Mitochondrial DNA instability disorders are responsible for a large clinical 
spectrum, among which amyotrophic lateral sclerosis-like symptoms and 
frontotemporal dementia are extremely rare. We report a large family with a 
late-onset phenotype including motor neuron disease, cognitive decline 
resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all 
patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative 
fibres with combined respiratory chain deficiency and abnormal assembly of 
complex V. The multiple mitochondrial DNA deletions found in skeletal muscle 
revealed a mitochondrial DNA instability disorder. Patient fibroblasts present 
with respiratory chain deficiency, mitochondrial ultrastructural alterations and 
fragmentation of the mitochondrial network. Interestingly, expression of 
matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not 
inhibited in patient fibroblasts. Using whole-exome sequencing we identified a 
missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a 
coiled-coil helix coiled-coil helix protein, whose function is unknown. We show 
that CHCHD10 is a mitochondrial protein located in the intermembrane space and 
enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa 
cells led to fragmentation of the mitochondrial network and ultrastructural 
major abnormalities including loss, disorganization and dilatation of cristae. 
The observation of a frontotemporal dementia-amyotrophic lateral sclerosis 
phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 
families with pathologically proven frontotemporal dementia-amyotrophic lateral 
sclerosis. We identified the same missense p.Ser59Leu mutation in one of these 
families. This work opens a novel field to explore the pathogenesis of the 
frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by 
showing that mitochondrial disease may be at the origin of some of these 
phenotypes.