ArticleCell2021
NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism.
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37 citing papers in PubMed, 67 citations in OpenAlex.
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- Membrane-Associated Ubiquitin Ligase RING Finger Protein 152 Orchestrates Melanogenesis via Tyrosinase Ubiquitination.Membranes · 2024Article
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Authors and funding
53 authors at 20 institutions in 17 countries.
Jennifer AlloucheCutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Inbal RachminCutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Kaustubh AdhikariSchool 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.
Luba M PardoDepartment of Dermatology, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.
Ju Hee LeeDepartment of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, 03722 Seoul, Korea.
Alicia M McConnellStem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and the Howard Hughes Medical Institute, Boston, MA 02115, USA.
Shinichiro KatoCutaneous 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.
Shaohua FanState Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Fudan University, 200438 Shanghai, China.
Akinori KawakamiCutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Yusuke SuitaCutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Kazumasa WakamatsuInstitute for Melanin Chemistry, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
Vivien IgrasCutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Jianming ZhangNational Research Center for Translational Medicine (Shanghai), State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.
Paula P NavarroDepartment of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Camila Makhlouta LugoDepartment of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Haley R NoonanStem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and the Howard Hughes Medical Institute, Boston, MA 02115, USA.
Kathleen A ChristieCenter for Genomic Medicine and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Kaspar ItinDepartment of Dermatology, University Hospital of Basel, 4031 Basel, Switzerland.
Nisma MujahidCutaneous 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.
Jennifer A LoCutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Chong Hyun WonDepartment of Dermatology, Asan Medical Center, Ulsan University College of Medicine, 05505 Seoul, Korea.
Conor L EvansWellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Qing Yu WengCutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Hequn WangWellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Sam OsseiranWellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Alyssa LovasWellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
István NémethDepartment of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary.
Antonio CozzioDepartment of Dermatology, Venerology, and Allergology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.
Alexander A NavariniDepartment of Dermatology, University Hospital of Basel, 4031 Basel, Switzerland.
Jennifer J HsiaoCutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Nhu NguyenCutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Lajos V KeményCutaneous 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.
Othon IliopoulosMassachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
Carola BerkingDepartment of Dermatology, Universitätsklinikum Erlangen, Friedrich Alexander University Erlangen-Nürnberg, 91054, Erlangen, Germany.
Thomas RuzickaDepartment of Dermatology and Allergy, University Hospital Munich, Ludwig Maximilian University, 80337 Munich, Germany.
Rolando Gonzalez-JoséInstituto Patagónico de Ciencias Sociales y Humanas-Centro Nacional Patagónico, CONICET, Puerto Madryn U912OACD, Argentina.
Maria-Cátira BortoliniDepartamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre 91501-970, Brazil.
Samuel Canizales-QuinterosUnidad 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.
Victor Acuna-AlonsoNational Institute of Anthropology and History, Mexico City 4510, Mexico.
Carla GalloLaboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima 15102, Peru.
Giovanni PolettiLaboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima 15102, Peru.
Gabriel BedoyaGenética Molecular (GENMOL), Universidad de Antioquia, Medellín 5001000, Colombia.
Francisco RothhammerInstituto de Alta Investigación, Universidad de Tarapacá, Arica 1000009, Chile; Programa de Genetica Humana, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 1027, Chile.
Shosuke ItoInstitute for Melanin Chemistry, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
Maria Vittoria SchiaffinoInternal Medicine, Diabetes and Endocrinology Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
Luke H ChaoDepartment of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Benjamin P KleinstiverCenter for Genomic Medicine and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Sarah TishkoffDepartments of Genetics and Biology, University of Pennsylvania, Philadelphia, PA, USA.
Leonard I ZonStem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and the Howard Hughes Medical Institute, Boston, MA 02115, USA.
Tamar NijstenDepartment of Dermatology, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.
Andrés Ruiz-LinaresMinistry of Education Key Laboratory of Contemporary Anthropology and Collaborative Innovation Center of Genetics and Development, School of Life Sciences and Human Phenome Institute, Fudan University, Shanghai 200433, China; UMR 7268, CNRS-EFS-ADES, Aix-Marseille University, Marseille 13005, France.
David E FisherCutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA. Electronic address: dfisher3@mgh.harvard.edu.
Elisabeth RoiderCutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Department of Dermatology, University Hospital of Basel, 4031 Basel, Switzerland; Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary. Electronic address: eroider@cbrc2.mgh.harvard.edu.
Harvard University · USMassachusetts General Hospital · USBoston Children's Hospital · USErasmus MC · NLFujita Health University · JPUniversidad Peruana Cayetano Heredia · PEUniversity Hospital of Basel · CHAsan Medical Center · KRCentre National de la Recherche Scientifique · FRCentro Científico Tecnológico Patagónico · ARFudan University · CNIstituti di Ricovero e Cura a Carattere Scientifico · ITKantonsspital St. Gallen · CHLudwig-Maximilians-Universität München · DENational Institute of Anthropology and History · MXShanghai Jiao Tong University · CNUniversidad de Antioquia · COUniversidade Federal do Rio Grande do Sul · BRUniversidad Nacional Autónoma de México · MXUniversitätsklinikum Erlangen · DE
Funding
The Harvard Clinical and Translational Science CenterUL1TR002541 · NCATS · HARVARD MEDICAL SCHOOL · PI NADLER, LEE MARSHALL · 2018 to 2022
$93.0MTranslational Research Support CoreP30ES013508 · NIEHS · UNIVERSITY OF PENNSYLVANIA · PI A. Clementina Mesaros · 2006 to 2026
$35.3MPilot & Feasibility ProgramP30DK043351 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI Ramnik J Xavier · 1991 to 2026
$35.3MTransgenic CoreP30DK057521 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI BROWN, DENNIS · 2000 to 2019
$31.4MTranscriptional mechanisms and melanomaP01CA163222 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI DAVID E FISHER · 2013 to 2026
$25.3MPROJECT 4: Somatic evolution of the hematopoietic system in cardiovascular diseaseP01HL142494 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI Matthias Nahrendorf · 2019 to 2026
$19.5MThe MITF transcriptional network: melanoma risk and carcinogenesisR01AR043369 · NIAMS · MASSACHUSETTS GENERAL HOSPITAL · PI DAVID E FISHER · 1996 to 2026
$9.4MDERMATOLOGY TRAINING GRANTT32AR007098 · NIAMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI THOMAS S. KUPPER · 1986 to 2026
$8.1MCancer Biology in the ZebrafishR01CA103846 · NCI · CHILDREN'S HOSPITAL BOSTON · PI ZON, LEONARD IRA · 2003 to 2022
$7.5MGenetic and molecular basis for variation in human skin pigmentationR01AR076241 · NIAMS · CHILDREN'S HOSP OF PHILADELPHIA · PI MARKS, MICHAEL S, OANCEA, ELENA · 2020 to 2024
$5.5MTherapeutic strategies for treatment of giant congenital melanocytic neviR01AR072304 · NIAMS · MASSACHUSETTS GENERAL HOSPITAL · PI DAVID E FISHER · 2017 to 2026
$3.9MIntegrative Genomic Analyses of Human Evolution and Adaptation in AfricaR35GM134957 · NIGMS · UNIVERSITY OF PENNSYLVANIA · PI TISHKOFF, SARAH ANNE · 2020 to 2024
$2.7MBiotechnology and Biological Sciences Research Council BB/I021213/1NCATS NIH HHS UL1 TR002541NCI NIH HHS P01 CA163222NCI NIH HHS R00 CA218870NCI NIH HHS R01 CA103846NCI NIH HHS R01 CA222871NHLBI NIH HHS P01 HL142494NIAMS NIH HHS R01 AR043369NIAMS NIH HHS R01 AR072304NIAMS NIH HHS R01 AR076241NIAMS NIH HHS T32 AR007098NIDDK NIH HHS P30 DK043351NIDDK NIH HHS P30 DK057521NIEHS NIH HHS P30 ES013508NIGMS NIH HHS R35 GM134957
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.
Indexed as
Ultraviolet RaysAnimalsCell LineCohort StudiesCyclic AMPDNA DamageEnzyme InhibitorsGenetic Predisposition to DiseaseHumansMelanocytesMelanosomesMiceMice, Inbred C57BLMicrophthalmia-Associated Transcription FactorMitochondriaMonophenol MonooxygenaseCyclic AMPEnzyme InhibitorsMicrophthalmia-Associated Transcription FactorMonophenol MonooxygenaseNADP TranshydrogenasesProteasome Endopeptidase ComplexRNA, MessengerUbiquitinmelanosomeMITFnicotinamide nucleotide transhydrogenasepigmentationredox regulationUVB
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