美国哈佛医学院Elisabeth Roider、David E. Fisher等研究人员合作发现，NNT通过不依赖于UVB和MITF的机制介导氧化还原依赖性色素沉着。相关论文于2021年7月6日在线发表在《细胞》杂志上。
研究人员报道了一种与紫外线（UV）和MITF（microphthalmia-associated transcriptionfactor）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）导致细胞氧化还原变化，并影响酪氨酸酶降解。这些变化调节黑色素体的成熟，从而调节真黑色素水平和色素沉着。小分子抑制剂的局部应用导致人类皮肤变黑，NNT功能降低的小鼠显示出色素沉着增加。此外，斑马鱼中NNT的遗传修饰会改变黑素细胞色素沉着。
对四个不同的人类队列的分析揭示了肤色、晒黑和防晒使用与NNT中各种单核苷酸多态性之间的显著关联。NNT水平与UVB照射和氧化还原改变无关。患有炎症后色素沉着过度或雀斑的个体表现出皮肤NNT水平的降低，这表明NNT驱动的氧化还原依赖性色素沉着机制可以通过NNT外用药物靶向，从而实现医疗和美容目的。
据介绍，UV光线和未完全了解的遗传和表观遗传变异决定了肤色。
附：英文原文
Title: NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism
Author: 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
Issue&Volume: 2021-07-06
Abstract: Ultraviolet (UV) light and incompletely understood genetic and epigenetic variationsdetermine skin color. Here we describe an UV- and microphthalmia-associated transcriptionfactor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrialredox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted incellular redox changes that affect tyrosinase degradation. These changes regulatemelanosome maturation and, consequently, eumelanin levels and pigmentation. Topicalapplication of small-molecule inhibitors yielded skin darkening in human skin, andmice with decreased NNT function displayed increased pigmentation. Additionally, geneticmodification of NNT in zebrafish alters melanocytic pigmentation. Analysis of fourdiverse human cohorts revealed significant associations of skin color, tanning, andsun protection use with various single-nucleotide polymorphisms within NNT. NNT levels were independent of UVB irradiation and redox modulation. Individualswith postinflammatory hyperpigmentation or lentigines displayed decreased skin NNTlevels, suggesting an NNT-driven, redox-dependent pigmentation mechanism that canbe targeted with NNT-modifying topical drugs for medical and cosmetic purposes.
DOI: 10.1016/j.cell.2021.06.022
Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00757-1