Autoregulatory control of mitochondrial glutathione homeostasis Journal Article
| Authors: | Liu, Y.; Liu, S.; Tomar, A.; Yen, F. S.; Unlu, G.; Ropek, N.; Weber, R. A.; Wang, Y.; Khan, A.; Gad, M.; Peng, J.; Terzi, E.; Alwaseem, H.; Pagano, A. E.; Heissel, S.; Molina, H.; Allwein, B.; Kenny, T. C.; Possemato, R. L.; Zhao, L.; Hite, R. K.; Vinogradova, E. V.; Mansy, S. S.; Birsoy, K. |
| Article Title: | Autoregulatory control of mitochondrial glutathione homeostasis |
| 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. In this work, 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 mitochondrial protease AFG3L2. Depletion of GSH dissociates AFG3L2 from SLC25A39, causing a compensatory increase in mitochondrial GSH uptake. Genetic and proteomic analyses identified a putative iron-sulfur cluster in the matrix-facing loop of SLC25A39 as 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. |
| Keywords: | carrier protein; metabolism; proteomics; iron; homeostasis; mitochondria; mitochondrion; glutathione; mitochondrial membrane transport proteins |
| Journal Title: | Science |
| Volume: | 382 |
| Issue: | 6672 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2023-11-17 |
| Start Page: | 820 |
| End Page: | 828 |
| Language: | English |
| DOI: | 10.1126/science.adf4154 |
| PUBMED: | 37917749 |
| PROVIDER: | scopus |
| PMCID: | PMC11170550 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Source: Scopus |
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