Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.

ABSTRACT: Mutations in CHCHD10, a mitochondrial intermembrane space (IMS) protein implicated in proteostasis and cristae maintenance, cause mitochondrial disease. Knock-in mice modeling the human CHCHD10^S59L variant associated with ALS-FTD develop a mitochondrial cardiomyopathy driven by CHCHD10 aggregation and activation of the mitochondrial integrated stress response (mtISR). We show that cardiac dysfunction is associated with dual defects originating at the onset of disease: (1) bioenergetic failure linked to impaired mitochondrial copper homeostasis and cytochrome c oxidation, and (2) maladaptive mtISR signaling via the OMA1-DELE1-HRI axis. Using protease-inactive Oma1^E324Q/E324Q knock-in mice, we show that blunting mtISR in Chchd10^S55L/+ mice delays cardiomyopat

SUBMITTER: Campos-Ribeiro MA 

PROVIDER: S-EPMC12905356 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature