TY - JOUR
T1 - CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis
AU - Genin, Emmanuelle C.
AU - Plutino, Morgane
AU - Bannwarth, Sylvie
AU - Villa, Elodie
AU - Cisneros-Barroso, Eugenia
AU - Roy, Madhuparna
AU - Ortega-Vila, Bernardo
AU - Fragaki, Konstantina
AU - Lespinasse, Françoise
AU - Pinero-Martos, Estefania
AU - Augé, Gaëlle
AU - Moore, David
AU - Burté, Florence
AU - Lacas-Gervais, Sandra
AU - Kageyama, Yusuke
AU - Itoh, Kie
AU - Yu-Wai-Man, Patrick
AU - Sesaki, Hiromi
AU - Ricci, Jean Ehrland
AU - Vives-Bauza, Cristofol
AU - Paquis-Flucklinger, Véronique
N1 - Publisher Copyright:
© 2016 EMBO.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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. Synopsis: CHCHD10 is found to be part of the MICOS complex. Mutations in CHCHD10, previously associated with ALS, cause MICOS disassembly, loss of mitochondrial cristae, mitochondrial genome repair impairment after oxidative stress, and inhibition of apoptosis. CHCHD10 is found to be a component of the MICOS complex. CHCHD10 mutations disassemble the MICOS complex leading to loss of mitochondrial cristae junctions. Assembly of OXPHOS complexes is impaired leading to respiratory chain deficiency. Nucleoids are disorganized resulting in mtDNA repair impairment after oxidative stress. CHCHD10 mutations do not affect mitophagy. Expression of CHCHD10 mutant alleles prevents cytochrome c release and thus inhibits apoptosis via the caspase-dependent pathway. CHCHD10 is found to be part of the MICOS complex. Mutations in CHCHD10, previously associated with ALS, cause MICOS disassembly, loss of mitochondrial cristae, mitochondrial genome repair impairment after oxidative stress, and inhibition of apoptosis.
AB - 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. Synopsis: CHCHD10 is found to be part of the MICOS complex. Mutations in CHCHD10, previously associated with ALS, cause MICOS disassembly, loss of mitochondrial cristae, mitochondrial genome repair impairment after oxidative stress, and inhibition of apoptosis. CHCHD10 is found to be a component of the MICOS complex. CHCHD10 mutations disassemble the MICOS complex leading to loss of mitochondrial cristae junctions. Assembly of OXPHOS complexes is impaired leading to respiratory chain deficiency. Nucleoids are disorganized resulting in mtDNA repair impairment after oxidative stress. CHCHD10 mutations do not affect mitophagy. Expression of CHCHD10 mutant alleles prevents cytochrome c release and thus inhibits apoptosis via the caspase-dependent pathway. CHCHD10 is found to be part of the MICOS complex. Mutations in CHCHD10, previously associated with ALS, cause MICOS disassembly, loss of mitochondrial cristae, mitochondrial genome repair impairment after oxidative stress, and inhibition of apoptosis.
KW - CHCHD10
KW - Mitochondria
KW - Mitochondrial disease
KW - Motor neuron disease
KW - mtDNA instability
UR - http://www.scopus.com/inward/record.url?scp=84956738385&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84956738385&partnerID=8YFLogxK
U2 - 10.15252/emmm.201505496
DO - 10.15252/emmm.201505496
M3 - Article
C2 - 26666268
AN - SCOPUS:84956738385
SN - 1757-4676
VL - 8
SP - 58
EP - 72
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 1
ER -