| Literature DB >> 34233163 |
Jennifer Allouche1, Inbal Rachmin1, Kaustubh Adhikari2, Luba M Pardo3, Ju Hee Lee4, Alicia M McConnell5, Shinichiro Kato6, Shaohua Fan7, Akinori Kawakami1, Yusuke Suita1, Kazumasa Wakamatsu8, Vivien Igras1, Jianming Zhang9, Paula P Navarro10, Camila Makhlouta Lugo10, Haley R Noonan5, Kathleen A Christie11, Kaspar Itin12, Nisma Mujahid13, Jennifer A Lo1, Chong Hyun Won14, Conor L Evans15, Qing Yu Weng1, Hequn Wang15, Sam Osseiran15, Alyssa Lovas15, István Németh16, Antonio Cozzio17, Alexander A Navarini12, Jennifer J Hsiao1, Nhu Nguyen1, Lajos V Kemény18, Othon Iliopoulos19, Carola Berking20, Thomas Ruzicka21, Rolando Gonzalez-José22, Maria-Cátira Bortolini23, Samuel Canizales-Quinteros24, Victor Acuna-Alonso25, Carla Gallo26, Giovanni Poletti26, Gabriel Bedoya27, Francisco Rothhammer28, Shosuke Ito8, Maria Vittoria Schiaffino29, Luke H Chao10, Benjamin P Kleinstiver11, Sarah Tishkoff30, Leonard I Zon5, Tamar Nijsten3, Andrés Ruiz-Linares31, David E Fisher32, Elisabeth Roider33.
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.Entities:
Keywords: MITF; UVB; melanosome; nicotinamide nucleotide transhydrogenase; pigmentation; redox regulation
Mesh：
Substances：
Year: 2021 PMID： 34233163 PMCID： PMC8349839 DOI： 10.1016/j.cell.2021.06.022
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 66.850