Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondrial cardiomyopathy

Mitochondrial cardiomyopathies are fatal diseases, with no effective treatment. Alterations of heart mitochondrial function activate the mitochondrial integrated stress response (ISRmt), a transcriptional program affecting cell metabolism, mitochondrial biogenesis, and proteostasis. In humans, mutations in CHCHD10, a mitochondrial protein with unknown function, were recently associated with dominant multi-system mitochondrial diseases, whose pathogenic mechanisms remain to be elucidated. Here, in CHCHD10 knockin mutant mice, we identify an extensive cardiac metabolic rewiring triggered by proteotoxic ISRmt. The stress response arises early on, before the onset of bioenergetic impairments, triggering a switch from oxidative to glycolytic metabolism, enhancement of transsulfuration and one carbon (1C) metabolism, and widespread metabolic imbalance. In parallel, increased NADPH oxidases elicit antioxidant responses, leading to heme depletion. As the disease progresses, the adaptive metabolic stress response fails, resulting in fatal cardiomyopathy. Our findings suggest that early interventions to counteract metabolic imbalance could ameliorate mitochondrial cardiomyopathy associated with proteotoxic ISRmt. [Display omitted] •Mutant CHCHD10 induces mitochondrial protein aggregation and ISRmt in mouse heart•Chronic cardiac ISRmt causes imbalanced nucleotide metabolism and mtDNA depletion•ISRmt and metabolic imbalance precede OXPHOS dysfunction in CHCHD10 mutant heart•NOX upregulation and oxidative stress trigger heme depletion and iron dysregulation Sayles et al. report that mutant CHCHD10 proteotoxicity activates the mitochondrial integrated stress response (ISRmt) in a mouse model of mitochondrial cardiomyopathy. Chronic ISRmt causes profound metabolic imbalances, culminating in oxidative stress and iron dysregulation, ultimately resulting in mitochondrial dysfunction and contributing to disease pathogenesis.