期刊
EMBO MOLECULAR MEDICINE
卷 8, 期 1, 页码 58-72出版社
WILEY
DOI: 10.15252/emmm.201505496
关键词
CHCHD10; mitochondria; mitochondrial disease; motor neuron disease; mtDNA instability
资金
- Fondation pour la Recherche Medicale (FRM)
- Association Francaise contre les Myopathies (AFM)
- National Institutes of Health [GM089853]
- Fondation ARC pour la Recherche sur le Cancer
- Clinician Scientist Fellowship Award from Medical Research Council (UK) [G1002570]
- Fight for Sight (UK)
- UK National Institute of Health Research (NIHR) as part of the Rare Diseases Translational Research Collaboration
- Spanish Instituto de Salud Carlos III [CP11/00046]
- FRM fellowship [DEA20130727390]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM089853] Funding Source: NIH RePORTER
- MRC [G1002570, G0701386] Funding Source: UKRI
- Medical Research Council [G1002570, G0701386] Funding Source: researchfish
- Fight for Sight [1479/80] Funding Source: researchfish
CHCHD10-related diseases include mitochondrial DNA instability disorder, frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) clinical spectrum, late-onset spinal motor neuropathy (SMAJ), and Charcot-Marie-Tooth disease type 2 (CMT2). Here, we show that CHCHD10 resides with mitofilin, CHCHD3 and CHCHD6 within the mitochondrial contact site and cristae organizing system (MICOS) complex. CHCHD10 mutations lead to MICOS complex disassembly and loss of mitochondrial cristae with a decrease in nucleoid number and nucleoid disorganization. Repair of the mitochondrial genome after oxidative stress is impaired in CHCHD10 mutant fibroblasts and this likely explains the accumulation of deleted mtDNA molecules in patient muscle. CHCHD10 mutant fibroblasts are not defective in the delivery of mitochondria to lysosomes suggesting that impaired mitophagy does not contribute to mtDNA instability. Interestingly, the expression of CHCHD10 mutant alleles inhibits apoptosis by preventing cytochrome c release.
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