2. Academic Validation
  3. Autoregulatory control of mitochondrial glutathione homeostasis

Autoregulatory control of mitochondrial glutathione homeostasis

  • Science. 2023 Nov 17;382(6672):820-828. doi: 10.1126/science.adf4154.
Yuyang Liu 1,  Shanshan Liu 1,  Anju Tomar 2 3,  Frederick S Yen 1,  Gokhan Unlu 1,  Nathalie Ropek 4,  Ross A Weber 1,  Ying Wang 1,  Artem Khan 1,  Mark Gad 1 5,  Junhui Peng 6,  Erdem Terzi 7,  Hanan Alwaseem 8,  Alexandra E Pagano 8,  Søren Heissel 8,  Henrik Molina 8,  Benjamin Allwein 5,  Timothy C Kenny 1,  Richard L Possemato 7,  Li Zhao 6,  Richard K Hite 5,  Ekaterina V Vinogradova 4,  Sheref S Mansy 2,  Kıvanç Birsoy 1
Affiliations

Affiliations

  • 1 Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA.
  • 2 Department of Chemistry, University of Alberta, Edmonton, ‎Alberta‎, Canada.
  • 3 Department of Cellular, Computational and Integrative Biology, Università di Trento, Trento, TN, Italy.
  • 4 Laboratory of Chemical Immunology and Proteomics, The Rockefeller University, New York, NY, USA.
  • 5 Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 6 Laboratory of Evolutionary Genetics and Genomics, The Rockefeller University, New York, NY, USA.
  • 7 Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.
  • 8 The Proteomics Resource Center, The Rockefeller University, New York, NY, USA.
PMID: 37917749 DOI: 10.1126/science.adf4154
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.

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