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NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism
Cell ( IF 64.5 ) Pub Date : 2021-07-06 , DOI: 10.1016/j.cell.2021.06.022
Jennifer Allouche 1 , Inbal Rachmin 1 , Kaustubh Adhikari 2 , Luba M Pardo 3 , Ju Hee Lee 4 , Alicia M McConnell 5 , Shinichiro Kato 6 , Shaohua Fan 7 , Akinori Kawakami 1 , Yusuke Suita 1 , Kazumasa Wakamatsu 8 , Vivien Igras 1 , Jianming Zhang 9 , Paula P Navarro 10 , Camila Makhlouta Lugo 10 , Haley R Noonan 5 , Kathleen A Christie 11 , Kaspar Itin 12 , Nisma Mujahid 13 , Jennifer A Lo 1 , Chong Hyun Won 14 , Conor L Evans 15 , Qing Yu Weng 1 , Hequn Wang 15 , Sam Osseiran 15 , Alyssa Lovas 15 , István Németh 16 , Antonio Cozzio 17 , Alexander A Navarini 12 , Jennifer J Hsiao 1 , Nhu Nguyen 1 , Lajos V Kemény 18 , Othon Iliopoulos 19 , Carola Berking 20 , Thomas Ruzicka 21 , Rolando Gonzalez-José 22 , Maria-Cátira Bortolini 23 , Samuel Canizales-Quinteros 24 , Victor Acuna-Alonso 25 , Carla Gallo 26 , Giovanni Poletti 26 , Gabriel Bedoya 27 , Francisco Rothhammer 28 , Shosuke Ito 8 , Maria Vittoria Schiaffino 29 , Luke H Chao 10 , Benjamin P Kleinstiver 11 , Sarah Tishkoff 30 , Leonard I Zon 5 , Tamar Nijsten 3 , Andrés Ruiz-Linares 31 , David E Fisher 32 , Elisabeth Roider 33
Affiliation  

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.



中文翻译:

NNT 通过不依赖 UVB 和 MITF 的机制介导氧化还原依赖性色素沉着

紫外线 (UV) 光和不完全了解的遗传和表观遗传变异决定了肤色。在这里,我们描述了一种与紫外线和小眼相关的转录因子 (MITF) 无关的皮肤色素沉着机制。靶向线粒体氧化还原调节酶烟酰胺核苷酸转氢酶 (NNT) 会导致影响酪氨酸酶降解的细胞氧化还原变化。这些变化调节黑素体成熟,从而调节真黑素水平和色素沉着。小分子抑制剂的局部应用导致人体皮肤变黑,NNT 功能降低的小鼠显示色素沉着增加。此外,斑马鱼中 NNT 的基因修饰会改变黑色素细胞色素沉着。对四个不同人群的分析揭示了肤色、晒黑、NNT。NNT 水平与 UVB 照射和氧化还原调制无关。炎症后色素沉着过度或痣的个体表现出皮肤 NNT 水平降低,这表明 NNT 驱动的氧化还原依赖性色素沉着机制可以用用于医疗和美容目的的 NNT 修饰外用药物靶向。

更新日期:2021-08-05
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