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

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.

Automated summary

This study reveals a mechanism of skin pigmentation that is independent of UV light and MITF, involving the regulation of melanosome maturation through targeting the mitochondrial enzyme NNT. Inhibition of NNT leads to increased pigmentation, as shown in human skin and mice experiments, and genetic modifications of NNT affect melanocytic pigmentation in zebrafish. Analysis of human cohorts also suggests significant associations between skin color and various single-nucleotide polymorphisms within NNT.