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

Jennifer Allouche; Inbal Rachmin; Kaustubh Adhikari; Luba M Pardo; Ju Hee Lee; Alicia M McConnell; Shinichiro Kato; Shaohua Fan; Akinori Kawakami; Yusuke Suita; Kazumasa Wakamatsu; Vivien Igras; Jianming Zhang; Paula P Navarro; Camila Makhlouta Lugo; Haley R Noonan; Kathleen A Christie; Kaspar Itin; Nisma Mujahid; Jennifer A Lo; Chong Hyun Won; Conor L Evans; Qing Yu Weng; Hequn Wang; Sam Osseiran; Alyssa Lovas; István Németh; Antonio Cozzio; Alexander A Navarini; Jennifer J Hsiao; Nhu Nguyen; Lajos V Kemény; Othon Iliopoulos; Carola Berking; Thomas Ruzicka; Rolando Gonzalez-José; Maria-Cátira Bortolini; Samuel Canizales-Quinteros; Victor Acuna-Alonso; Carla Gallo; Giovanni Poletti; Gabriel Bedoya; Francisco Rothhammer; Shosuke Ito; Maria Vittoria Schiaffino; Luke H Chao; Benjamin P Kleinstiver; Sarah Tishkoff; Leonard I Zon; Tamar Nijsten; Andrés Ruiz-Linares; David E Fisher; Elisabeth Roider

doi:10.1016/j.cell.2021.06.022

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

Cell. 2021 Aug 5;184(16):4268-4283.e20. doi: 10.1016/j.cell.2021.06.022. Epub 2021 Jul 6.

Authors

Jennifer Allouche¹, Inbal Rachmin¹, Kaustubh Adhikari², Luba M Pardo³, Ju Hee Lee⁴, Alicia M McConnell⁵, Shinichiro Kato⁶, Shaohua Fan⁷, Akinori Kawakami¹, Yusuke Suita¹, Kazumasa Wakamatsu⁸, Vivien Igras¹, Jianming Zhang⁹, Paula P Navarro¹⁰, Camila Makhlouta Lugo¹⁰, Haley R Noonan⁵, Kathleen A Christie¹¹, Kaspar Itin¹², Nisma Mujahid¹³, Jennifer A Lo¹, Chong Hyun Won¹⁴, Conor L Evans¹⁵, Qing Yu Weng¹, Hequn Wang¹⁵, Sam Osseiran¹⁵, Alyssa Lovas¹⁵, István Németh¹⁶, Antonio Cozzio¹⁷, Alexander A Navarini¹², Jennifer J Hsiao¹, Nhu Nguyen¹, Lajos V Kemény¹⁸, Othon Iliopoulos¹⁹, Carola Berking²⁰, Thomas Ruzicka²¹, Rolando Gonzalez-José²², Maria-Cátira Bortolini²³, Samuel Canizales-Quinteros²⁴, Victor Acuna-Alonso²⁵, Carla Gallo²⁶, Giovanni Poletti²⁶, Gabriel Bedoya²⁷, Francisco Rothhammer²⁸, Shosuke Ito⁸, Maria Vittoria Schiaffino²⁹, Luke H Chao¹⁰, Benjamin P Kleinstiver¹¹, Sarah Tishkoff³⁰, Leonard I Zon⁵, Tamar Nijsten³, Andrés Ruiz-Linares³¹, David E Fisher³², Elisabeth Roider³³

Affiliations

¹ Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
² 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.
³ Department of Dermatology, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.
⁴ Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, 03722 Seoul, Korea.
⁵ Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and the Howard Hughes Medical Institute, Boston, MA 02115, USA.
⁶ 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.
⁷ State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences, Fudan University, 200438 Shanghai, China.
⁸ Institute for Melanin Chemistry, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
⁹ 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.
¹⁰ Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
¹¹ 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.
¹² Department of Dermatology, University Hospital of Basel, 4031 Basel, Switzerland.
¹³ 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.
¹⁴ Department of Dermatology, Asan Medical Center, Ulsan University College of Medicine, 05505 Seoul, Korea.
¹⁵ Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
¹⁶ Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary.
¹⁷ Department of Dermatology, Venerology, and Allergology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.
¹⁸ 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.
¹⁹ Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
²⁰ Department of Dermatology, Universitätsklinikum Erlangen, Friedrich Alexander University Erlangen-Nürnberg, 91054, Erlangen, Germany.
²¹ Department of Dermatology and Allergy, University Hospital Munich, Ludwig Maximilian University, 80337 Munich, Germany.
²² Instituto Patagónico de Ciencias Sociales y Humanas-Centro Nacional Patagónico, CONICET, Puerto Madryn U912OACD, Argentina.
²³ Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre 91501-970, Brazil.
²⁴ 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.
²⁵ National Institute of Anthropology and History, Mexico City 4510, Mexico.
²⁶ Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima 15102, Peru.
²⁷ Genética Molecular (GENMOL), Universidad de Antioquia, Medellín 5001000, Colombia.
²⁸ Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000009, Chile; Programa de Genetica Humana, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 1027, Chile.
²⁹ Internal Medicine, Diabetes and Endocrinology Unit, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
³⁰ Departments of Genetics and Biology, University of Pennsylvania, Philadelphia, PA, USA.
³¹ 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.
³² 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.
³³ 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.

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.

Keywords: MITF; UVB; melanosome; nicotinamide nucleotide transhydrogenase; pigmentation; redox regulation.

Publication types

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

MeSH terms

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

Substances

Enzyme Inhibitors
Microphthalmia-Associated Transcription Factor
RNA, Messenger
Ubiquitin
Cyclic AMP
Monophenol Monooxygenase
NADP Transhydrogenases
Proteasome Endopeptidase Complex

Abstract

Publication types

MeSH terms

Substances

Grants and funding