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

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.

SUBMITTER: Allouche J

PROVIDER: S-EPMC8349839 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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

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

Cell 20210706 16

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 ...[more]

PMID: 34233163

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Project description:ObjectiveThe glucose stimulation of insulin secretion (GSIS) by pancreatic β-cells critically depends on increased production of metabolic coupling factors, including NADPH. Nicotinamide nucleotide transhydrogenase (NNT) typically produces NADPH at the expense of NADH and ΔpH in energized mitochondria. Its spontaneous inactivation in C57BL/6J mice was previously shown to alter ATP production, Ca2+ influx, and GSIS, thereby leading to glucose intolerance. Here, we tested the role of NNT in the glucose regulation of mitochondrial NADPH and glutathione redox state and reinvestigated its role in GSIS coupling events in mouse pancreatic islets.MethodsIslets were isolated from female C57BL/6J mice (J-islets), which lack functional NNT, and genetically close C57BL/6N mice (N-islets). Wild-type mouse NNT was expressed in J-islets by adenoviral infection. Mitochondrial and cytosolic glutathione oxidation was measured with glutaredoxin 1-fused roGFP2 probes targeted or not to the mitochondrial matrix. NADPH and NADH redox state was measured biochemically. Insulin secretion and upstream coupling events were measured under dynamic or static conditions by standard procedures.ResultsNNT is largely responsible for the acute glucose-induced rise in islet NADPH/NADP+ ratio and decrease in mitochondrial glutathione oxidation, with a small impact on cytosolic glutathione. However, contrary to current views on NNT in β-cells, these effects resulted from a glucose-dependent reduction in NADPH consumption by NNT reverse mode of operation, rather than from a stimulation of its forward mode of operation. Accordingly, the lack of NNT in J-islets decreased their sensitivity to exogenous H2O2 at non-stimulating glucose. Surprisingly, the lack of NNT did not alter the glucose-stimulation of Ca2+ influx and upstream mitochondrial events, but it markedly reduced both phases of GSIS by altering Ca2+-induced exocytosis and its metabolic amplification.ConclusionThese results drastically modify current views on NNT operation and mitochondrial function in pancreatic β-cells.

Dataset Information

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

Publications

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

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