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

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

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4268-4283.e20
JournalCell
Volume184
Issue number16
DOIs
Publication statusPublished - 2021 Aug 5

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Inc.

All Science Journal Classification (ASJC) codes

  • General Biochemistry,Genetics and Molecular Biology

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