| Autor: |
Anderson CJ; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA., Bredvik K; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA., Burstein SR; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA., Davis C; The Rare and Orphan Disease Center, JAX Center for Precision Genetics, 600 Main Street, Bar Harbor, ME, 04609, USA., Meadows SM; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA.; Neuroscience Graduate Program, Weill Cornell Graduate School of Medical Sciences, 1300 York Ave, New York, NY, 10065, USA., Dash J; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA., Case L; The Rare and Orphan Disease Center, JAX Center for Precision Genetics, 600 Main Street, Bar Harbor, ME, 04609, USA., Milner TA; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA.; Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, USA., Kawamata H; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA., Zuberi A; The Rare and Orphan Disease Center, JAX Center for Precision Genetics, 600 Main Street, Bar Harbor, ME, 04609, USA., Piersigilli A; Tri-Institutional Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, and The Rockefeller University, New York, NY, 10065, USA., Lutz C; The Rare and Orphan Disease Center, JAX Center for Precision Genetics, 600 Main Street, Bar Harbor, ME, 04609, USA., Manfredi G; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st Street, New York, NY, 10065, USA. gim2004@med.cornell.edu. |
| Abstrakt: |
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 S55L 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 S55L 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 S55L -dependent disease pathology is not caused by loss-of-function. Overall, CHCHD10 S55L 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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