Title | Autoregulatory control of mitochondrial glutathione homeostasis. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Liu Y, Liu S, Tomar A, Yen FS, Unlu G, Ropek N, Weber RA, Wang Y, Khan A, Gad M, Peng J, Terzi E, Alwaseem H, Pagano AE, Heissel S, Molina H, Allwein B, Kenny TC, Possemato RL, Zhao L, Hite RK, Vinogradova EV, Mansy SS, Birsoy K |
Journal | Science |
Volume | 382 |
Issue | 6672 |
Pagination | 820-828 |
Date Published | 2023 Nov 17 |
ISSN | 1095-9203 |
Keywords | ATP-Dependent Proteases, ATPases Associated with Diverse Cellular Activities, Feedback, Physiological, Glutathione, HEK293 Cells, Homeostasis, Humans, Iron, Iron-Sulfur Proteins, Mitochondria, Mitochondrial Membrane Transport Proteins, Mitochondrial Proteins, Phosphate Transport Proteins, Proteolysis, Proteomics |
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. |
DOI | 10.1126/science.adf4154 |
Alternate Journal | Science |
PubMed ID | 37917749 |
Grant List | R01 CA273233 / CA / NCI NIH HHS / United States T32 GM144299 / GM / NIGMS NIH HHS / United States |
Submitted by bel2021 on February 16, 2024 - 10:42am