Melanocytes are epidermal cells characterized by the presence of melanosomes, highly specialized organelles responsible for the process of melanin production, melanogenesis. Despite the growing interest in inter-organelle dynamics, the interaction of melanosomes with other organelles is poorly studied: only few studies provide hints of a relationship between melanosomes and mitochondria.
Mitochondria are organized as a dynamic network: the term “mitochondria dynamics” refers to the ensemble of mechanisms that regulate their turnover, shape, function and interaction with other organelles. The interplay between mitochondria and endoplasmic reticulum was one of the first interactions to be described and has been thoroughly studied and implicated in several signaling pathways. Mitochondria-ER communication occurs at sites of contact (known as MERCs) in which the surfaces of the two organelles almost touch each other. Nevertheless, the contribution of MERCs to melanogenesis has never been explored in depth.
This project aims to elucidate the MERCs-driven mechanisms underlying melanogenesis by taking advantage of MERCs chemical modulators, and to elucidate MERCs-associated signaling pathways in melanocytes and keratinocytes, either in basal conditions or upon UV-B exposure.
In collaboration with the Department of Pharmaceutical Sciences, we screened a library of 600 (mostly proprietary) compounds upon miniaturization of a FRET-based MERCs assay in human primary fibroblasts, finally identifying molecules able to modify MERCs. We also tested a group of selected compounds in human primary melanocytes to confirm that they also exert their effect in this cell model.
In parallel, we also observed that increasing UV-B exposure and other pro-melanogenic stimuli alters the MERCs.
The outcomes of this project will provide new knowledge on the molecular pathways that regulate melanocyte physiology, paving the way to the discovery of new pharmacological targets and therapeutical strategies not only for skin pigmentation disorders, but also for other human disorders characterized by altered mitochondria dynamics.