Journal
CELL
Volume 184, Issue 16, Pages 4268-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2021.06.022
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Funding
- Mildred Scheel Grant of the German Cancer Society
- University of Zurich, Switzerland
- NIH [5P01-CA163222, 5R01CA222871, 5R01AR043369, 5R01AR072304, R01AR076241, R35GM134957-01]
- Dr. Miriam and Sheldon Adelson Medical Research Foundation
- Harvard Catalyst | The Harvard Clinical and Translational Science Center (NationalCenter for Advancing Translational Sciences, National Institutes of Health) [UL 1TR002541]
- Harvard University
- Swiss National Science Foundation (SNSF)
- Early Postdoctoral Mobility Fellowship [CRSII3_154461]
- Postdoctoral Mobility Fellowship [P400PB_199252]
- NCI [R00 CA218870]
- NHLBI [P01 HL142494]
- Santander
- University College London
- Leverhulme Trust [F/07 134/DF]
- BBSRC [BB/I021213/1]
- Excellence Initiative of Aix-Marseille University -A*MIDEX (French Investissements d'Avenir program) [2RUIZLRE/RHRE/ID18HRU201, 20-07874]
- National Natural Science Foundation of China [31771393]
- Scientific and Technology Committee of Shanghai Municipality [18490750300]
- Ministry of Science and Technology of China [2020YFE0201600]
- Shanghai Municipal Science and Technology Major Project [2017SHZDZX01]
- 111 Project [B13016]
- Universidad de Antioquia
- Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences
- Netherlands Organization for the Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- European Commission (DG XII)
- Municipality of Rotterdam
- Inflammatory Bowel Disease Center grant [DK043351]
- Boston Area Diabetes Endocrinology Research Center grant [DK057521]
- Erasmus Medical Center (Netherlands)
- Erasmus University Rotterdam (Netherlands)
- Swiss National Science Foundation (SNF) [P400PB_199252, CRSII3_154461] Funding Source: Swiss National Science Foundation (SNF)
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This study reveals a mechanism of skin pigmentation that is independent of UV light and MITF, involving the regulation of melanosome maturation through targeting the mitochondrial enzyme NNT. Inhibition of NNT leads to increased pigmentation, as shown in human skin and mice experiments, and genetic modifications of NNT affect melanocytic pigmentation in zebrafish. Analysis of human cohorts also suggests significant associations between skin color and various single-nucleotide polymorphisms within NNT.
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.
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