Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases

Abstract

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 CHCHD10 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 CHCHD10 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 CHCHD10 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.

Dominant toxicity of ALS–FTD-associated CHCHD10S59L is mediated by TDP-43 and PINK1

“…Despite efforts to elucidate their pathogenic mechanisms, many controversial findings suggest that mutations in CHCHD10 do not share a common disease-causing mechanism (1,11,12,(19)(20)(21)(22)25). Our results also mirror these current controversial findings.…”

“…However, CHCHD10 is not well localized with MICOS, and CHCHD10-CHCHD2 hetero-complex formation decreases in patient fibroblasts carrying CHCHD10 R15L (21). Although CHCHD10 and TDP-43 physically interact (19), phosphorylated TDP-43 levels are not associated with the phenotypic severity of CHCHD10 S59L or CHCHD10 G66V (22). Indeed, severity is more closely associated with MICOS formation (22).…”

“…Although CHCHD10 and TDP-43 physically interact (19), phosphorylated TDP-43 levels are not associated with the phenotypic severity of CHCHD10 S59L or CHCHD10 G66V (22). Indeed, severity is more closely associated with MICOS formation (22).…”

EGCG protects cardiomyocytes against hypoxia-reperfusion injury through inhibition of OMA1 activation

“…In addition to OPA1, the mitochondrial contact site and cristae organizing system (MICOS) is also central in the maintenance of the cristae structure and it is located in the mitochondrial inner membrane (Kozjak-Pavlovic, 2017). MICOS is also crucial for the regulation of mitochondrial function (Genin et al, 2018). Four core components of MICOS, including the MICOS complex subunits MIC60, MIC25 and MIC19 (officially known as IMMT, CHCHD6 and CHCHD3, respectively), and the sorting and assembly machinery component 50 homolog (Samm50), were evaluated by Fig.…”

A CHCHD10 variant causing ALS elicits an unfolded protein response through the IRE1/XBP1 pathway

“…Although all reported pathogenic mutations in CHCHD10 are autosomal dominant, the molecular basis of pathogenicity of CHCHD10 is variable. For instance, the p.S59L variant reported in patients with ALS-FTD (frontotemporal dementia) is associated with a fragmented mitochondrial network, protein aggregates in mitochondria, and the activation of the integrated stress response (ISR), ascribed to a toxic gain of function (Anderson, Bredvik et al, 2019, Genin, Bannwarth et al, 2018, Genin, Madji Hounoum et al, 2019. On the other hand, the p.R15L and p.G66V variants, in which reduced levels of CHCHD10 protein are associated with mitochondrial respiratory chain dysfunction, appear to be haploinsufficient (Brockmann, Freischmidt et al, 2018, Penttila, Jokela et al, 2015, Straub et al, 2018.…”