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Nuclear genetic modulation of tissue-specific mitochondrial RNA processing contributes to common disease risk.

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Τίτλος: Nuclear genetic modulation of tissue-specific mitochondrial RNA processing contributes to common disease risk.
Συγγραφείς: Centanini E; Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King's College London, London, UK.; Mitochondrial Neurobiology Laboratory, The Francis Crick Institute, London, UK., Pain O; Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK., Chinnery PF; Department of Clinical Neuroscience & Medical Research Council Mitochondrial Biology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK., Hodgkinson A; Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King's College London, London, UK. alan.hodgkinson@kcl.ac.uk.
Πηγή: Nature communications [Nat Commun] 2026 Apr 30; Vol. 17 (1). Date of Electronic Publication: 2026 Apr 30.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
Imprint Name(s): Original Publication: [London] : Nature Pub. Group
Ιατρικοί όροι (MeSH): RNA, Mitochondrial*/genetics , RNA, Mitochondrial*/metabolism , Mitochondria*/genetics , Mitochondria*/metabolism , Cell Nucleus*/genetics , Cell Nucleus*/metabolism , RNA Processing, Post-Transcriptional*/genetics, DNA, Mitochondrial/genetics ; DNA, Mitochondrial/metabolism ; Organ Specificity/genetics ; Parkinson Disease/genetics ; Hypertension/genetics ; Humans ; Genetic Predisposition to Disease ; Genetic Variation ; UK Biobank
Περίληψη: Mitochondrial dysfunction is widely implicated in human disease, yet whether it plays a causal role and why effects are tissue-specific remain unclear. Here, we analyse over 15,000 RNA-sequencing datasets from 49 tissue types integrated with germline genetic data to investigate the impact of mitochondrial DNA (mtDNA) transcription on disease risk. We identify 25 nuclear genetic variants associated with mtDNA transcript abundance, revealing gene- and tissue-specific regulatory architectures. We then develop tissue-specific genetic scores to predict mtDNA transcript levels and validate them in independent datasets. Applying these scores to 377,439 UK Biobank participants reveals significant associations between predicted mtDNA transcript abundance and multiple common diseases and quantitative traits, many showing marked tissue specificity, including associations with hypertension and Parkinson's disease in biologically relevant tissues. These findings provide genetic evidence that variation in mtDNA transcriptional processes contributes to complex disease biology and highlight mitochondrial RNA processing as a compelling therapeutic target.
(© 2026. The Author(s).)
Competing Interests: Competing interests: The authors declare no competing interests.
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Grant Information: BB/R006075/1 RCUK | Biotechnology and Biological Sciences Research Council (BBSRC); BB/T008709/1 RCUK | Biotechnology and Biological Sciences Research Council (BBSRC); BB/Y003209/1 RCUK | Biotechnology and Biological Sciences Research Council (BBSRC); 222811/Z/21/Z Wellcome Trust (Wellcome); 226653/Z/22/Z Wellcome Trust (Wellcome); 224486/Z/21/Z Wellcome Trust (Wellcome); MC_UU_00028/7 RCUK | Medical Research Council (MRC); PGL23/100048 Rosetrees Trust; 10748 LifeArc
Substance Nomenclature: 0 (RNA, Mitochondrial)
0 (DNA, Mitochondrial)
Entry Date(s): Date Created: 20260430 Date Completed: 20260707 Latest Revision: 20260813
Update Code: 20260813
PubMed Central ID: PMC13338043
DOI: 10.1038/s41467-026-72649-5
PMID: 42062290
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:2041-1723
DOI:10.1038/s41467-026-72649-5