Abstract
Mitochondrial protein import machineries are essential for organelle homeostasis. Metaxin-2 (Mtx2) is an evolutionarily conserved component of the mitochondrial sorting and assembly machinery, and its mutations are associated with a progeroid syndrome, named mandibuloacral dysplasia associated to Mtx2 (MADaM). To investigate the pathologic mechanisms of MADaM, we developed Mtx2 genetic models in Drosophila. Mtx2 null mutants are lethal at a preadult stage, and this phenotype can be rescued by expression of either Drosophila Mtx2 (dMtx2) or its human ortholog, demonstrating functional conservation across species. Tissue-specific conditional knockout and transgene rescue experiments pinpoint muscle as a critical tissue requiring dMtx2 function. Loss of dMtx2 impairs myofibril assembly and induces structural and functional abnormalities in muscle mitochondria. Notably, Mtx2 deficiency significantly reduces the expression of myogenic, mitochondrial, and ribosomal proteins. Overexpression of Drosophila Myc, a master regulator of ribosome biogenesis and cell growth, successfully rescues the preadult lethality caused by dMtx2 deficiency, and partially restores sarcomere and mitochondrial defects. Our results reveal an interaction between Mtx2-related mitochondrial and ribosomal homeostasis, and elucidate potential Myc-dependent pharmaceutic mechanisms underlying MADaM pathologies.
