CHCHD10 mutations: how mitochondrial dysfunction leads to motor neuron disease – MitoMotor

Recently, we provided genetic basis to support the conclusion that mitochondrial dysfunction can have a causative effect in motor neuron degeneration. We reported a large family with a mitochondrial myopathy associated with motor neuron disease and cognitive decline looking like frontotemporal dementia (FTD). We identified a missense mutation (p.Ser59Leu) in the CHCHD10 gene coding for a mitochondrial protein whose function was unknown. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) phenotype in a mitochondrial disease led to analyse CHCHD10 in cohorts of patients with FTD and ALS clinical spectrum. Rapidly, our group and others reported CHCHD10 mutations in patients with FTD-ALS and familial or sporadic pure ALS. Furthermore, a founder mutation in CHCHD10 was identified in 17 Finnish families with late-onset spinal motor neuropathy (SMAJ), a benign motor neuron disease. We also showed that CHCHD10 is a mitochondrial protein located in the intermembrane space that belongs to MICOS complex involved in mitochondrial cristae maintenance. Disassembly of MICOS complex in patient fibroblasts carrying the CHCHD10S59L mutant allele leads to loss of mitochondrial cristae, disorganisation of nucleoids and defect in caspase-dependent apoptosis.

Amyotrophic lateral sclerosis is a devastating disease affecting upper and lower motor neurons leading to progressive failure of the neuromuscular system and death from respiratory failure. Among all factors involved in ALS pathogenesis, mitochondrial dysfunction has always been recognized as a candidate major player. However, whether mitochondria have a causative role in ALS has been always debated. Our results open a new field to explore the pathogenesis of motor neuron disease by showing that mitochondrial dysfunction may be at the origin of some of these phenotypes. The aims of this project are (i) to better characterize the role of the CHCHD10 protein and to compare the effects of different CHCHD10 mutations leading to different clinical phenotypes, (ii) to understand how CHCHD10 mutations lead to motor neuron cell death by generating specific human cellular and mouse models, (iii) to search whether CHCHD10 mutations could be involved in other clinical phenotypes and, (iv) to determine which interventions aimed to restore correct specific mitochondrial functions may be a therapeutic option.