ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response.

TitleALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response.
Publication TypeJournal Article
Year of Publication2019
AuthorsAnderson CJ, Bredvik K, Burstein SR, Davis C, Meadows SM, Dash J, Case L, Milner TA, Kawamata H, Zuberi A, Piersigilli A, Lutz C, Manfredi G
JournalActa Neuropathol
Date Published2019 Mar 14

Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10), a mitochondrial protein of unknown function, cause a disease spectrum with clinical features of motor neuron disease, dementia, myopathy and cardiomyopathy. To investigate the pathogenic mechanisms of CHCHD10, we generated mutant knock-in mice harboring the mouse-equivalent of a disease-associated human S59L mutation, S55L in the endogenous mouse gene. CHCHD10 mice develop progressive motor deficits, myopathy, cardiomyopathy and accelerated mortality. Critically, CHCHD10 accumulates in aggregates with its paralog CHCHD2 specifically in affected tissues of CHCHD10 mice, leading to aberrant organelle morphology and function. Aggregates induce a potent mitochondrial integrated stress response (mtISR) through mTORC1 activation, with elevation of stress-induced transcription factors, secretion of myokines, upregulated serine and one-carbon metabolism, and downregulation of respiratory chain enzymes. Conversely, CHCHD10 ablation does not induce disease pathology or activate the mtISR, indicating that CHCHD10-dependent disease pathology is not caused by loss-of-function. Overall, CHCHD10 mice recapitulate crucial aspects of human disease and reveal a novel toxic gain-of-function mechanism through maladaptive mtISR and metabolic dysregulation.

Alternate JournalActa Neuropathol.
PubMed ID30877432
Grant ListMDA382033 / / Muscular Dystrophy Association /
602894 / / Muscular Dystrophy Association /
CA034196 / / National Cancer Institute /
U54 OD020351 / / National Institutes of Health /
R01NS062055 / / National Institute of Neurological Disorders and Stroke /