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

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.

• Autores: Bedoya Berrío, Gabriel de Jesús; Ruíz Linares, Andrés; Rachmin, Inbal; Adhikari, Kaustubh; Pardo, Luba M.; Lee, Ju Hee; McConnell, Alicia M.; Kato, Shinichiro; Fan, Shaohua; Kawakami, Akinori; Suita, Yusuke; Wakamatsu, Kazumasa; Igras, Vivien; Zhang, Jianming; Navarro, Paula P; Makhlouta Lugo, Camila; R Noonan, Haley; Christie, Kathleen A.; Itin, Kaspar; Mujahid, Nisma; Lo, Jennifer V.; Hyun Won, Chong; Evans, Conor L.; Yu Weng, Qing; Wang, Hequn; Osseiran, Sam; Lovas, Alyssa; Németh, István; Cozzio, Antonio; Navarini, Alexander A.; Hsiao, Jennifer J.; Nguyen, Nhu; Kemény, Lajos V.; Iliopoulos, Othon; Berking, Carola; Ruzicka, Thomas; Gonzalez-José, Rolando; Bortolini, Maria Cátira; Canizales Quinteros, Samuel; Acuna Alonso, Víctor; Gallo, Carla; Poletti, Giovanni; Rothhammer, Francisco; Ito, Shosuke; Schiaffino, Maria Vittoria; Chao, Luke H.; Kleinstiver, Benjamin P.; Tishkoff, Sarah; Zon, Leonard I.; Nijsten, Tamar; Allouche, Jennifer; Fisher, David E; Roider, Elisabeth
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2021
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/41091
• Acceso en línea: https://hdl.handle.net/10495/41091
• Palabra clave: Cell Line; Línea Celular; Cohort Studies; Estudios de Cohortes; Cyclic AMP; AMP Cíclico; DNA Damage; Daño del ADN; Enzyme Inhibitors; Inhibidores Enzimáticos; Genetic Predisposition to Disease; Predisposición Genética a la Enfermedad; Melanocytes; Melanocitos; Melanosomes; Melanosomas; Mice, Inbred C57BL; Ratones Endogámicos C57BL; Microphthalmia-Associated Transcription Factor; Factor de Transcripción Asociado a Microftalmía; Mitochondria; Mitocondria; Monophenol Monooxygenase; Monofenol Monooxigenasa; NADP Transhydrogenases; NADP Transhidrogenasas; Oxidation-Reduction; Oxidación-Reducción; Polymorphism, Single Nucleotide; Polimorfismo de Nucleótido Simple; Proteasome Endopeptidase Complex; Complejo de la Endopetidasa Proteasomal; Proteolysis; Proteólisis; RNA, Messenger; ARN Mensajero; Skin Pigmentation; Pigmentación de la Piel; Ubiquitin; Ultraviolet Rays; Rayos Ultravioletas; Ubiquitina; https://id.nlm.nih.gov/mesh/D002460; https://id.nlm.nih.gov/mesh/D015331; https://id.nlm.nih.gov/mesh/D000242; https://id.nlm.nih.gov/mesh/D004249; https://id.nlm.nih.gov/mesh/D004791; https://id.nlm.nih.gov/mesh/D020022; https://id.nlm.nih.gov/mesh/D008544; https://id.nlm.nih.gov/mesh/D020460; https://id.nlm.nih.gov/mesh/D008810; https://id.nlm.nih.gov/mesh/D051739; https://id.nlm.nih.gov/mesh/D008928; https://id.nlm.nih.gov/mesh/D014442; https://id.nlm.nih.gov/mesh/D009250; https://id.nlm.nih.gov/mesh/D010084; https://id.nlm.nih.gov/mesh/D020641; https://id.nlm.nih.gov/mesh/D046988; https://id.nlm.nih.gov/mesh/D059748; https://id.nlm.nih.gov/mesh/D012333; https://id.nlm.nih.gov/mesh/D012880; https://id.nlm.nih.gov/mesh/D025801; https://id.nlm.nih.gov/mesh/D014466
• Rights: openAccess
• License: http://creativecommons.org/licenses/by-nc/2.5/co/