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

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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.
Author(s)
원종현이주희Akinori KawakamiAlexander A. NavariniAlicia M. McConnellAlyssa LovasAndre´ s Ruiz-LinaresAntonio CozzioBenjamin P. KleinstiverCamila Makhlouta LugoCarla GalloCarola BerkingConor L. EvansDavid E. FisherElisabeth RoiderFrancisco RothhammerGabriel BedoyaGiovanni PolettiHa
Issued Date
2021
Type
Article
Keyword
AnimalsCell LineCohort StudiesCyclic AMP - metabolismDNA DamageEnzyme Inhibitors - chemistryEnzyme Inhibitors - pharmacologyGenetic Predisposition to DiseaseHumansMelanocytes - drug effectsMelanocytes - metabolismmelanosomeMelanosomes - drug effectsMelanosomes - metabolismMelanosomes - radiation effectsMiceMiceInbred C57BLMicrophthalmia-Associated Transcription Factor - metabolismMITFMitochondria - drug effectsMitochondria - metabolismMonophenol Monooxygenase - geneticsMonophenol Monooxygenase - metabolismNADP Transhydrogenases - antagonists & inhibitorsNADP Transhydrogenases - metabolismnicotinamide nucleotide transhydrogenaseOxidation-Reduction - drug effectsOxidation-Reduction - radiation effectspigmentationPolymorphismSingle Nucleotide - geneticsProteasome Endopeptidase Complex - metabolismProteolysis - drug effectsProteolysis - radiation effectsredox regulationRNAMessenger - geneticsRNAMessenger - metabolismSkin Pigmentation - drug effectsSkin Pigmentation - geneticsSkin Pigmentation - radiation effectsUbiquitin - metabolismUltraviolet RaysUVBZebrafish
DOI
10.1016/j.cell.2021.06.022
URI
https://oak.ulsan.ac.kr/handle/2021.oak/8038
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_proquest_miscellaneous_2549690911&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,NNT%20mediates%20redox-dependent%20pigmentation%20via%20a%20UVB-%20and%20MITF-independent%20mechanism&offset=0&pcAvailability=true
Publisher
CELL
Location
영국
Language
영어
ISSN
0092-8674
Citation Volume
184
Citation Number
184
Citation Start Page
4268
Citation End Page
4268
Appears in Collections:
Medicine > Medicine
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