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

Détails

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ID Serval
serval:BIB_720E1B68F1F4
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Production externe
Titre
NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism.
Périodique
Cell
Auteur⸱e⸱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
Statut éditorial
Publié
Date de publication
05/08/2021
Peer-reviewed
Oui
Volume
184
Numéro
16
Pages
4268-4283.e20
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
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.
Mots-clé
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
Oui
Création de la notice
22/07/2024 10:28
Dernière modification de la notice
23/07/2024 5:57
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