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

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.Fil: Allouche, Jennifer. Harvard Medical School. Department of Medicine. Massachusetts General Hospital; Estados UnidosFil: Rachmin, Inbal. Harvard Medical School. Department of Medicine. Massachusetts General Hospital; Estados UnidosFil: Adhikari, Kaustubh. Colegio Universitario de Londres; Reino Unido. The Open University (ou); Reino UnidoFil: Pardo, Luba M.. Erasmus Medical Center; Países BajosFil: Lee, Ju Hee. Yonsei University College of Medicine; Corea del SurFil: McConnell, Alicia M.. Howard Hughes Medical Institute; Estados UnidosFil: Kato, Shinichiro. Nagoya University Graduate School of Medicine; Japón. Harvard Medical School. Department of Medicine. Massachusetts General Hospital; Estados UnidosFil: Fan, Shaohua. Fudan University; ChinaFil: Kawakami, Akinori. Harvard Medical School. Department of Medicine. Massachusetts General Hospital; Estados UnidosFil: Suita, Yusuke. Harvard Medical School. Department of Medicine. Massachusetts General Hospital; Estados UnidosFil: Wakamatsu, Kazumasa. Fujita Health University; JapónFil: Igras, Vivien. Harvard Medical School. Department of Medicine. Massachusetts General Hospital; Estados UnidosFil: Zhang, Jianming. Shanghai Jiao Tong University School of Medicine; ChinaFil: Navarro, Paula P.. Harvard Medical School. Department of Medicine. Massachusetts General Hospital; Estados UnidosFil: Lugo, Camila Makhlouta. Harvard Medical School. Department of Medicine. Massachusetts General Hospital; Estados UnidosFil: Noonan, Haley R.. Howard Hughes Medical Institute; Estados Unidos. Boston Children’s Hospital; Estados UnidosFil: Christie, Kathleen A.. Harvard Medical School. Department of Medicine. Massachusetts General Hospital; Estados UnidosFil: Itin, Kaspar. Hospital Universitario de Basilea; SuizaFil: Mujahid, Nisma. University of Boston. School of Medicine; Estados Unidos. University of Utah; Estados Unidos. Harvard Medical School. Department of Medicine. Massachusetts General Hospital; Estados UnidosFil: Lo, Jennifer A.. Harvard Medical School. Department of Medicine. Massachusetts General Hospital; Estados UnidosFil: Won, Chong Hyun. Ulsan University College of Medicine; Corea del SurFil: Evans, Conor L.. Harvard Medical School. Department of Medicine. Massachusetts General Hospital; Estados UnidosFil: Weng, Qing Yu. Harvard Medical School. Department of Medicine. Massachusetts General Hospital; Estados UnidosFil: Wang, Hequn. Harvard Medical School. Department of Medicine. Massachusetts General Hospital; Estados UnidosFil: Osseiran, Sam. Harvard Medical School. Department of Medicine. Massachusetts General Hospital; Estados UnidosFil: Lovas, Alyssa. Harvard Medical School. Department of Medicine. Massachusetts General Hospital; Estados UnidosFil: Németh, István. University of Szeged; HungríaFil: Cozzio, Antonio. Kantonsspital St. Gallen; SuizaFil: Navarini, Alexander A.. Hospital Universitario de Basilea; SuizaFil: Gonzalez-Jose, Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico de Ciencias Sociales y Humanas; Argentin

Gene expression profiling in pachyonychia congenita skin

BACKGROUND: Pachyonychia congenita (PC) is a skin disorder resulting from mutations in keratin (K) proteins including K6a, K6b, K16, and K17. One of the major symptoms is painful plantar keratoderma. The pathogenic sequelae resulting from the keratin mutations remain unclear. OBJECTIVE: To better understand PC pathogenesis. METHODS: RNA profiling was performed on biopsies taken from PC-involved and uninvolved plantar skin of seven genotyped PC patients (two K6a, one K6b, three K16, and one K17) as well as from control volunteers. Protein profiling was generated from tape-stripping samples. RESULTS: A comparison of PC-involved skin biopsies to adjacent uninvolved plantar skin identified 112 differentially-expressed mRNAs common to patient groups harboring K6 (i.e., both K6a and K6b) and K16 mutations. Among these mRNAs, 25 encode structural proteins including keratins, small proline-rich and late cornified envelope proteins, 20 are related to metabolism and 16 encode proteases, peptidases, and their inhibitors including kallikrein-related peptidases (KLKs), and serine protease inhibitors (SERPINs). mRNAs were also identified to be differentially expressed only in K6 (81) or K16 (141) patient samples. Furthermore, 13 mRNAs were identified that may be involved in pain including nociception and neuropathy. Protein profiling, comparing three K6a plantar tape-stripping samples to non-PC controls, showed changes in the PC corneocytes similar, but not identical, to the mRNA analysis. CONCLUSION: Many differentially-expressed genes identified in PC-involved skin encode components critical for skin barrier homeostasis including keratinocyte proliferation, differentiation, cornification, and desquamation. The profiling data provide a foundation for unraveling the pathogenesis of PC and identifying targets for developing effective PC therapeutics

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

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