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

Animals Cell Line Cohort Studies Cyclic AMP / metabolism DNA Damage Enzyme Inhibitors / chemistry Genetic Predisposition to Disease Humans Melanocytes / drug effects Melanosomes / drug effects Mice Mice, Inbred C57BL Microphthalmia-Associated Transcription Factor / metabolism Mitochondria / drug effects Monophenol Monooxygenase / genetics NADP Transhydrogenases / antagonists & inhibitors Oxidation-Reduction / drug effects Polymorphism, Single Nucleotide / genetics Proteasome Endopeptidase Complex / metabolism Proteolysis / drug effects RNA, Messenger / genetics Skin Pigmentation / drug effects Ubiquitin / metabolism Ultraviolet Rays Zebrafish
MITF UVB melanosome nicotinamide nucleotide transhydrogenase pigmentation redox regulation

Journal

Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066

Informations de publication

Date de publication:
05 08 2021
Historique:
received: 21 09 2020
revised: 09 03 2021
accepted: 15 06 2021
pubmed: 8 7 2021
medline: 6 1 2022
entrez: 7 7 2021
Statut: 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.

Identifiants

DOI: 10.1016/j.cell.2021.06.022 PMID: 34233163 PMC: PMC8349839
pubmed: 34233163
pii: S0092-8674(21)00757-1
doi: 10.1016/j.cell.2021.06.022
pmc: PMC8349839
mid: NIHMS1720180
pii:
doi:

Substances chimiques

Enzyme Inhibitors 0
Microphthalmia-Associated Transcription Factor 0
RNA, Messenger 0
Ubiquitin 0
Cyclic AMP E0399OZS9N
Monophenol Monooxygenase EC 1.14.18.1
NADP Transhydrogenases EC 1.6.1.-
Proteasome Endopeptidase Complex EC 3.4.25.1

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

4268-4283.e20

Subventions

Organisme : NIAMS NIH HHS
ID : R01 AR072304
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA218870
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK043351
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002541
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA163222
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR076241
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA103846
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK057521
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM134957
Pays : United States
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/I021213/1
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : P01 HL142494
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES013508
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA222871
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR043369
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2021 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests D.E.F. and E.R. have a patent filed on “Methods and compositions for enhancing skin pigmentation” (publication number WO/2016/077817, May 19, 2016.). D.E.F. has a financial interest in Soltego, Inc., a company developing SIK inhibitors for topical skin darkening treatments that might be used for a broad set of human applications. D.E.F.’s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. B.P.K. is an inventor on patents and patent applications filed by Mass General Brigham that describe genome engineering technologies. B.P.K. consults for Avectas Inc., ElevateBio, and EcoR1 capital and is an advisor to Acrigen Biosciences. Q.Y.W. is a shareholder in Mymiel Skincare. L.I.Z. is a founder and stockholder of Fate Therapeutics, CAMP4 Therapeutics, Amagma Therapeutics, and Scholar Rock. He is a consultant for Celularity and Cellarity. H.W. is an employee and shareholder of Johnson and Johnson.

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Auteurs

Jennifer Allouche (J)

Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

Inbal Rachmin (I)

Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

Kaustubh 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.

Luba M Pardo (LM)

Department of Dermatology, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.

Ju Hee Lee (JH)

Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, 03722 Seoul, Korea.

Alicia M McConnell (AM)

Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and the Howard Hughes Medical Institute, Boston, MA 02115, USA.

Shinichiro 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.

Shaohua Fan (S)

State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Fudan University, 200438 Shanghai, China.

Akinori Kawakami (A)

Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

Yusuke Suita (Y)

Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

Kazumasa Wakamatsu (K)

Institute for Melanin Chemistry, Fujita Health University, Toyoake, Aichi 470-1192, Japan.

Vivien Igras (V)

Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

Jianming 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.

Paula P Navarro (PP)

Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

Camila Makhlouta Lugo (CM)

Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

Haley R Noonan (HR)

Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and the Howard Hughes Medical Institute, Boston, MA 02115, USA.

Kathleen A 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.

Kaspar Itin (K)

Department of Dermatology, University Hospital of Basel, 4031 Basel, Switzerland.

Nisma 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.

Jennifer A Lo (JA)

Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

Chong Hyun Won (CH)

Department of Dermatology, Asan Medical Center, Ulsan University College of Medicine, 05505 Seoul, Korea.

Conor L Evans (CL)

Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

Qing Yu Weng (QY)

Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

Hequn Wang (H)

Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

Sam Osseiran (S)

Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

Alyssa Lovas (A)

Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

István Németh (I)

Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary.

Antonio Cozzio (A)

Department of Dermatology, Venerology, and Allergology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.

Alexander A Navarini (AA)

Department of Dermatology, University Hospital of Basel, 4031 Basel, Switzerland.

Jennifer J Hsiao (JJ)

Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

Nhu Nguyen (N)

Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

Lajos V 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.

Othon Iliopoulos (O)

Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.

Carola Berking (C)

Department of Dermatology, Universitätsklinikum Erlangen, Friedrich Alexander University Erlangen-Nürnberg, 91054, Erlangen, Germany.

Thomas Ruzicka (T)

Department of Dermatology and Allergy, University Hospital Munich, Ludwig Maximilian University, 80337 Munich, Germany.

Rolando Gonzalez-José (R)

Instituto Patagónico de Ciencias Sociales y Humanas-Centro Nacional Patagónico, CONICET, Puerto Madryn U912OACD, Argentina.

Maria-Cátira Bortolini (MC)

Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre 91501-970, Brazil.

Samuel 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.

Victor Acuna-Alonso (V)

National Institute of Anthropology and History, Mexico City 4510, Mexico.

Carla Gallo (C)

Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima 15102, Peru.

Giovanni Poletti (G)

Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima 15102, Peru.

Gabriel Bedoya (G)

Genética Molecular (GENMOL), Universidad de Antioquia, Medellín 5001000, Colombia.

Francisco 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.

Shosuke Ito (S)

Institute for Melanin Chemistry, Fujita Health University, Toyoake, Aichi 470-1192, Japan.

Maria Vittoria Schiaffino (MV)

Internal Medicine, Diabetes and Endocrinology Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.

Luke H Chao (LH)

Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

Benjamin P 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.

Sarah Tishkoff (S)

Departments of Genetics and Biology, University of Pennsylvania, Philadelphia, PA, USA.

Leonard I Zon (LI)

Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and the Howard Hughes Medical Institute, Boston, MA 02115, USA.

Tamar Nijsten (T)

Department of Dermatology, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.

Andrés Ruiz-Linares (A)

Ministry 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 Fisher (DE)

Cutaneous 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 Roider (E)

Cutaneous 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.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Cellules › Cellules cultivées › Lignée cellulaire › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléotides › Ribonucléotides › Nucléotides adényliques › AMP cyclique › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Phénomènes génétiques › Altération de l'ADN › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Cellules › Cellules épithéliales › Mélanocytes › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Cellules › Cellules épithéliales › Mélanocytes › Mélanosomes › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif basique et à glissière à leucines › Facteurs de transcription à motifs basiques hélice-boucle-hélice et à glissière à leucines › Facteur de transcription associé à la microphtalmie › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Cellules › Structures cellulaires › Fractions subcellulaires › Mitochondries › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Oxygénases › Mixed function oxygenases › Catechol oxidase › Monophenol monooxygenase › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › NADH, NADPH oxidoreductases › NADP transhydrogenases › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Métabolisme › Métabolisme énergétique › Oxydoréduction › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Complexes multienzymatiques › Proteasome endopeptidase complex › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Métabolisme › Protéolyse › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN messager › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Phénomènes biologiques › Pigmentation › Pigmentation de la peau › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Ubiquitines › Ubiquitine › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Environnement et santé publique › Environnement › Concepts météorologiques › Atmosphère › Temps (météorologie) › Lumière du soleil › Rayons ultraviolets › NNT mediates redox-dependent pigmentation via...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Poissons › Cypriniformes › Cyprinidae › Danio zébré › NNT mediates redox-dependent pigmentation via...