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. CHCHD10S55L mice develop progressive motor deficits, myopathy, cardiomyopathy and accelerated mortality. Critically, CHCHD10 accumulates in aggregates with its paralog CHCHD2 specifically in affected tissues of CHCHD10S55L 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 CHCHD10S55L-dependent disease pathology is not caused by loss-of-function. Overall, CHCHD10S55L mice recapitulate crucial aspects of human disease and reveal a novel toxic gain-of-function mechanism through maladaptive mtISR and metabolic dysregulation.
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We acknowledge the funding support of Muscular Dystrophy Association Grant MDA382033 (to G. M.) for this project. We also acknowledge The Jackson Laboratory Genome Engineering Technology and Physiology cores. Costs were defrayed by Cancer Center Support, National Cancer Institute (Grant CA034196) to The Jackson Laboratory. Additional studies were supported using Grant NIH Precision Genetics U54 OD020351 (to C. L.) and NIH/NINDS R01NS062055 (to G. M.). We also acknowledge the WCMC’s Center of Comparative Medicine and Pathology, the Neuroanatomy EM Core in the BMRI, and the EM Imaging Core of WCM.
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Anderson, C.J., Bredvik, K., Burstein, S.R. et al. ALS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response. Acta Neuropathol 138, 103–121 (2019). https://doi.org/10.1007/s00401-019-01989-y
- Knock-in mice
- Mitochondrial myopathy
- Protein aggregation
- Mitochondrial integrated stress response