Abstract
Copper is an essential trace element required for mitochondrial respiration and cellular metabolism, yet its role in skeletal muscle remains incompletely understood. Here, we show that skeletal muscle-specific deletion of the high-affinity copper importer Ctr1 (SMKO) in mice leads to copper deficiency, resulting in exercise intolerance, metabolic dysfunction, and hallmarks of mitochondrial myopathy, including ragged-red fibers, lactic acidosis, and aberrant mitochondrial morphology. Copper deficiency disrupted electron transport chain proteome and induced mitochondrial hyperfusion. We identified mitochondrial carrier homolog 2 (MTCH2), an outer mitochondrial membrane protein, as a copper-binding regulator of mitochondrial copper distribution and morphology. Restoring copper levels via the copper ionophore or AAV-mediated Ctr1 re-expression rescued mitochondrial function and alleviated myopathic features in SMKO. These findings highlight MTCH2 as a key mediator of a critical link between copper homeostasis and mitochondrial remodeling required for skeletal muscle function.