1. NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism.
- Author
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Allouche J, Rachmin I, Adhikari K, Pardo LM, Lee JH, McConnell AM, Kato S, Fan S, Kawakami A, Suita Y, Wakamatsu K, Igras V, Zhang J, Navarro PP, Lugo CM, Noonan HR, Christie KA, Itin K, Mujahid N, Lo JA, Won CH, Evans CL, Weng QY, Wang H, Osseiran S, Lovas A, Németh I, Cozzio A, Navarini AA, Hsiao JJ, Nguyen N, Kemény LV, Iliopoulos O, Berking C, Ruzicka T, Gonzalez-José R, Bortolini MC, Canizales-Quinteros S, Acuna-Alonso V, Gallo C, Poletti G, Bedoya G, Rothhammer F, Ito S, Schiaffino MV, Chao LH, Kleinstiver BP, Tishkoff S, Zon LI, Nijsten T, Ruiz-Linares A, Fisher DE, and Roider E
- 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, Melanosomes drug effects, Melanosomes metabolism, Melanosomes radiation effects, Mice, Mice, Inbred C57BL, Mitochondria drug effects, Mitochondria metabolism, Monophenol Monooxygenase genetics, Monophenol Monooxygenase metabolism, NADP Transhydrogenases antagonists & inhibitors, 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, Ubiquitin metabolism, Zebrafish, Microphthalmia-Associated Transcription Factor metabolism, NADP Transhydrogenases metabolism, Skin Pigmentation radiation effects, Ultraviolet Rays
- 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., Competing Interests: Declaration of interests D.E.F. and E.R. have a patent filed on “Methods and compositions for enhancing skin pigmentation” (publication number WO/2016/077817, May 19, 2016.). D.E.F. has a financial interest in Soltego, Inc., a company developing SIK inhibitors for topical skin darkening treatments that might be used for a broad set of human applications. D.E.F.’s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. B.P.K. is an inventor on patents and patent applications filed by Mass General Brigham that describe genome engineering technologies. B.P.K. consults for Avectas Inc., ElevateBio, and EcoR1 capital and is an advisor to Acrigen Biosciences. Q.Y.W. is a shareholder in Mymiel Skincare. L.I.Z. is a founder and stockholder of Fate Therapeutics, CAMP4 Therapeutics, Amagma Therapeutics, and Scholar Rock. He is a consultant for Celularity and Cellarity. H.W. is an employee and shareholder of Johnson and Johnson., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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