While the UV-MITF pathway is well-established as a key player of pigmentation, implication of other MITF independent pathways in this biological process is still unclear. Illustrating this, several evidence demonstrated a role of oxidative stress in pigmentation disorders but the exact mechanisms by which oxidative stress potentially impacts skin pigmentation are incompletely elucidated. Here, we identified a conserved mechanism of skin pigmentation demonstrating an interplay between melanin and redox metabolism. In this study, we showed that the enzyme nicotinamide nucleotide transhydrogenase (NNT), involved in the regulation of oxidative stress, could be also implicated in the regulation of melanogenesis. By loss and gain of function experiments and by using pharmacological compounds, we demonstrated that NNT-mediated redox changes impact skin pigmentation in mice and zebrafish models as well as in ex vivo human skin explants. At the mechanistic level, we have shown by loss-of-function experiments that NNT-mediated redox affects ubiquitin-proteasome-mediated tyrosinase degradation, the key enzyme in melanin synthesis. Finally, to study the biological relevance of these findings in humans, GWAS analysis was performed by using databases of 462, 885 individuals in total. Four SNP within the NNT gene were found to significantly correlate with human skin color. In addition, we have demonstrated the therapeutic potential of NNT-modifying topical drugs on human skin explants of different skin types. Altogether, these results highlight the existence of a redox-dependent pigmentation mechanism that can be targeted with NNT-modifying topical drugs for cosmetic and medical purposes.

ESDR510 - NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.