Open AccessCHCHD 10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis
Author(s) -
Genin Emmanuelle C,
Plutino Morgane,
Bannwarth Sylvie,
Villa Elodie,
CisnerosBarroso Eugenia,
Roy Madhuparna,
OrtegaVila Bernardo,
Fragaki Konstantina,
Lespinasse Françoise,
PineroMartos Estefania,
Augé Gaëlle,
Moore David,
Burté Florence,
LacasGervais Sandra,
Kageyama Yusuke,
Itoh Kie,
YuWaiMan Patrick,
Sesaki Hiromi,
Ricci JeanEhrland,
VivesBauza Cristofol,
PaquisFlucklinger Véronique
Publication year - 2016
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201505496
Subject(s) - mitochondrial dna , mitochondrion , biology , microbiology and biotechnology , mutant , mitophagy , mutation , genome , genome instability , apoptosis , c9orf72 , genetics , dna repair , dna damage , allele , gene , dna , trinucleotide repeat expansion , autophagy
CHCHD 10 ‐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 ( CMT 2). Here, we show that CHCHD 10 resides with mitofilin, CHCHD 3 and CHCHD 6 within the “mitochondrial contact site and cristae organizing system” ( MICOS ) complex. CHCHD 10 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 CHCHD 10 mutant fibroblasts and this likely explains the accumulation of deleted mt DNA molecules in patient muscle. CHCHD 10 mutant fibroblasts are not defective in the delivery of mitochondria to lysosomes suggesting that impaired mitophagy does not contribute to mt DNA instability. Interestingly, the expression of CHCHD 10 mutant alleles inhibits apoptosis by preventing cytochrome c release.