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Publication : NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism.

First Author  Allouche J Year  2021
Journal  Cell Volume  184
Issue  16 Pages  4268-4283.e20
PubMed ID  34233163 Mgi Jnum  J:328623
Mgi Id  MGI:6757894 Doi  10.1016/j.cell.2021.06.022
Citation  Allouche J, et al. (2021) NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism. Cell 184(16):4268-4283.e20
abstractText  Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated transcription factor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrial redox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted in cellular redox changes that affect tyrosinase degradation. These changes regulate melanosome maturation and, consequently, eumelanin levels and pigmentation. Topical application of small-molecule inhibitors yielded skin darkening in human skin, and mice with decreased NNT function displayed increased pigmentation. Additionally, genetic modification of NNT in zebrafish alters melanocytic pigmentation. Analysis of four diverse human cohorts revealed significant associations of skin color, tanning, and sun protection use with various single-nucleotide polymorphisms within NNT. NNT levels were independent of UVB irradiation and redox modulation. Individuals with postinflammatory hyperpigmentation or lentigines displayed decreased skin NNT levels, suggesting an NNT-driven, redox-dependent pigmentation mechanism that can be targeted with NNT-modifying topical drugs for medical and cosmetic purposes.
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