A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. V. Paquis1,2, S. Bannwarth1,2, S. Ait-El-Mkadem1,2, A. Chaussenot1,2, E. C. Genin1, S. Lacas-Gervais3, K. Fragaki1,2, L. Berg-Alonso1, Y. Kageyama4, V. Serre5, D. G. Moore6, A. Verschueren7, C. Rouzier1,2, I. Le Ber8,9, G. Augé1,2, C. Cochaud2, F. Lespinasse1, K. NGuyen10, A. de Septenville8, A. Brice8, P. Yu-Wai-Man6, H. Sesaki4, J. Pouget7 1) Department of Medical Genetics, IRCAN, UMR CNRS 7284/INSERM U1081/UNS, Nice, France; 2) Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, France; 3) Joint Center for Applied Electron Microscopy, Nice Sophia-Antipolis University, France; 4) Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; 5) UMR7592 CNRS, Jacques Monod Institute, Paris Diderot University, France; 6) Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK; 7) Department of Neurology, Timone Hospital, Marseille Teaching Hospital, France; 8) Sorbonne Université, UPMC Univ Paris 06, UM75, Inserm U1127, Cnrs UMR7225, Institut du Cerveau et de la Moelle épinière (ICM), F-75013 Paris, France; 9) National Reference Centre on Rare Dementias, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; 10) Department of Medical Genetics, Timone Hospital, Marseille Teaching Hospital, France.

   Mitochondrial DNA (mtDNA) 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 looking like frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and COX negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mtDNA deletions found in skeletal muscle revealed a mtDNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. By whole-exome sequencing (WES), 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 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 (FTD-ALS) phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven FTD-ALS. We identified the same missense p.Ser59Leu mutation in one of these FTD-ALS families. This work opens a novel field to explore the pathogenesis of FTD-ALS clinical spectrum by showing that mitochondrial disease may be at the origin of some of these phenotypes.