Glutathione is a class of small-molecule thiol group compounds that are abundant in all eukaryotic cells and play an important role in redox reactions and cellular metabolism. Intracellular redox reactions mainly occur in mitochondria, so mitochondria must have enough glutathione to maintain normal mitochondrial biosynthetic function. Because the enzymes that synthesize glutathione are only present in the cytoplasm, glutathione must be transported to the mitochondria after it is synthesized within the cell. However, the molecular mechanism of how glutathione is transported into mitochondria remains unclear.
On October 27, 2021, K?van? Birsoy's team at The Rockefeller University (co-authored as Ying Wang, Frederick S. Yen, Xiphias Ge Zhu, Rebecca C. Timson) published the article SLC25A39 is necessary for mitochondrial glutathione in Nature import in mammalian cells, revealing that SLC25A39 plays an important role in the transport of glutathione to mitochondria.
Using organelle-specific proteomic and metabolomic methods, the researchers discovered that an orphan transport channel protein SLC25A39 located in the inner mitochondrial membrane can regulate the transmitochondrial transport of glutathione. Intramitochondrial glutathione content and transmitochondrial glutathione transport were significantly reduced after SLC25A39 knockout, while overall intracellular glutathione content was unchanged. The researchers also found that another cognate channel protein of SLC25A39, SLC25A40, also regulates transmitochondrial transport of glutathione. When SLC25A39 and SLC25A40 were simultaneously knocked out (SLC25A39/40 double knockout), cell division was inhibited, and the activity and stability of iron-sulfur proteins (proteins containing Fe-S clusters) were reduced. In addition, transmitochondrial transport of glutathione plays an important role in red blood cell development in experimental mice.
Bacterial glutathione synthase (GshF) has multiple functions, and only one protein can complete the entire process of glutathione synthesis. After the researchers skillfully introduced GshF, which originally existed only in the cytoplasm, into the mitochondria of SLC25A39/40 double-knockout cells, they found that the glutathione content in the mitochondria of SLC25A39/40 double-knockout cells could be significantly increased, and cell division returned to normal. , the activity and stability of iron-sulfur protein were significantly improved. Finally, the researchers also found that the expression of SLC25A39 protein is regulated by the content of glutathione in mitochondria, so SLC25A39 is an important mechanism to achieve cellular redox homeostasis by regulating trans-mitochondrial glutathione.
