In the last decade, dominant mutations in the mitochondrial protein CHCHD10 and its paralogue CHCHD2 were shown to cause familial amyotrophic lateral sclerosis and Parkinson’s disease, respectively, with phenotypes that often resemble the idiopathic forms of the diseases. Different mutations in CHCHD10 cause additional neuromuscular disorders, including the lower motor neuron disease spinal muscular atrophy Jokela type and autosomal dominant isolated mitochondrial myopathy. Modelling these disorders is revealing how mitochondrial dysfunction contributes to the aetiology of neuromuscular and neurodegenerative diseases.

In this dissertation I generate and characterise a knockin mouse model of the CHCHD10 p.G58R mutation, which in humans causes a mitochondrial myopathy and cardiomyopathy. The G58R mouse recapitulates the human phenotype, developing a severe myopathy from birth and a cardiomyopathy later in life. I found that mutant CHCHD10 forms aggregates in affected tissues, applying a toxic protein stress to the inner mitochondrial membrane as evidenced by prominent dilations of cristae containing membranous inclusions. Unexpectedly, the survival of CHCHD10-KI mice depends on a protective stress response mediated by the mitochondrial metalloendopeptidase OMA1. The OMA1 stress response acts both locally within mitochondria, causing mitochondrial fragmentation, and signals outside the mitochondria, activating the integrated stress response through cleavage of DAP3-binding cell death enhancer 1 (DELE1). I additionally identify an isoform switch in the terminal complex of the electron transport chain as a component of this response.

Furthermore, I perform ultra-high depth sequencing of mitochondrial DNA (mtDNA) of CHCHD10 mutant mice and show that mtDNA deletion levels are higher in affected tissue, and the accumulation of these deletions happens in an age-dependent manner. I finally show that in addition to accelerating the rate of naturally occurring deletions, CHCHD10 mutations also lead to the accumulation of a novel set of deletions characterised by shorter direct repeats flanking the deletion breakpoints.

I therefore here demonstrate that CHCHD10 mutations cause protein aggregation, inner membrane instability and mtDNA deletions with a distinct signature. This leads to the activation of an OMA1 stress response which is critical for neonatal survival, coordinating local and global stress responses to reshape the mitochondrial network and proteome.