Heart mitochondrial proteome of Chchd10(S55L), Oma1(E324A), Chchd10(S55L)/Oma1(E324A) and WT

ABSTRACT: Mutations in CHCHD10, a mitochondrial protein implicated in proteostasis and cristae maintenance, cause autosomal dominant mitochondrial diseases characterized by cardiomyopathy and neurodegeneration. Heterozygous Chchd10 S55L knock-in mice (modeling the human S59L variant) develop progressive mitochondrial cardiomyopathy driven by CHCHD10 aggregation, which is associated with chronic activation of the mitochondrial integrated stress response (mtISR). Here, we demonstrate that cardiac dysfunction is affected by biological sex and is associated with dual defects originating at the onset of disease: (1) early respiratory chain failure linked to cytochrome c depletion and impaired copper homeostasis and (2) maladaptive mtISR signaling via the OMA1-DELE1-HRI axis. Genetic inactivation of OMA1 delays cardiomyopathy without rescuing CHCHD10 insolubility, proteomic remodeling, cristae defects or OXPHOS impairment, demonstrating that mtISR can be uncoupled from the bioenergetic collapse triggered by CHCHD10 protein aggregation. Proteomic profiling of soluble and insoluble mitochondrial proteins reveals wide-spread disruptions of mitochondrial proteostasis, including IMS proteins involved in cytochrome c biogenesis. Defective respiration in mutant mitochondria could be rescued by the exogenous addition of cytochrome c, pinpointing IMS proteostasis disruption as a key pathogenic mechanism. Our work reveals that CHCHD10 insolubility and aggregation compromises metabolic resilience by impairing both electron transport and stress adaptation within the IMS, offering new perspectives for the development of therapeutic targets. This repository contains the heart whole proteome of the four different genotypes. a) whole proteome dataset is indicated by the identifier: KmUUbGabck

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Hendrik Nolte  

LAB HEAD: Thomas Langer

PROVIDER: PXD064045 | Pride | 2025-11-07

REPOSITORIES: Pride