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CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis

Lookup NU author(s): Dr Florence Burte, Dr Patrick Yu Wai Man



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.

Publication metadata

Author(s): Genin EC, Plutino M, Bannwarth S, Villa E, Cisneros-Barroso E, Roy M, Ortega-Vila B, Fragaki K, Lespinasse F, Pinero-Martos E, Auge G, Moore D, Burte F, Lacas-Gervais S, Kageyama Y, Itoh K, Yu-Wai-Man P, Sesaki H, Ricci JE, Vives-Bauza C, Paquis-Flucklinger V

Publication type: Article

Publication status: Published

Journal: EMBO Molecular Medicine

Year: 2016

Volume: 8

Issue: 1

Pages: 58-72

Print publication date: 01/01/2016

Online publication date: 14/12/2015

Acceptance date: 16/11/2015

Date deposited: 09/03/2016

ISSN (print): 1757-4676

ISSN (electronic): 1757-4684

Publisher: Wiley-Blackwell Publishing Ltd.


DOI: 10.15252/emmm.201505496


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Funder referenceFunder name
Association Francaise contre les Myopathies (AFM)
Fight for Sight (UK)
Fondation ARC pour la Recherche sur le Cancer
Fondation pour la Recherche Medicale (FRM)
UK National Institute of Health Research (NIHR) as part of the Rare Diseases Translational Research Collaboration
CP11/00046Spanish Instituto de Salud Carlos III
DEA20130727390FRM fellowship
G1002570Clinician Scientist Fellowship Award from Medical Research Council (UK)
GM089853National Institutes of Health