DrosophilaMetaxin-2 controls beta-barrel protein biogenesis and muscle growth in a stage-dependent fashion

Metaxin-2 (Mtx2) is an evolutionarily conserved mitochondrial outer membrane protein. Mutations in humanMtx2cause mandibuloacral dysplasia (MADaM), a progeroid disorder. However, the pathologic mechanisms ofMtx2loss-of-function remain largely unknown. UsingDrosophila, we showMtx2null mutants exhibit pupal lethality, rescued byDrosophilaor human Mtx2, underscoring functional conservation across species. Tissue-specific conditional knockout and rescue experiments reveal muscle as a critical site of dMtx2 action, with alternations of myofibril assembly and myogenic proteins being observed indMtx2mutants. Structural and functional mitochondrial abnormalities are also detected, verifying dMtx2’s function in mitochondrial homeostasis. Notably, Mtx2 deficiency affects beta-barrel protein biogenesis and muscle development in pupa but not in larva, demonstrating Mtx2’s dynamic regulation in mitochondrial proteostasis and muscle development. Our results elucidate mitochondrial mechanisms driving potential muscle-autonomous defects in MADaM patients and highlights stage-specific Mtx2 function as a prospective therapeutic target for this progeroid syndrome.