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

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Serval ID
serval:BIB_720E1B68F1F4
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Production externe
Title
NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism.
Journal
Cell
Author(s)
Allouche J., Rachmin I., Adhikari K., Pardo L.M., Lee J.H., McConnell A.M., Kato S., Fan S., Kawakami A., Suita Y., Wakamatsu K., Igras V., Zhang J., Navarro P.P., Lugo C.M., Noonan H.R., Christie K.A., Itin K., Mujahid N., Lo J.A., Won C.H., Evans C.L., Weng Q.Y., Wang H., Osseiran S., Lovas A., Németh I., Cozzio A., Navarini A.A., Hsiao J.J., Nguyen N., Kemény L.V., Iliopoulos O., Berking C., Ruzicka T., Gonzalez-José R., Bortolini M.C., Canizales-Quinteros S., Acuna-Alonso V., Gallo C., Poletti G., Bedoya G., Rothhammer F., Ito S., Schiaffino M.V., Chao L.H., Kleinstiver B.P., Tishkoff S., Zon L.I., Nijsten T., Ruiz-Linares A., Fisher D.E., Roider E.
ISSN
1097-4172 (Electronic)
ISSN-L
0092-8674
Publication state
Published
Issued date
05/08/2021
Peer-reviewed
Oui
Volume
184
Number
16
Pages
4268-4283.e20
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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.
Keywords
Animals, Cell Line, Cohort Studies, Cyclic AMP/metabolism, DNA Damage, Enzyme Inhibitors/chemistry, Enzyme Inhibitors/pharmacology, Genetic Predisposition to Disease, Humans, Melanocytes/drug effects, Melanocytes/metabolism, Melanosomes/drug effects, Melanosomes/metabolism, Melanosomes/radiation effects, Mice, Mice, Inbred C57BL, Microphthalmia-Associated Transcription Factor/metabolism, Mitochondria/drug effects, Mitochondria/metabolism, Monophenol Monooxygenase/genetics, Monophenol Monooxygenase/metabolism, NADP Transhydrogenases/antagonists & inhibitors, NADP Transhydrogenases/metabolism, Oxidation-Reduction/drug effects, Oxidation-Reduction/radiation effects, Polymorphism, Single Nucleotide/genetics, Proteasome Endopeptidase Complex/metabolism, Proteolysis/drug effects, Proteolysis/radiation effects, RNA, Messenger/genetics, RNA, Messenger/metabolism, Skin Pigmentation/drug effects, Skin Pigmentation/genetics, Skin Pigmentation/radiation effects, Ubiquitin/metabolism, Ultraviolet Rays, Zebrafish, MITF, UVB, melanosome, nicotinamide nucleotide transhydrogenase, pigmentation, redox regulation
DOI
10.1016/j.cell.2021.06.022
Pubmed
34233163
Web of science
000682521800013
Open Access
Yes
Create date
22/07/2024 11:28
Last modification date
23/07/2024 6:57
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