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NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism.
Allouche, Jennifer; 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; Lugo, Camila Makhlouta; Noonan, Haley R; Christie, Kathleen A; Itin, Kaspar; Mujahid, Nisma; Lo, Jennifer A; Won, Chong Hyun; Evans, Conor L; Weng, Qing Yu; 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, Victor; Gallo, Carla; Poletti, Giovanni; Bedoya, Gabriel; Rothhammer, Francisco; Ito, Shosuke; Schiaffino, Maria Vittoria; Chao, Luke H; Kleinstiver, Benjamin P; Tishkoff, Sarah; Zon, Leonard I; Nijsten, Tamar.
Affiliation
  • Allouche J; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • Rachmin I; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • Adhikari K; School of Mathematics and Statistics, The Open University, Milton Keynes, MK7 6AA, UK; Department of Genetics, Evolution and Environment and UCL Genetics Institute, University College London, London WC1E 6BT, UK.
  • Pardo LM; Department of Dermatology, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.
  • Lee JH; Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, 03722 Seoul, Korea.
  • McConnell AM; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and the Howard Hughes Medical Institute, Boston, MA 02115, USA.
  • Kato S; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Department of Immunology, Center for 5D Cell Dynamics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
  • Fan S; State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Fudan University, 200438 Shanghai, China.
  • Kawakami A; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • Suita Y; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • Wakamatsu K; Institute for Melanin Chemistry, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
  • Igras V; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • Zhang J; National Research Center for Translational Medicine (Shanghai), State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.
  • Navarro PP; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Lugo CM; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Noonan HR; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and the Howard Hughes Medical Institute, Boston, MA 02115, USA.
  • Christie KA; Center for Genomic Medicine and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
  • Itin K; Department of Dermatology, University Hospital of Basel, 4031 Basel, Switzerland.
  • Mujahid N; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Boston University School of Medicine, Boston, MA 02118, USA; University of Utah, Department of Dermatology, Salt Lake City, UT 84132, USA.
  • Lo JA; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • Won CH; Department of Dermatology, Asan Medical Center, Ulsan University College of Medicine, 05505 Seoul, Korea.
  • Evans CL; Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • Weng QY; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • Wang H; Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • Osseiran S; Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • Lovas A; Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • Németh I; Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary.
  • Cozzio A; Department of Dermatology, Venerology, and Allergology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.
  • Navarini AA; Department of Dermatology, University Hospital of Basel, 4031 Basel, Switzerland.
  • Hsiao JJ; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • Nguyen N; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • Kemény LV; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Department of Dermatology, Venereology, and Dermatooncology, Semmelweis University, 1085 Budapest, Hungary.
  • Iliopoulos O; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
  • Berking C; Department of Dermatology, Universitätsklinikum Erlangen, Friedrich Alexander University Erlangen-Nürnberg, 91054, Erlangen, Germany.
  • Ruzicka T; Department of Dermatology and Allergy, University Hospital Munich, Ludwig Maximilian University, 80337 Munich, Germany.
  • Gonzalez-José R; Instituto Patagónico de Ciencias Sociales y Humanas-Centro Nacional Patagónico, CONICET, Puerto Madryn U912OACD, Argentina.
  • Bortolini MC; Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre 91501-970, Brazil.
  • Canizales-Quinteros S; Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, Universidad Nacional Autónoma de México e Instituto Nacional de Medicina Genómica, Mexico City 04510, Mexico.
  • Acuna-Alonso V; National Institute of Anthropology and History, Mexico City 4510, Mexico.
  • Gallo C; Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima 15102, Peru.
  • Poletti G; Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima 15102, Peru.
  • Bedoya G; Genética Molecular (GENMOL), Universidad de Antioquia, Medellín 5001000, Colombia.
  • Rothhammer F; Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000009, Chile; Programa de Genetica Humana, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 1027, Chile.
  • Ito S; Institute for Melanin Chemistry, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
  • Schiaffino MV; Internal Medicine, Diabetes and Endocrinology Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
  • Chao LH; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • Kleinstiver BP; Center for Genomic Medicine and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
  • Tishkoff S; Departments of Genetics and Biology, University of Pennsylvania, Philadelphia, PA, USA.
  • Zon LI; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and the Howard Hughes Medical Institute, Boston, MA 02115, USA.
  • Nijsten T; Department of Dermatology, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.
Cell ; 184(16): 4268-4283.e20, 2021 08 05.
Article in En | MEDLINE | ID: mdl-34233163
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ultraviolet Rays / Skin Pigmentation / Microphthalmia-Associated Transcription Factor / NADP Transhydrogenases Type of study: Etiology_studies / Incidence_studies / Observational_studies / Risk_factors_studies Language: En Journal: Cell Year: 2021 Document type: Article Affiliation country: United States Country of publication: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ultraviolet Rays / Skin Pigmentation / Microphthalmia-Associated Transcription Factor / NADP Transhydrogenases Type of study: Etiology_studies / Incidence_studies / Observational_studies / Risk_factors_studies Language: En Journal: Cell Year: 2021 Document type: Article Affiliation country: United States Country of publication: United States