RNAseq of murine melanocytes cell lines, normal and albino

Melanosomes are lysosome-associated 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 proceeds with the export and recycling of non-required cargo, through tubular carriers and vesicular fission derived from melanosome membranes. Although constriction events have been observed at melanosome membranes, the mechanisms underlying their fission remain unclear. We found that MFF is delivered to melanosomes by mitochondria-derived vesicles (MDVs) and that it is located at melanosome membrane fission sites. Downregulation of MFF leads to an increase in the size of early melanosomes, accumulation of intracellular melanin, and increased melanosome lumen catabolism. Exploration of the MFF interactome in melanocytes revealed that its activity depends on a complex network of cytoskeletal factors: inhibition of actin nucleation is indeed sufficient to restore the effects on melanosome size. Our data show for the first time that MDVs-mediated MFF trafficking to melanosomes is necessary for their membrane remodeling and fission, promoting the transition from early to mature stage melanosomes