@article {329058,
	title = {NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism.},
	journal = {Cell},
	volume = {184},
	year = {2021},
	month = {2021 Aug 05},
	pages = {4268-4283.e20},
	abstract = {<p>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.</p>
},
	keywords = {Animals, Cell Line, Cohort Studies, Cyclic AMP, DNA Damage, Enzyme Inhibitors, Genetic Predisposition to Disease, Humans, melanocytes, Melanosomes, Mice, Mice, Inbred C57BL, Microphthalmia-Associated Transcription Factor, Mitochondria, Monophenol Monooxygenase, NADP Transhydrogenases, Oxidation-Reduction, Polymorphism, Single Nucleotide, Proteasome Endopeptidase Complex, Proteolysis, RNA, Messenger, Skin Pigmentation, Ubiquitin, Ultraviolet Rays, Zebrafish},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2021.06.022},
	author = {Allouche, Jennifer and Rachmin, Inbal and Adhikari, Kaustubh and Pardo, Luba M and Lee, Ju Hee and McConnell, Alicia M and Kato, Shinichiro and Fan, Shaohua and Kawakami, Akinori and Suita, Yusuke and Wakamatsu, Kazumasa and Igras, Vivien and Zhang, Jianming and Navarro, Paula P and Lugo, Camila Makhlouta and Noonan, Haley R and Christie, Kathleen A and Itin, Kaspar and Mujahid, Nisma and Lo, Jennifer A and Won, Chong Hyun and Evans, Conor L and Weng, Qing Yu and Wang, Hequn and Osseiran, Sam and Lovas, Alyssa and N{\'e}meth, Istv{\'a}n and Cozzio, Antonio and Navarini, Alexander A and Hsiao, Jennifer J and Nguyen, Nhu and Kem{\'e}ny, Lajos V and Iliopoulos, Othon and Berking, Carola and Ruzicka, Thomas and Gonz{\'a}lez-Jos{\'e}, Rolando and Bortolini, Maria-C{\'a}tira and Canizales-Quinteros, Samuel and Acuna-Alonso, Victor and Gallo, Carla and Poletti, Giovanni and Bedoya, Gabriel and Rothhammer, Francisco and Ito, Shosuke and Schiaffino, Maria Vittoria and Chao, Luke H and Kleinstiver, Benjamin P and Tishkoff, Sarah and Zon, Leonard I and Nijsten, Tamar and Ruiz-Linares, Andres and Fisher, David E and Roider, Elisabeth}
}
