MFF budding from mitochondria regulates melanosome size and maturation

Abstract Melanosomes are lysosome-related organelles that produce and accumulate melanin. Melanosome maturation is regulated by their association with mitochondria and requires the export and recycling of unneeded cargo via tubular carriers and fission, the mechanisms of which are unknown. Here we show that melanosome fission requires the outer mitochondrial membrane protein mitochondrial fission factor (MFF). We retrieved MFF on melanosomes at different stages of maturation and at early melanosome fission sites: upon downregulation of MFF, but not of the dynamin related protein 1 (DRP1) that executes mitochondrial fission, early melanosomes enlarged, intracellular melanin accumulated and melanosome lumen catabolism increased. The MFF interactome in melanocytes posited a role for a complex network of cytoskeletal factors in its activity. Indeed inhibition of actin nucleation was sufficient to curtail the effects of MFF silencing on melanosomes. Our data unveil an extramitochondrial role for MFF in the regulation of melanosome morphology and maturation that is independent of DRP1 but requires actin polymerization and nucleation factors.