小柯机器人

美国洛克菲勒大学Kvan Birsoy研究组取得一项新突破。他们发现SLC25A39 是哺乳动物细胞中线粒体谷胱甘肽 (GSH)输入所必需的。该研究于2021年10月27日发表于国际一流学术期刊《自然》杂志上。

他们使用细胞器蛋白质组学和代谢组学方法，确定SLC25A39，一种功能未知的线粒体膜载体，作为 GSH 转运到线粒体的调节剂。SLC25A39 的缺失减少了线粒体 GSH 的输入和丰度，而不影响细胞 GSH水平。缺乏 SLC25A39 及其旁系同源物 SLC25A40 的细胞在含有铁硫簇的蛋白质的活性和稳定性方面表现出缺陷。他们发现线粒体 GSH 的输入是体外细胞增殖和小鼠红细胞发育所必需的。工程双功能细菌 GSH 生物合成酶 (GshF) 在线粒体中的异源表达使线粒体 GSH 产生并改善由其消耗引起的代谢和增殖缺陷。

最后，GSH 可用性负调节 SLC25A39 蛋白丰度，将氧化还原稳态与哺乳动物细胞中线粒体 GSH 输入耦合。他们的工作将 SLC25A39 确定为线粒体 GSH 输入机制的重要和受调控组成部分。

据悉， GSH是一种小分子硫醇，存在于所有真核生物中，在氧化代谢中起关键作用。线粒体作为氧化反应的主要场所，必须保持足够水平的 GSH 才能发挥保护和生物合成功能。GSH 仅在细胞质中合成，但参与线粒体 GSH 输入的分子机制仍然未知。

附：英文原文

Title: SLC25A39 is necessary for mitochondrial glutathione import in mammalian cells

Author: Wang, Ying, Yen, Frederick S., Zhu, Xiphias Ge, Timson, Rebecca C., Weber, Ross, Xing, Changrui, Liu, Yuyang, Allwein, Benjamin, Luo, Hanzhi, Yeh, Hsi-Wen, Heissel, Sren, Unlu, Gokhan, Gamazon, Eric R., Kharas, Michael G., Hite, Richard, Birsoy, Kvan

Issue&Volume: 2021-10-27

Abstract: Glutathione (GSH) is a small-molecule thiol that is abundant in all eukaryotes and has key roles in oxidative metabolism1. Mitochondria, as the major site of oxidative reactions, must maintain sufficient levels of GSH to perform protective and biosynthetic functions2. GSH is synthesized exclusively in the cytosol, yet the molecular machinery involved in mitochondrial GSH import remains unknown. Here, using organellar proteomics and metabolomics approaches, we identify SLC25A39, a mitochondrial membrane carrier of unknown function, as a regulator of GSH transport into mitochondria. Loss of SLC25A39 reduces mitochondrial GSH import and abundance without affecting cellular GSH levels. Cells lacking both SLC25A39 and its paralogue SLC25A40 exhibit defects in the activity and stability of proteins containing iron–sulfur clusters. We find that mitochondrial GSH import is necessary for cell proliferation in vitro and red blood cell development in mice. Heterologous expression of an engineered bifunctional bacterial GSH biosynthetic enzyme (GshF) in mitochondria enables mitochondrial GSH production and ameliorates the metabolic and proliferative defects caused by its depletion. Finally, GSH availability negatively regulates SLC25A39 protein abundance, coupling redox homeostasis to mitochondrial GSH import in mammalian cells. Our work identifies SLC25A39 as an essential and regulated component of the mitochondrial GSH-import machinery.

DOI: 10.1038/s41586-021-04025-w

Source: https://www.nature.com/articles/s41586-021-04025-w

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html