MFF budding from mitochondria regulates melanosome size and maturation

Melanosomes are lysosome-related organelles that produce and accumulate melanin. Their biogenesis begins with the trafficking of melanogenic proteins from the endo-lysosomal system into non-pigmented vacuoles derived from endosomes. Subsequently, 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 the outer mitochondrial membrane protein mitochondrial fission factor (MFF) is actively released from mitochondria to melanosomes. We found MFF on melanosomes at different stages of maturation and early melanosome fission sites. Upon downregulation of MFF, but not DRP1, 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. Inhibition of actin nucleation was sufficient to restore the effects of MFF silencing on melanosomes. Our data unveil an extramitochondrial role for MFF in the regulation of melanosome morphology and maturation that, independently of DRP1, is supported by actin polymerization and nucleation factors.