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

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, Roider E (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Book Volume: 184

Pages Range: 4268-4283.e20

Journal Issue: 16

DOI: 10.1016/j.cell.2021.06.022

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.

Authors with CRIS profile

Involved external institutions

Erasmus University Medical Center (MC) Netherlands (NL) Yonsei University Health System (YUHS) Korea, Republic of (KR) Howard Hughes Medical Institute United States (USA) (US) Harvard University United States (USA) (US) Fudan University / 复旦大学 China (CN) University of Szeged / József Attila Tudományegyetem Szeged Hungary (HU) Kantonsspital St.Gallen Switzerland (CH) Universitätsspital Basel Switzerland (CH) Universidad Peruana Cayetano Heredia Peru (PE) Universidad de Antioquía (UDEA) Colombia (CO) University of Tarapacá / Universidad de Tarapacá Chile (CL) Fujita Health University Japan (JP) Ospedale San Raffaele (früher: Centro San Raffaele del Monte Tabor Foundation) Italy (IT) Massachusetts General Hospital United States (USA) (US) University of Pennsylvania (UPenn) United States (USA) (US) Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) / National Scientific and Technical Research Council Argentina (AR) Universidade Federal do Rio Grande do Sul (UFRGS) Brazil (BR) National Autonomous University of Mexico / Universidad Nacional Autónoma de México (UNAM) Mexico (MX) National Institute of Anthropology and History / Instituto Nacional de Antropología e Historia (INAH) Mexico (MX) Open University (OU) United Kingdom (GB) University of Ulsan / 울산대학교 Korea, Republic of (KR) Shanghai Jiao Tong University / 上海交通大学 China (CN) Klinikum der Universität München Germany (DE)

How to cite

APA:

Allouche, J., Rachmin, I., Adhikari, K., Pardo, L.M., Lee, J.H., McConnell, A.M.,... Roider, E. (2021). NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism. Cell, 184(16), 4268-4283.e20. https://doi.org/10.1016/j.cell.2021.06.022

MLA:

Allouche, Jennifer, et al. "NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism." Cell 184.16 (2021): 4268-4283.e20.

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