Hernandez-Camacho, J. D. | bioRxiv Science

bioRxiv2026

Loss of CHCHD2 and CHCHD10 reveals differential vulnerability to bioenergetic failure in cardiac and skeletal muscle

Mutations in the mitochondrial proteins CHCHD2 and CHCHD10 cause severe neurodegenerative and neuromuscular disorders, yet their physiological functions remain poorly defined. CHCHD2 and CHCHD10 localize to the mitochondrial intermembrane space, where they assemble into a high-molecular-weight complex. Here, we generated Chchd2/Chchd10 double-knockout (DKO) mice to define the in vivo role of this complex. DKO mice developed reduced lean mass, progressive muscle weakness, and oxidative phosphorylation defects in both cardiac and skeletal muscle. Despite comparable bioenergetic impairment, CHCHD2-CHCHD10 deficiency elicited tissue-specific responses distinct from those induced by the disease-associated CHCHD10 S59L mutation. The heart accumulated enlarged mitochondria with disrupted ultrastructure and underwent adaptive proteomic remodeling that preserved myocardial contractility into adulthood. By contrast, skeletal muscle exhibited limited proteomic alterations, accompanied by profound changes in lipid composition, reduced expression of the myogenic regulators, and altered myofiber size. Mechanistically, depletion of CHCHD2 and CHCHD10 in primary satellite cells impaired proliferation and myogenic differentiation, suggesting that defective postnatal myogenesis contributes to the muscle growth defect in DKO mice. Together, these findings identify the CHCHD2-CHCHD10 complex as a critical regulator of mitochondrial integrity and demonstrate that its loss drives tissue-specific defects culminating in diverse pathological outcomes.

cell biology↗

bioRxiv2025

Mutant CHCHD10 disrupts cytochrome c oxidation and activates retrograde signaling in a model of cardiomyopathy.

Mutations in CHCHD10, a mitochondrial intermembrane space (IMS) protein implicated in proteostasis and cristae maintenance, cause multi-systemic mitochondrial disease. Heterozygous Chchd10 knock-in mice modeling the human CHCHD10S59L variant associated with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS-FTD) develop a mitochondrial cardiomyopathy driven by CHCHD10 insolubility and aggregation, which is associated with chronic activation of the mitochondrial integrated stress response (mtISR). Here, we demonstrate that cardiac dysfunction in Chchd10S55L/+ mice carrying the orthologous pathogenic variant is associated with dual defects originating at the onset of disease: (1) early bioenergetic dysfunction linked to defects in the mitochondrial copper homeostasis and the oxidation of cytochrome c and (2) maladaptive mtISR signaling via the OMA1-DELE1-HRI axis. Using Oma1E324Q/E324Qknock-in mice, we show that the catalytic inactivation of the mitochondrial protease OMA1 in Chchd10S55L/+ mice delays cardiomyopathy onset without rescuing CHCHD10 insolubility, proteomic remodeling, cristae defects or OXPHOS impairment, demonstrating that mtISR can be uncoupled from the bioenergetic collapse triggered by mutant CHCHD10. Proteomic profiling of soluble and insoluble mitochondrial proteins in Chchd10S55L/+ mice 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 mutant CHCHD10 insolubility compromises metabolic resilience by impairing both mitochondrial bioenergetics and stress adaptation, offering new perspectives for the development of therapeutic targets.

cell biology↗