TY - JOUR
T1 - Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases
AU - Genin, Emmanuelle C.
AU - Bannwarth, Sylvie
AU - Lespinasse, Françoise
AU - Ortega-Vila, Bernardo
AU - Fragaki, Konstantina
AU - Itoh, Kie
AU - Villa, Elodie
AU - Lacas-Gervais, Sandra
AU - Jokela, Manu
AU - Auranen, Mari
AU - Ylikallio, Emil
AU - Mauri-Crouzet, Alessandra
AU - Tyynismaa, Henna
AU - Vihola, Anna
AU - Augé, Gaelle
AU - Cochaud, Charlotte
AU - Sesaki, Hiromi
AU - Ricci, Jean Ehrland
AU - Udd, Bjarne
AU - Vives-Bauza, Cristofol
AU - Paquis-Flucklinger, Véronique
N1 - Funding Information:
This work was made possible by grants to V.P-F from the ANR (French Research Agency) N°ANR-16-CE16-0024-01. J-E.R. is financed by the Fondation ARC ( Association pour la Recherche sur le Cancer ) and E.V. is supported by La Ligue contre le Cancer .
Funding Information:
We acknowledge Pr. W. Rossoll (Department of Neurosciences, Mayo Clinic , FL32224 , US) for kindly providing plasmid vectors. We also thank the IRCAN's Molecular and Cellular Core Imaging (PICMI) Facility. PICMI was supported financially by FEDER , Région Provence Alpes-Côte d'Azur, Conseil Départemental 06, Cancéropôle PACA and Inserm.
Funding Information:
This work was made possible by grants to V.P-F from the ANR (French Research Agency) N°ANR-16-CE16-0024-01. J-E.R. is financed by the Fondation ARC (Association pour la Recherche sur le Cancer) and E.V. is supported by La Ligue contre le Cancer.
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/11
Y1 - 2018/11
N2 - Following the involvement of CHCHD10 in FrontoTemporal-Dementia-Amyotrophic Lateral Sclerosis (FTD-ALS) clinical spectrum, a founder mutation (p.Gly66Val) in the same gene was identified in Finnish families with late-onset spinal motor neuronopathy (SMAJ). SMAJ is a slowly progressive form of spinal muscular atrophy with a life expectancy within normal range. In order to understand why the p.Ser59Leu mutation, responsible for severe FTD-ALS, and the p.Gly66Val mutation could lead to different levels of severity, we compared their effects in patient cells. Unlike affected individuals bearing the p.Ser59Leu mutation, patients presenting with SMAJ phenotype have neither mitochondrial myopathy nor mtDNA instability. The expression of CHCHD10S59L mutant allele leads to disassembly of mitochondrial contact site and cristae organizing system (MICOS) with mitochondrial dysfunction and loss of cristae in patient fibroblasts. We also show that G66V fibroblasts do not display the loss of MICOS complex integrity and mitochondrial damage found in S59L cells. However, S59L and G66V fibroblasts show comparable accumulation of phosphorylated mitochondrial TDP-43 suggesting that the severity of phenotype and mitochondrial damage do not depend on mitochondrial TDP-43 localization. The expression of the CHCHD10G66V allele is responsible for mitochondrial network fragmentation and decreased sensitivity towards apoptotic stimuli, but with a less severe effect than that found in cells expressing the CHCHD10S59L allele. Taken together, our data show that cellular phenotypes associated with p.Ser59Leu and p.Gly66Val mutations in CHCHD10 are different; loss of MICOS complex integrity and mitochondrial dysfunction, but not TDP-43 mitochondrial localization, being likely essential to develop a severe motor neuron disease.
AB - Following the involvement of CHCHD10 in FrontoTemporal-Dementia-Amyotrophic Lateral Sclerosis (FTD-ALS) clinical spectrum, a founder mutation (p.Gly66Val) in the same gene was identified in Finnish families with late-onset spinal motor neuronopathy (SMAJ). SMAJ is a slowly progressive form of spinal muscular atrophy with a life expectancy within normal range. In order to understand why the p.Ser59Leu mutation, responsible for severe FTD-ALS, and the p.Gly66Val mutation could lead to different levels of severity, we compared their effects in patient cells. Unlike affected individuals bearing the p.Ser59Leu mutation, patients presenting with SMAJ phenotype have neither mitochondrial myopathy nor mtDNA instability. The expression of CHCHD10S59L mutant allele leads to disassembly of mitochondrial contact site and cristae organizing system (MICOS) with mitochondrial dysfunction and loss of cristae in patient fibroblasts. We also show that G66V fibroblasts do not display the loss of MICOS complex integrity and mitochondrial damage found in S59L cells. However, S59L and G66V fibroblasts show comparable accumulation of phosphorylated mitochondrial TDP-43 suggesting that the severity of phenotype and mitochondrial damage do not depend on mitochondrial TDP-43 localization. The expression of the CHCHD10G66V allele is responsible for mitochondrial network fragmentation and decreased sensitivity towards apoptotic stimuli, but with a less severe effect than that found in cells expressing the CHCHD10S59L allele. Taken together, our data show that cellular phenotypes associated with p.Ser59Leu and p.Gly66Val mutations in CHCHD10 are different; loss of MICOS complex integrity and mitochondrial dysfunction, but not TDP-43 mitochondrial localization, being likely essential to develop a severe motor neuron disease.
KW - CHCHD10
KW - FTD-ALS
KW - Mitochondria
KW - SMAJ
KW - TDP-43
UR - http://www.scopus.com/inward/record.url?scp=85052438409&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052438409&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2018.07.027
DO - 10.1016/j.nbd.2018.07.027
M3 - Article
C2 - 30092269
AN - SCOPUS:85052438409
SN - 0969-9961
VL - 119
SP - 159
EP - 171
JO - Neurobiology of Disease
JF - Neurobiology of Disease
ER -