiago, Chile.,Cells for Cells and REGENERO, The Chilean Consortium for Regenerative Medicine, Santiago, Chile.,IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
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36
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Ziemann M, Lim SC, Kang Y, Samuel S, Sanchez IL, Gantier M, Stojanovski D, McKenzie M. MicroRNA-101-3p Modulates Mitochondrial Metabolism via the Regulation of Complex II Assembly. J Mol Biol 2021; 434:167361. [PMID: 34808225 DOI: 10.1016/j.jmb.2021.167361] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/17/2021] [Accepted: 11/11/2021] [Indexed: 12/27/2022]
Abstract
MicroRNA-101-3p (miR-101-3p) is a tumour suppressor that regulates cancer proliferation and apoptotic signalling. Loss of miR-101-3p increases the expression of the Polycomb Repressive Complex 2 (PRC2) subunit enhancer of zeste homolog 2 (EZH2), resulting in alterations to the epigenome and enhanced tumorigenesis. MiR-101-3p has also been shown to modulate various aspects of cellular metabolism, however little is known about the mechanisms involved. To investigate the metabolic pathways that are regulated by miR-101-3p, we performed transcriptome and functional analyses of osteosarcoma cells transfected with miR-101-3p. We found that miR-101-3p downregulates multiple mitochondrial processes, including oxidative phosphorylation, pyruvate metabolism, the citric acid cycle and phospholipid metabolism. We also found that miR-101-3p transfection disrupts the transcription of mitochondrial DNA (mtDNA) via the downregulation of the mitochondrial transcription initiation complex proteins TFB2M and Mic60. These alterations in transcript expression disrupt mitochondrial function, with significant decreases in both basal (54%) and maximal (67%) mitochondrial respiration rates. Native gel electrophoresis revealed that this diminished respiratory capacity was associated with reduced steady-state levels of mature succinate dehydrogenase (complex II), with a corresponding reduction of complex II enzymatic activity. Furthermore, miR-101-3p transfection reduced the expression of the SDHB subunit, with a concomitant disruption of the assembly of the SDHC subunit into mature complex II. Overall, we describe a new role for miR-101-3p as a modulator of mitochondrial metabolism via its regulation of multiple mitochondrial processes, including mtDNA transcription and complex II biogenesis.
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Affiliation(s)
- Mark Ziemann
- School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 3216 Geelong, Australia. https://twitter.com/@mdziemann
| | - Sze Chern Lim
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 3168 Melbourne, Australia
| | - Yilin Kang
- Department of Biochemistry and Pharmacology and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 3052 Melbourne, Australia
| | - Sona Samuel
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria 3002, Australia
| | - Isabel Lopez Sanchez
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria 3002, Australia; Ophthalmology, University of Melbourne, Department of Surgery Melbourne, Victoria 3000, Australia. https://twitter.com/@DrIsabelLopez
| | - Michael Gantier
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 3168 Melbourne, Australia; Department of Molecular and Translational Science, Monash University, 3168 Melbourne, Australia. https://twitter.com/@GantierLab
| | - Diana Stojanovski
- Department of Biochemistry and Pharmacology and The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 3052 Melbourne, Australia
| | - Matthew McKenzie
- School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 3216 Geelong, Australia; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 3168 Melbourne, Australia; Department of Molecular and Translational Science, Monash University, 3168 Melbourne, Australia.
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37
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Rencelj A, Gvozdenovic N, Cemazar M. MitomiRs: their roles in mitochondria and importance in cancer cell metabolism. Radiol Oncol 2021; 55:379-392. [PMID: 34821131 PMCID: PMC8647792 DOI: 10.2478/raon-2021-0042] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 09/28/2021] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) are short non-coding RNAs that play important roles in almost all biological pathways. They regulate post-transcriptional gene expression by binding to the 3'untranslated region (3'UTR) of messenger RNAs (mRNAs). MitomiRs are miRNAs of nuclear or mitochondrial origin that are localized in mitochondria and have a crucial role in regulation of mitochondrial function and metabolism. In eukaryotes, mitochondria are the major sites of oxidative metabolism of sugars, lipids, amino acids, and other bio-macromolecules. They are also the main sites of adenosine triphosphate (ATP) production. CONCLUSIONS In the review, we discuss the role of mitomiRs in mitochondria and introduce currently well studied mitomiRs, their target genes and functions. We also discuss their role in cancer initiation and progression through the regulation of mRNA expression in mitochondria. MitomiRs directly target key molecules such as transporters or enzymes in cell metabolism and regulate several oncogenic signaling pathways. They also play an important role in the Warburg effect, which is vital for cancer cells to maintain their proliferative potential. In addition, we discuss how they indirectly upregulate hexokinase 2 (HK2), an enzyme involved in glucose phosphorylation, and thus may affect energy metabolism in breast cancer cells. In tumor tissues such as breast cancer and head and neck tumors, the expression of one of the mitomiRs (miR-210) correlates with hypoxia gene signatures, suggesting a direct link between mitomiR expression and hypoxia in cancer. The miR-17/92 cluster has been shown to act as a key factor in metabolic reprogramming of tumors by regulating glycolytic and mitochondrial metabolism. This cluster is deregulated in B-cell lymphomas, B-cell chronic lymphocytic leukemia, acute myeloid leukemia, and T-cell lymphomas, and is particularly overexpressed in several other cancers. Based on the current knowledge, we can conclude that there is a large number of miRNAs present in mitochondria, termed mitomiR, and that they are important regulators of mitochondrial function. Therefore, mitomiRs are important players in the metabolism of cancer cells, which need to be further investigated in order to develop a potential new therapies for cancer.
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Affiliation(s)
- Andrej Rencelj
- Institute of Oncology Ljubljana, Department of Experimental Oncology, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Nada Gvozdenovic
- Institute of Oncology Ljubljana, Department of Experimental Oncology, Ljubljana, Slovenia
| | - Maja Cemazar
- Institute of Oncology Ljubljana, Department of Experimental Oncology, Ljubljana, Slovenia
- Faculty of Health Sciences, University of Primorska, Izola, Slovenia
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38
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Jia L, Zhu M, Yang J, Pang Y, Wang Q, Li Y, Li T, Li F, Wang Q, Li Y, Wei Y. Prediction of P-tau/Aβ42 in the cerebrospinal fluid with blood microRNAs in Alzheimer's disease. BMC Med 2021; 19:264. [PMID: 34775974 PMCID: PMC8591889 DOI: 10.1186/s12916-021-02142-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 09/27/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The most common biomarkers of Alzheimer's disease (AD) are amyloid β (Aβ) and tau, detected in cerebrospinal fluid (CSF) or with positron emission tomography imaging. However, these procedures are invasive and expensive, which hamper their availability to the general population. Here, we report a panel of microRNAs (miRNAs) in serum that can predict P-tau/Aβ42 in CSF and readily differentiate AD from other dementias, including vascular dementia (VaD), Parkinson disease dementia (PDD), behavioral variant frontotemporal dementia (bvFTD), and dementia with Lewy body (DLB). METHODS RNA samples were extracted from the participant's blood. P-tau/Aβ42 of CSF was examined for diagnostic purposes. A pilot study (controls, 21; AD, 23), followed by second (controls, 216; AD, 190) and third groups (controls, 153; AD, 151), is used to establish and verify a predictive model of P-tau/Aβ42 in CSF. The test is then applied to a fourth group of patients with different dementias (controls, 139; AD,155; amnestic mild cognitive impairment [aMCI], 55; VaD, 51; PDD, 53; bvFTD, 53; DLB, 52) to assess its diagnostic capacity. RESULTS In the pilot study, 29 upregulated and 31 downregulated miRNAs in the AD group were found. In Dataset 2, these miRNAs were then included as independent variables in the linear regression model. A seven-microRNA panel (miR-139-3p, miR-143-3p, miR-146a-5p, miR-485-5p, miR-10a-5P, miR-26b-5p, and miR-451a-5p) accurately predicted values of P-tau/Aβ42 of CSF. In Datasets 3 and 4, by applying the predicted P-tau/Aβ42, the predictive model successfully differentiates AD from controls and VaD, PDD, bvFTD, and DLB. CONCLUSIONS This study suggests that the panel of microRNAs is a promising substitute for traditional measurement of P-tau/Aβ42 in CSF as an effective biomarker of AD.
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Affiliation(s)
- Longfei Jia
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, China.
| | - Min Zhu
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, China
| | - Jianwei Yang
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, China
| | - Yana Pang
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, China
| | - Qi Wang
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, China
| | - Ying Li
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, China
| | - Tingting Li
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, China
| | - Fangyu Li
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, China
| | - Qigeng Wang
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, China
| | - Yan Li
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, China
| | - Yiping Wei
- Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, 45 Changchun St, Beijing, China
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Mesquita-Ribeiro R, Fort RS, Rathbone A, Farias J, Lucci C, James V, Sotelo-Silveira J, Duhagon MA, Dajas-Bailador F. Distinct small non-coding RNA landscape in the axons and released extracellular vesicles of developing primary cortical neurons and the axoplasm of adult nerves. RNA Biol 2021; 18:832-855. [PMID: 34882524 PMCID: PMC8782166 DOI: 10.1080/15476286.2021.2000792] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Neurons have highlighted the needs for decentralized gene expression and specific RNA function in somato-dendritic and axonal compartments, as well as in intercellular communication via extracellular vesicles (EVs). Despite advances in miRNA biology, the identity and regulatory capacity of other small non-coding RNAs (sncRNAs) in neuronal models and local subdomains has been largely unexplored.We identified a highly complex and differentially localized content of sncRNAs in axons and EVs during early neuronal development of cortical primary neurons and in adult axons in vivo. This content goes far beyond miRNAs and includes most known sncRNAs and precisely processed fragments from tRNAs, sno/snRNAs, Y RNAs and vtRNAs. Although miRNAs are the major sncRNA biotype in whole-cell samples, their relative abundance is significantly decreased in axons and neuronal EVs, where specific tRNA fragments (tRFs and tRHs/tiRNAs) mainly derived from tRNAs Gly-GCC, Val-CAC and Val-AAC predominate. Notably, although 5'-tRHs compose the great majority of tRNA-derived fragments observed in vitro, a shift to 3'-tRNAs is observed in mature axons in vivo.The existence of these complex sncRNA populations that are specific to distinct neuronal subdomains and selectively incorporated into EVs, equip neurons with key molecular tools for spatiotemporal functional control and cell-to-cell communication.
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Affiliation(s)
| | - Rafael Sebastián Fort
- Laboratorio de Interacciones Moleculares, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.,Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay
| | - Alex Rathbone
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | - Joaquina Farias
- Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay.,Polo de Desarrollo Universitario "Espacio de Biología Vegetal del Noreste", Centro Universitario Regional Noreste, UdelaR, Uruguay
| | - Cristiano Lucci
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | - Victoria James
- School of Veterinary Medicine and Science, University of Nottingham, Nottingham, UK
| | - Jose Sotelo-Silveira
- Departamento de Genómica, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay
| | - Maria Ana Duhagon
- Laboratorio de Interacciones Moleculares, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay
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40
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Singh V. Intracellular metabolic reprogramming mediated by micro-RNAs in differentiating and proliferating cells under non-diseased conditions. Mol Biol Rep 2021; 48:8123-8140. [PMID: 34643930 DOI: 10.1007/s11033-021-06769-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 09/14/2021] [Indexed: 11/30/2022]
Abstract
Intracellular metabolic reprogramming is a critical process the cells carry out to increase biomass, energy fulfillment and genome replication. Cells reprogram their demands from internal catabolic or anabolic activities in coordination with multiple genes and microRNAs which further control the critical processes of differentiation and proliferation. The microRNAs reprogram the metabolism involving mitochondria, the nucleus and the biochemical processes utilizing glucose, amino acids, lipids, and nucleic acids resulting in ATP production. The processes of glycolysis, tricarboxylic acid cycle, or oxidative phosphorylation are also mediated by micro-RNAs maintaining cells and organs in a non-diseased state. Several reports have shown practical applications of metabolic reprogramming for clinical utility to assess various diseases, mostly studying cancer and immune-related disorders. Cells under diseased conditions utilize glycolysis for abnormal growth or proliferation, respectively, affecting mitochondrial paucity and biogenesis. Similar metabolic processes also affect gene expressions and transcriptional regulation for carrying out biochemical reactions. Metabolic reprogramming is equally vital for regulating cell environment to maintain organs and tissues in non-diseased states. This review offers in depth insights and analysis of how miRNAs regulate metabolic reprogramming in four major types of cells undergoing differentiation and proliferation, i.e., immune cells, neuronal cells, skeletal satellite cells, and cardiomyocytes under a non-diseased state. Further, the work systematically summarizes and elaborates regulation of genetic switches by microRNAs through predominantly through cellular reprogramming and metabolic processes for the first time. The observations will lead to a better understanding of disease initiation during the differentiation and proliferation stages of cells, as well as fresh approaches to studying clinical onset of linked metabolic diseases targeting metabolic processes.
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Affiliation(s)
- Varsha Singh
- Centre for Life Sciences, Chitkara School of Health Sciences, Chitkara University, Rajpura, Punjab, 140401, India.
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41
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Huang WK, Shi H, Akçakaya P, Zeljic K, Gangaev A, Caramuta S, Yeh CN, Bränström R, Larsson C, Lui WO. Imatinib Regulates miR-483-3p and Mitochondrial Respiratory Complexes in Gastrointestinal Stromal Tumors. Int J Mol Sci 2021; 22:ijms221910600. [PMID: 34638938 PMCID: PMC8508888 DOI: 10.3390/ijms221910600] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 09/25/2021] [Accepted: 09/26/2021] [Indexed: 12/17/2022] Open
Abstract
Metabolic adaptation to increased oxidative phosphorylation (OXPHOS) has been found in gastrointestinal stromal tumor (GIST) upon imatinib treatment. However, the underlying mechanism of imatinib-induced OXPHOS is unknown. Discovering molecules that mediate imatinib-induced OXPHOS may lead to the development of therapeutic strategies synergizing the efficacy of imatinib. In this study, we explored the role of microRNAs in regulating OXPHOS in GIST upon imatinib treatment. Using a microarray approach, we found that miR-483-3p was one of the most downregulated miRNAs in imatinib-treated tumors compared to untreated tumors. Using an extended series of GIST samples, we further validated the downregulation of miR-483-3p in imatinib-treated GIST samples by RT-qPCR. Using both gain- and loss-of-function experiments, we showed that miR-483-3p could regulate mitochondrial respiratory Complex II expression, suggesting its role in OXPHOS regulation. Functionally, miR-483-3p overexpression could rescue imatinib-induced cell death. These findings provide the molecular link for imatinib-induced OXPHOS expression and the biological role of miR-483-3p in regulating cell viability upon imatinib treatment.
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Affiliation(s)
- Wen-Kuan Huang
- Department of Oncology-Pathology, Karolinska Institutet, BioClinicum J6:20, Karolinska University Hospital, 171 64 Solna, Sweden; (H.S.); (P.A.); (K.Z.); (A.G.); (S.C.); (C.L.)
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan
- Correspondence: (W.-K.H.); (W.-O.L.)
| | - Hao Shi
- Department of Oncology-Pathology, Karolinska Institutet, BioClinicum J6:20, Karolinska University Hospital, 171 64 Solna, Sweden; (H.S.); (P.A.); (K.Z.); (A.G.); (S.C.); (C.L.)
| | - Pinar Akçakaya
- Department of Oncology-Pathology, Karolinska Institutet, BioClinicum J6:20, Karolinska University Hospital, 171 64 Solna, Sweden; (H.S.); (P.A.); (K.Z.); (A.G.); (S.C.); (C.L.)
| | - Katarina Zeljic
- Department of Oncology-Pathology, Karolinska Institutet, BioClinicum J6:20, Karolinska University Hospital, 171 64 Solna, Sweden; (H.S.); (P.A.); (K.Z.); (A.G.); (S.C.); (C.L.)
| | - Anastasia Gangaev
- Department of Oncology-Pathology, Karolinska Institutet, BioClinicum J6:20, Karolinska University Hospital, 171 64 Solna, Sweden; (H.S.); (P.A.); (K.Z.); (A.G.); (S.C.); (C.L.)
| | - Stefano Caramuta
- Department of Oncology-Pathology, Karolinska Institutet, BioClinicum J6:20, Karolinska University Hospital, 171 64 Solna, Sweden; (H.S.); (P.A.); (K.Z.); (A.G.); (S.C.); (C.L.)
| | - Chun-Nan Yeh
- Department of Surgery, Chang Gung Memorial Hospital and GIST Team at Linkou, Chang Gung University College of Medicine, Taoyuan 33305, Taiwan;
| | - Robert Bränström
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden;
| | - Catharina Larsson
- Department of Oncology-Pathology, Karolinska Institutet, BioClinicum J6:20, Karolinska University Hospital, 171 64 Solna, Sweden; (H.S.); (P.A.); (K.Z.); (A.G.); (S.C.); (C.L.)
| | - Weng-Onn Lui
- Department of Oncology-Pathology, Karolinska Institutet, BioClinicum J6:20, Karolinska University Hospital, 171 64 Solna, Sweden; (H.S.); (P.A.); (K.Z.); (A.G.); (S.C.); (C.L.)
- Correspondence: (W.-K.H.); (W.-O.L.)
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Wang F, Zhang D, Zhang D, Li P, Gao Y. Mitochondrial Protein Translation: Emerging Roles and Clinical Significance in Disease. Front Cell Dev Biol 2021; 9:675465. [PMID: 34277617 PMCID: PMC8280776 DOI: 10.3389/fcell.2021.675465] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 06/09/2021] [Indexed: 12/28/2022] Open
Abstract
Mitochondria are one of the most important organelles in cells. Mitochondria are semi-autonomous organelles with their own genetic system, and can independently replicate, transcribe, and translate mitochondrial DNA. Translation initiation, elongation, termination, and recycling of the ribosome are four stages in the process of mitochondrial protein translation. In this process, mitochondrial protein translation factors and translation activators, mitochondrial RNA, and other regulatory factors regulate mitochondrial protein translation. Mitochondrial protein translation abnormalities are associated with a variety of diseases, including cancer, cardiovascular diseases, and nervous system diseases. Mutation or deletion of various mitochondrial protein translation factors and translation activators leads to abnormal mitochondrial protein translation. Mitochondrial tRNAs and mitochondrial ribosomal proteins are essential players during translation and mutations in genes encoding them represent a large fraction of mitochondrial diseases. Moreover, there is crosstalk between mitochondrial protein translation and cytoplasmic translation, and the imbalance between mitochondrial protein translation and cytoplasmic translation can affect some physiological and pathological processes. This review summarizes the regulation of mitochondrial protein translation factors, mitochondrial ribosomal proteins, mitochondrial tRNAs, and mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) in the mitochondrial protein translation process and its relationship with diseases. The regulation of mitochondrial protein translation and cytoplasmic translation in multiple diseases is also summarized.
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Affiliation(s)
- Fei Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Deyu Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Dejiu Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Peifeng Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Yanyan Gao
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China.,Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, China
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43
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Li L, Voloboueva L, Griffiths BB, Xu L, Giffard RG, Stary CM. MicroRNA-338 inhibition protects against focal cerebral ischemia and preserves mitochondrial function in vitro in astrocytes and neurons via COX4I1. Mitochondrion 2021; 59:105-112. [PMID: 33933660 PMCID: PMC8292173 DOI: 10.1016/j.mito.2021.04.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 03/19/2021] [Accepted: 04/26/2021] [Indexed: 01/23/2023]
Abstract
Brain-enriched microRNA-338 (miR-338) is known to play a central role in brain mitochondrial function, however the role of miR-338 in stroke injury remains unknown. This study investigated the role of miR-338 in injury from transient focal cerebral ischemia in mice, and in cell survival and mitochondrial function after in vitro ischemia in astrocyte and neuronal cultures. Pre-treatment of mice with intracerebroventricular injection of miR-338 antagomir 24 h prior to 1 h of middle cerebral artery occlusion (MCAO) significantly reduced infarct size and improved neurological score at both 24 h and 7d after injury. Levels of the miR-338 target cytochrome-c oxidase subunit 4I1 (COX4I1), which plays an essential role in maintaining brain mitochondrial ATP production, were increased in miR-338 antagomir-treated mice. Mouse primary astrocyte cell cultures subjected to glucose deprivation exhibited increased cell survival when pre-treated with miR-338 inhibitor, and greater cell death with miR-338 mimic. Decreased miR-338 levels were associated with increased ATP production, augmented cytochrome c oxidative (CcO) activity and preservation of COX4I1. In vitro protection with miR-338 inhibitor was blocked by concurrent knockdown of COX4I1 with small interfering RNA. Parallel studies in mouse neuronal N2a cultures resulted in preserved ATP content and CcO activity with miR-338 inhibition, indicating a shared miR-338-dependent response to ischemic stress between brain cell types. These results suggest that miR-338 inhibition and/or COX4I1-targeted therapies may be novel clinical strategies to protect against stroke injury via preservation of mitochondrial function in multiple cell types.
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Affiliation(s)
- Le Li
- Dept of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA; Dept of Anesthesiology, Southern Medical University, Guangzhou, China
| | - Ludmila Voloboueva
- Dept of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Brian B Griffiths
- Dept of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Lijun Xu
- Dept of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Rona G Giffard
- Dept of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Creed M Stary
- Dept of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA.
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Meseguer S. MicroRNAs and tRNA-Derived Small Fragments: Key Messengers in Nuclear-Mitochondrial Communication. Front Mol Biosci 2021; 8:643575. [PMID: 34026824 PMCID: PMC8138316 DOI: 10.3389/fmolb.2021.643575] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 03/08/2021] [Indexed: 12/18/2022] Open
Abstract
Mitochondria are not only important as energy suppliers in cells but also participate in other biological processes essential for cell growth and survival. They arose from α-proteobacterial predecessors through endosymbiosis and evolved transferring a large part of their genome to the host cell nucleus. Such a symbiotic relationship has been reinforced over time through increasingly complex signaling mechanisms between the host cell and mitochondria. So far, we do not have a complete view of the mechanisms that allow the mitochondria to communicate their functional status to the nucleus and trigger adaptive and compensatory responses. Recent findings place two classes of small non-coding RNAs (sncRNAs), microRNAs (miRNAs), and tRNA-derived small fragments, in such a scenario, acting as key pieces in the mitochondria-nucleus cross-talk. This review highlights the emerging roles and the interrelation of these sncRNAs in different signaling pathways between mitochondria and the host cell. Moreover, we describe in what way alterations of these complex regulatory mechanisms involving sncRNAs lead to diseases associated with mitochondrial dysfunction. In turn, these discoveries provide novel prognostic biomarker candidates and/or potential therapeutic targets.
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Affiliation(s)
- Salvador Meseguer
- Molecular and Cellular Immunology Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain
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Moghbeli M. Molecular interactions of miR-338 during tumor progression and metastasis. Cell Mol Biol Lett 2021; 26:13. [PMID: 33827418 PMCID: PMC8028791 DOI: 10.1186/s11658-021-00257-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 03/25/2021] [Indexed: 02/08/2023] Open
Abstract
Background Cancer, as one of the main causes of human deaths, is currently a significant global health challenge. Since the majority of cancer-related deaths are associated with late diagnosis, it is necessary to develop minimally invasive early detection markers to manage and reduce mortality rates. MicroRNAs (miRNAs), as highly conserved non-coding RNAs, target the specific mRNAs which are involved in regulation of various fundamental cellular processes such as cell proliferation, death, and signaling pathways. MiRNAs can also be regulated by long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). They are highly stable in body fluids and have tumor-specific expression profiles, which suggest their suitability as efficient non-invasive diagnostic and prognostic tumor markers. Aberrant expression of miR-338 has been widely reported in different cancers. It regulates cell proliferation, migration, angiogenesis, and apoptosis in tumor cells. Main body In the present review, we have summarized all miR-338 interactions with other non-coding RNAs (ncRNAs) and associated signaling pathways to clarify the role of miR-338 during tumor progression. Conclusions It was concluded that miR-338 mainly functions as a tumor suppressor in different cancers. There were also significant associations between miR-338 and other ncRNAs in tumor cells. Moreover, miR-338 has a pivotal role during tumor progression using the regulation of WNT, MAPK, and PI3K/AKT signaling pathways. This review highlights miR-338 as a pivotal ncRNA in biology of tumor cells.
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Affiliation(s)
- Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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46
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Wang JC, Huang Y, Zhang RX, Han ZJ, Zhou LL, Sun N, Dong WY, Zhuang GS. miR-338-3p inhibits autophagy in a rat model of allergic rhinitis after PM2.5 exposure through AKT/mTOR signaling by targeting UBE2Q1. Biochem Biophys Res Commun 2021; 554:1-6. [PMID: 33770685 DOI: 10.1016/j.bbrc.2021.03.085] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 03/15/2021] [Indexed: 10/21/2022]
Abstract
Exposure to fine particulate matter (PM2.5) increases the incidence of allergic rhinitis (AR). microRNA (miRNA) can regulate cell proliferation, invasion and apoptosis. However, the mechanism of miR-338-3p in mediating PM2.5-induced autophagy in AR animal models remains unknown. To explore the mechanism of miR-338-3p in PM2.5-induced autophagy in AR, the human nasal epithelium cells and AR model exposed to PM2.5 were deployed. The results showed that miR-338-3p was down-regulated in both nasal mucosa of PM2.5-exacerbated AR rat models and PM2.5-treated RPMI-2650 cells. Forced expression of miR-338-3p could inhibit autophagy in vitro. miR-338-3p specifically bound to UBE2Q1 3'-untranslated region (3' UTR) and negatively regulated its expression. Overexpression of UBE2Q1 attenuated the inhibitory effects of miR-338-3p on PM2.5-induced autophagy of RPMI-2650 cells through AKT/mTOR pathway. Moreover, our in vivo study found that after administration of agomiR-338-3p in AR rats model, the expression of autophagy-related proteins decreased and nasal symptoms alleviated. In conclusion, this study revealed that miR-338-3p acts as an autophagy suppressor in PM2.5-exacerbated AR by directly targeting UBE2Q1 and affecting AKT/mTOR pathway.
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Affiliation(s)
- Jin-Chao Wang
- Department of Otolaryngology, Huadong Hospital, Fudan University, Shanghai, 200040, China
| | - Yu Huang
- Department of Otolaryngology, Huadong Hospital, Fudan University, Shanghai, 200040, China
| | - Ru-Xin Zhang
- Department of Otolaryngology, Huadong Hospital, Fudan University, Shanghai, 200040, China.
| | - Zhi-Jin Han
- Department of Otolaryngology, Huadong Hospital, Fudan University, Shanghai, 200040, China
| | - Ling-Ling Zhou
- Department of Otolaryngology, Huadong Hospital, Fudan University, Shanghai, 200040, China
| | - Na Sun
- Department of Otolaryngology, Huadong Hospital, Fudan University, Shanghai, 200040, China
| | - Wei-Yang Dong
- Center for Atmospheric Chemistry Study, Department of Environmental Science and Engineering, Fudan University, Shanghai, 200040, China
| | - Guo-Shun Zhuang
- Center for Atmospheric Chemistry Study, Department of Environmental Science and Engineering, Fudan University, Shanghai, 200040, China
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Tabak S, Schreiber-Avissar S, Beit-Yannai E. Crosstalk between MicroRNA and Oxidative Stress in Primary Open-Angle Glaucoma. Int J Mol Sci 2021; 22:2421. [PMID: 33670885 PMCID: PMC7957693 DOI: 10.3390/ijms22052421] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/23/2021] [Accepted: 02/24/2021] [Indexed: 12/13/2022] Open
Abstract
Reactive oxygen species (ROS) plays a key role in the pathogenesis of primary open-angle glaucoma (POAG), a chronic neurodegenerative disease that damages the trabecular meshwork (TM) cells, inducing apoptosis of the retinal ganglion cells (RGC), deteriorating the optic nerve head, and leading to blindness. Aqueous humor (AH) outflow resistance and intraocular pressure (IOP) elevation contribute to disease progression. Nevertheless, despite the existence of pharmacological and surgical treatments, there is room for the development of additional treatment approaches. The following review is aimed at investigating the role of different microRNAs (miRNAs) in the expression of genes and proteins involved in the regulation of inflammatory and degenerative processes, focusing on the delicate balance of synthesis and deposition of extracellular matrix (ECM) regulated by chronic oxidative stress in POAG related tissues. The neutralizing activity of a couple of miRNAs was described, suggesting effective downregulation of pro-inflammatory and pro-fibrotic signaling pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), transforming growth factor-beta 2 (TGF-β2), Wnt/β-Catenin, and PI3K/AKT. In addition, with regards to the elevated IOP in many POAG patients due to increased outflow resistance, Collagen type I degradation was stimulated by some miRNAs and prevented ECM deposition in TM cells. Mitochondrial dysfunction as a consequence of oxidative stress was suppressed following exposure to different miRNAs. In contrast, increased oxidative damage by inhibiting the mTOR signaling pathway was described as part of the action of selected miRNAs. Summarizing, specific miRNAs may be promising therapeutic targets for lowering or preventing oxidative stress injury in POAG patients.
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Affiliation(s)
| | | | - Elie Beit-Yannai
- Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; (S.T.); (S.S.-A.)
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Rodrigues SC, Cardoso RMS, Duarte FV. Mitochondrial microRNAs: A Putative Role in Tissue Regeneration. BIOLOGY 2020; 9:biology9120486. [PMID: 33371511 PMCID: PMC7767490 DOI: 10.3390/biology9120486] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/16/2020] [Accepted: 12/19/2020] [Indexed: 12/12/2022]
Abstract
The most famous role of mitochondria is to generate ATP through oxidative phosphorylation, a metabolic pathway that involves a chain of four protein complexes (the electron transport chain, ETC) that generates a proton-motive force that in turn drives the ATP synthesis by the Complex V (ATP synthase). An impressive number of more than 1000 mitochondrial proteins have been discovered. Since mitochondrial proteins have a dual genetic origin, it is predicted that ~99% of these proteins are nuclear-encoded and are synthesized in the cytoplasmatic compartment, being further imported through mitochondrial membrane transporters. The lasting 1% of mitochondrial proteins are encoded by the mitochondrial genome and synthesized by the mitochondrial ribosome (mitoribosome). As a result, an appropriate regulation of mitochondrial protein synthesis is absolutely required to achieve and maintain normal mitochondrial function. Regarding miRNAs in mitochondria, it is well-recognized nowadays that several cellular mechanisms involving mitochondria are regulated by many genetic players that originate from either nuclear- or mitochondrial-encoded small noncoding RNAs (sncRNAs). Growing evidence collected from whole genome and transcriptome sequencing highlight the role of distinct members of this class, from short interfering RNAs (siRNAs) to miRNAs and long noncoding RNAs (lncRNAs). Some of the mechanisms that have been shown to be modulated are the expression of mitochondrial proteins itself, as well as the more complex coordination of mitochondrial structure and dynamics with its function. We devote particular attention to the role of mitochondrial miRNAs and to their role in the modulation of several molecular processes that could ultimately contribute to tissue regeneration accomplishment.
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Affiliation(s)
- Sílvia C. Rodrigues
- Exogenus Therapeutics, 3060-197 Cantanhede, Portugal;
- Doctoral Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra, 3004-504 Coimbra, Portugal
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
| | | | - Filipe V. Duarte
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
- Correspondence:
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Kumar S, Reddy PH. The role of synaptic microRNAs in Alzheimer's disease. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165937. [PMID: 32827646 PMCID: PMC7680400 DOI: 10.1016/j.bbadis.2020.165937] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 08/04/2020] [Accepted: 08/17/2020] [Indexed: 12/11/2022]
Abstract
Structurally and functionally active synapses are essential for neurotransmission and for maintaining normal synaptic and cognitive functions. Researchers have found that synaptic dysfunction is associated with the onset and progression of neurodegenerative diseases, such as Alzheimer's disease (AD), and synaptic dysfunction is even one of the main physiological hallmarks of AD. MiRNAs are present in small, subcellular compartments of the neuron such as neural dendrites, synaptic vesicles, and synaptosomes are known as synaptic miRNAs. Synaptic miRNAs involved in governing multiple synaptic functions that lead to healthy brain functioning and synaptic activity. However, the precise role of synaptic miRNAs has not been determined in AD progression. This review emphasizes the presence of miRNAs at the synapse, synaptic compartments and roles of miRNAs in multiple synaptic functions. We focused on synaptic miRNAs alteration in AD, and how the modulation of miRNAs effect the synaptic functions in AD. We also discussed the impact of synaptic miRNAs in AD progression concerning the synaptic ATP production, mitochondrial function, and synaptic activity.
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Affiliation(s)
- Subodh Kumar
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
| | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department Public Health, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Speech, Language and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
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50
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Zhang Y, Qin Y, Chopp M, Li C, Kemper A, Liu X, Wang X, Zhang L, Zhang ZG. Ischemic Cerebral Endothelial Cell-Derived Exosomes Promote Axonal Growth. Stroke 2020; 51:3701-3712. [PMID: 33138691 PMCID: PMC7686085 DOI: 10.1161/strokeaha.120.031728] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 10/07/2020] [Indexed: 01/08/2023]
Abstract
BACKGROUND AND PURPOSE Cerebral endothelial cells (CECs) and axons of neurons interact to maintain vascular and neuronal homeostasis and axonal remodeling in normal and ischemic brain, respectively. However, the role of exosomes in the interaction of CECs and axons in brain under normal conditions and after stroke is unknown. METHODS Exosomes were isolated from CECs of nonischemic rats and is chemic rats (nCEC-exos and isCEC-exos), respectively. A multicompartmental cell culture system was used to separate axons from neuronal cell bodies. RESULTS Axonal application of nCEC-exos promotes axonal growth of cortical neurons, whereas isCEC-exos further enhance axonal growth than nCEC-exos. Ultrastructural analysis revealed that CEC-exos applied into distal axons were internalized by axons and reached to their parent somata. Bioinformatic analysis revealed that both nCEC-exos and isCEC-exos contain abundant mature miRNAs; however, isCEC-exos exhibit more robust elevation of select miRNAs than nCEC-exos. Mechanistically, axonal application of nCEC-exos and isCEC-exos significantly elevated miRNAs and reduced proteins in distal axons and their parent somata that are involved in inhibiting axonal outgrowth. Blockage of axonal transport suppressed isCEC-exo-altered miRNAs and proteins in somata but not in distal axons. CONCLUSIONS nCEC-exos and isCEC-exos facilitate axonal growth by altering miRNAs and their target protein profiles in recipient neurons.
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Affiliation(s)
- Yi Zhang
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, 48202
| | - Yi Qin
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, 48202
| | - Michael Chopp
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, 48202
- Department of Physics, Oakland University, Rochester, Michigan, 48309
| | - Chao Li
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, 48202
| | - Amy Kemper
- Department of Pathology, Henry Ford Hospital, Detroit, Michigan, 48202
| | - Xianshuang Liu
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, 48202
| | - Xinli Wang
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, 48202
| | - Li Zhang
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, 48202
| | - Zheng Gang Zhang
- Department of Neurology, Henry Ford Hospital, Detroit, Michigan, 48202
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