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Your Environment. Your Health.

Publication Detail

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

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

Published In Cell, (2021 08 05)

Abstract: 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.

PubMed ID: 34233163 Exiting the NIEHS site

MeSH Terms: 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; Melanosomes/drug effects; Melanosomes/metabolism; Melanosomes/radiation effects; Mice; Mice, Inbred C57BL; Microphthalmia-Associated Transcription Factor/metabolism*; Mitochondria/drug effects; Mitochondria/metabolism; Monophenol Monooxygenase/genetics; Monophenol Monooxygenase/metabolism; NADP Transhydrogenases/antagonists & inhibitors; NADP Transhydrogenases/metabolism*; Oxidation-Reduction/drug effects; Oxidation-Reduction/radiation effects; Polymorphism, Single Nucleotide/genetics; Proteasome Endopeptidase Complex/metabolism; Proteolysis/drug effects; Proteolysis/radiation effects; RNA, Messenger/genetics; RNA, Messenger/metabolism; Skin Pigmentation/drug effects; Skin Pigmentation/genetics; Skin Pigmentation/radiation effects*; Ubiquitin/metabolism; Ultraviolet Rays*; Zebrafish

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