期刊
ANNALS OF NEUROLOGY
卷 84, 期 2, 页码 289-301出版社
WILEY
DOI: 10.1002/ana.25288
关键词
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资金
- Wellcome Centre for Mitochondrial Research [203105/Z/16/Z]
- Medical Research Council (MRC) Centre for Translational Research in Neuromuscular Disease Mitochondrial Disease Patient Cohort [G0800674]
- UK National Institute for Health Research Biomedical Research Centre in Age and Age Related Diseases
- MRC/Engineering and Physical Sciences Research Council Molecular Pathology Node
- Lily Foundation
- UK NHS Specialist Commissioners Rare Mitochondrial Disorders of Adults and Children Service
- MRC as part of the MRC Centre for Neuromuscular Disease [MR/K501074/1, MR/K000608/1]
- MRC as part of the Centre for Ageing and Vitality [MR/L016354/1]
- National Research Fund of Luxembourg
- Barbour Foundation
- Wharton Fund
- NIH [R35GM119793]
- senior Parkinson's UK fellowship [F-1401]
- BBSRC [BB/M012093/1] Funding Source: UKRI
- MRC [MC_U147585819, MR/K000608/1, MR/L016354/1, MC_U147585827, G0400491, G0800674] Funding Source: UKRI
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R35GM119793, R01GM127625] Funding Source: NIH RePORTER
ObjectiveIn patients with mitochondrial DNA (mtDNA) maintenance disorders and with aging, mtDNA deletions sporadically form and clonally expand within individual muscle fibers, causing respiratory chain deficiency. This study aimed to identify the sub-cellular origin and potential mechanisms underlying this process. MethodsSerial skeletal muscle cryosections from patients with multiple mtDNA deletions were subjected to subcellular immunofluorescent, histochemical, and genetic analysis. ResultsWe report respiratory chain-deficient perinuclear foci containing mtDNA deletions, which show local elevations of both mitochondrial mass and mtDNA copy number. These subcellular foci of respiratory chain deficiency are associated with a local increase in mitochondrial biogenesis and unfolded protein response signaling pathways. We also find that the commonly reported segmental pattern of mitochondrial deficiency is consistent with the three-dimensional organization of the human skeletal muscle mitochondrial network. InterpretationWe propose that mtDNA deletions first exceed the biochemical threshold causing biochemical deficiency in focal regions adjacent to the myonuclei, and induce mitochondrial biogenesis before spreading across the muscle fiber. These subcellular resolution data provide new insights into the possible origin of mitochondrial respiratory chain deficiency in mitochondrial myopathy. Ann Neurol 2018;84:289-301
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