Mitochondrial unfolded protein response as a central stress-integration hub: mechanisms and implications in disease contexts.

Maintaining integrity of the plasma membrane requires robust resealing and repair. Cell types that repeatedly face mechanical stress, like skeletal muscle fibers, cardiomyocytes, and epithelial cells, are susceptible to plasma membrane disruption (). To maintain normal tissue health and function, cells have evolved a conserved, rapid, and efficient mechanism of membrane repair. This process relies on calcium-dependent signaling and a coordinated recruitment of repair machinery, including annexins and dysferlin, to reseal the membrane (). Failure to efficiently repair membrane lesions can result in cell death, inflammation, and chronic tissue degeneration (). In skeletal muscle, genetic defects affecting the sarcolemma produce muscular dystrophy, associated with distinct mechanisms. Loss of membrane-stabilizing proteins, such as dystrophin and sarcoglycan proteins, destabilize the muscle membrane, increasing susceptibility to damage, while the membrane repair machinery remains functionally intact (, ). In contrast, loss-of-function mutations in the membrane resealing protein dysferlin result in defective membrane repair and prolonged leak despite a stable membrane (, ). Annexins are calcium-sensitive, membrane-binding proteins involved in membrane repair. With plasma membrane disruption, annexins translocate to the membrane lesion and induce membrane folding at and around the site of damage to facilitate resealing (, ). , the gene that encodes annexin A6 (ANXA6), was identified as a genetic modifier of muscular dystrophy (). Within seconds following membrane injury, ANXA6 translocates to the site of membrane injury and forms a repair cap that acts as a molecular “band-aid” over the lesion, a mechanism conserved across different cell types (–). ANXA6 facilitates the prompt recruitment of other annexins, including annexin A1 (ANXA1) and annexin A2 (ANXA2), to the repair cap at the site of membrane rupture (, ). Despite its role in membrane repair, removal of ANXA2 in dysferlin-deficient () muscle paradoxically reduced inflammation and fat deposition in muscle and improved muscle function (). Dysferlin localizes adjacent to the annexin protein cap at the site of membrane injury and promotes phosphatidylserine (PS) accumulation at the lesion, a key step in the repair process that engages macrophages (, , , ). Annexins interact with dysferlin but not with dystrophin (), and skeletal muscle–specific expression of dysferlin is sufficient to resolve the inflammatory response in mice ().