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

• Published in: Cell Vol. 184; no. 16; pp. 4268 - 4283.e20
• Main Authors: Allouche, Jennifer, Rachmin, Inbal, Adhikari, Kaustubh, Pardo, Luba M., Lee, Ju Hee, McConnell, Alicia M., Kato, Shinichiro, Fan, Shaohua, Kawakami, Akinori, Suita, Yusuke, Wakamatsu, Kazumasa, Igras, Vivien, Zhang, Jianming, Navarro, Paula P., Lugo, Camila Makhlouta, Noonan, Haley R., Christie, Kathleen A., Itin, Kaspar, Mujahid, Nisma, Lo, Jennifer A., Won, Chong Hyun, Evans, Conor L., Weng, Qing Yu, Wang, Hequn, Osseiran, Sam, Lovas, Alyssa, Németh, István, Cozzio, Antonio, Navarini, Alexander A., Hsiao, Jennifer J., Nguyen, Nhu, Kemény, Lajos V., Iliopoulos, Othon, Berking, Carola, Ruzicka, Thomas, Gonzalez-José, Rolando, Bortolini, Maria-Cátira, Canizales-Quinteros, Samuel, Acuna-Alonso, Victor, Gallo, Carla, Poletti, Giovanni, Bedoya, Gabriel, Rothhammer, Francisco, Ito, Shosuke, Schiaffino, Maria Vittoria, Chao, Luke H., Kleinstiver, Benjamin P., Tishkoff, Sarah, Zon, Leonard I., Nijsten, Tamar, Ruiz-Linares, Andrés, Fisher, David E., Roider, Elisabeth
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.08.2021
• Subjects: Animals; Cell Line; Cohort Studies; Cyclic AMP - metabolism; DNA Damage; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Genetic Predisposition to Disease; Humans; Melanocytes - drug effects; Melanocytes - metabolism; melanosome; Melanosomes - drug effects; Melanosomes - metabolism; Melanosomes - radiation effects; Mice; Mice, Inbred C57BL; Microphthalmia-Associated Transcription Factor - metabolism; MITF; Mitochondria - drug effects; Mitochondria - metabolism; Monophenol Monooxygenase - genetics; Monophenol Monooxygenase - metabolism; NADP Transhydrogenases - antagonists & inhibitors; NADP Transhydrogenases - metabolism; nicotinamide nucleotide transhydrogenase; Oxidation-Reduction - drug effects; Oxidation-Reduction - radiation effects; pigmentation; Polymorphism, Single Nucleotide - genetics; Proteasome Endopeptidase Complex - metabolism; Proteolysis - drug effects; Proteolysis - radiation effects; redox regulation; RNA, Messenger - genetics; RNA, Messenger - metabolism; Skin Pigmentation - drug effects; Skin Pigmentation - genetics; Skin Pigmentation - radiation effects; Ubiquitin - metabolism; Ultraviolet Rays; UVB; Zebrafish; UVB; pigmentation; MITF; redox regulation; melanosome; nicotinamide nucleotide transhydrogenase
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2021.06.022

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. [Display omitted] •Identification of a redox-dependent skin pigmentation mechanism•Modification of NNT affects ubiquitin-proteasome-mediated tyrosinase degradation•Alteration of NNT levels affects skin pigmentation through melanosome maturation•Human NNT SNPs are associated with skin pigmentation, tanning, and use of sun protection Nicotinamide nucleotide transhydrogenase (NNT) is a mitochondrial redox-regulating enzyme that mediates pigmentation via a UVB- and MITF-independent mechanism.