SLC25A39 is necessary for mitochondrial glutathione import in mammalian cells

Ying Wang, Frederick S. Yen, Xiphias Ge Zhu, Rebecca C. Timson, Ross Weber, Changrui Xing, Yuyang Liu, Benjamin Allwein, Hanzhi Luo, Hsi-Wen Yeh, Søren Heissel, Gokhan Unlu, Eric R. Gamazon, Michael G. Kharas, Richard Hite and Kıvanç Birsoy ()
Additional contact information
Ying Wang: The Rockefeller University
Frederick S. Yen: The Rockefeller University
Xiphias Ge Zhu: The Rockefeller University
Rebecca C. Timson: The Rockefeller University
Ross Weber: The Rockefeller University
Changrui Xing: Memorial Sloan Kettering Cancer Center
Yuyang Liu: The Rockefeller University
Benjamin Allwein: Memorial Sloan Kettering Cancer Center
Hanzhi Luo: Memorial Sloan Kettering Cancer Center
Hsi-Wen Yeh: The Rockefeller University
Søren Heissel: The Rockefeller University
Gokhan Unlu: The Rockefeller University
Eric R. Gamazon: Vanderbilt University Medical Center
Michael G. Kharas: Memorial Sloan Kettering Cancer Center
Richard Hite: Memorial Sloan Kettering Cancer Center
Kıvanç Birsoy: The Rockefeller University

Nature, 2021, vol. 599, issue 7883, 136-140

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-04025-w

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