研究人员测试了线粒体中一种重要的氧化还原代谢物——谷胱甘肽（GSH），并确定了一种通过线粒体GSH转运体SLC25A39控制其丰度的反馈机制。在生理条件下，SLC25A39会被线粒体蛋白酶AFG3L2快速降解。GSH的耗竭会使AFG3L2与SLC25A39分离，从而导致线粒体GSH摄取量的补偿性增加。
遗传学和蛋白质组分析发现，SLC25A39面向基质的环中的一个假定铁硫簇对这种调控至关重要，它将线粒体的铁平衡与GSH的输入联系在一起。总之，这项工作揭示了细胞器代谢平衡自动调节控制的一个范例。
据了解，线粒体必须保持足够数量的代谢物，以发挥保护和生物合成功能。然而，人们对线粒体如何感知代谢物的丰度并调节代谢平衡还不甚了解。
附：英文原文
Title: Autoregulatory control of mitochondrial glutathione homeostasis
Author: Yuyang Liu, Shanshan Liu, Anju Tomar, Frederick S. Yen, Gokhan Unlu, Nathalie Ropek, Ross A. Weber, Ying Wang, Artem Khan, Mark Gad, Junhui Peng, Erdem Terzi, Hanan Alwaseem, Alexandra E. Pagano, Sren Heissel, Henrik Molina, Benjamin Allwein, Timothy C. Kenny, Richard L. Possemato, Li Zhao, Richard K. Hite, Ekaterina V. Vinogradova, Sheref S. Mansy, Kvan Birsoy
Issue&Volume: 2023-11-02
Abstract: Mitochondria must maintain adequate amounts of metabolites for protective and biosynthetic functions. However, how mitochondria sense the abundance of metabolites and regulate metabolic homeostasis is not well understood. We focused on glutathione (GSH), a critical redox metabolite in mitochondria and identified a feedback mechanism that controls its abundance through the mitochondrial GSH transporter, SLC25A39. Under physiological conditions, SLC25A39 is rapidly degraded by a mitochondrial protease, AFG3L2. Depletion of GSH dissociates AFG3L2 from SLC25A39, causing a compensatory increase in mitochondrial GSH uptake. Genetic and proteomic analysis identified a putative iron-sulfur cluster in the matrix-facing loop of SLC25A39 to be essential for this regulation, coupling mitochondrial iron homeostasis to GSH import. Altogether, our work revealed a paradigm for the autoregulatory control of metabolic homeostasis in organelles.
DOI: adf4154
Source: https://www.science.org/doi/10.1126/science.adf4154