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

Publication

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

Journal Paper/Review - Jul 6, 2021

Roider Elisabeth, Acuna-Alonso Victor, Canizales-Quinteros Samuel, Bortolini Maria-Cátira, Gonzalez-José Rolando, Ruzicka Thomas, Berking Carola, Iliopoulos Othon, Kemény Lajos V, Nguyen Nhu, Hsiao Jennifer J, Navarini Alexander A, Gallo Carla, Poletti Giovanni, Fisher David E, Ruiz-Linares Andrés, Nijsten Tamar, Zon Leonard I, Tishkoff Sarah, Kleinstiver Benjamin P, Chao Luke H, Schiaffino Maria Vittoria, Ito Shosuke, Rothhammer Francisco, Bedoya Gabriel, Cozzio Antonio, Németh István, Lovas Alyssa, Igras Vivien, Wakamatsu Kazumasa, Suita Yusuke, Kawakami Akinori, Fan Shaohua, Kato Shinichiro, McConnell Alicia M, Lee Ju Hee, Pardo Luba M, Adhikari Kaustubh, Rachmin Inbal, Zhang Jianming, Navarro Paula P, Osseiran Sam, Wang Hequn, Weng Qing Yu, Evans Conor L, Won Chong Hyun, Lo Jennifer A, Mujahid Nisma, Itin Kaspar, Christie Kathleen A, Noonan Haley R, Lugo Camila Makhlouta, Allouche Jennifer

Citation

Roider E, Acuna-Alonso V, Canizales-Quinteros S, Bortolini M, Gonzalez-José R, Ruzicka T, Berking C, Iliopoulos O, Kemény L, Nguyen N, Hsiao J, Navarini A, Gallo C, Poletti G, Fisher D, Ruiz-Linares A, Nijsten T, Zon L, Tishkoff S, Kleinstiver B, Chao L, Schiaffino M, Ito S, Rothhammer F, Bedoya G, Cozzio A, Németh I, Lovas A, Igras V, Wakamatsu K, Suita Y, Kawakami A, Fan S, Kato S, McConnell A, Lee J, Pardo L, Adhikari K, Rachmin I, Zhang J, Navarro P, Osseiran S, Wang H, Weng Q, Evans C, Won C, Lo J, Mujahid N, Itin K, Christie K, Noonan H, Lugo C, Allouche J. NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism. Cell 2021; 184:4268-4283.e20.

Type

Journal Paper/Review (English)

Journal

Cell 2021; 184

Publication Date

Jul 6, 2021

Issn Electronic

1097-4172

Pages

4268-4283.e20

Brief description/objective

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.