SLC25A39 is necessary for mitochondrial glutathione import in mammalian cells

Controlling glutathione entry into mitochondria: potential roles for SLC25A39 in health and (treatment of) disease

“…Furthermore, they could show that cells lacking both SLC25A39 as well as its paralogue SLC25A40 exhibit defects in the activity and stability of proteins containing iron–sulfur clusters (ISCs). 1 In addition, the results presented strongly support the view that mitochondrial GSH play essential roles for mediating ISC biogenesis as opposed to redox buffering.…”

“…Members of the mitochondrial solute carrier (SLC) family 25 (SLC25) provide transport steps for substances across the mitochondrial inner membrane into the mitochondria that are needed for biochemical pathways and cellular homoeostasis. In a recent paper in Nature, Wang et al 1 could demonstrate that glutathione (GSH) transport seems to be mediated by SLC25A39, since loss of SLC25A39 reduces mitochondrial GSH import and abundance without affecting cellular GSH levels. Furthermore, they could show that cells lacking both SLC25A39 as well as its paralogue SLC25A40 exhibit defects in the activity and stability of proteins containing iron–sulfur clusters (ISCs).…”

Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis

“…Mitochondrial proteomics combined with pharmacological manipulation revealed that SLC25A39 (and its paralog SLC25A40) is required for mitochondrial GSH import. Interestingly, the expression of SLC25A39 only depends on GSH levels, and not oxidative stress or nuclear factor-erythroid 2-related factor 2 (NRF2) activation [ 86 ]. In another study, gene-by-gene analysis from a dual CRISPR screen showed a buffering interaction between SLC25A39 and the iron transporter, SLC25A37 [ 87 ].…”

“…In another study, gene-by-gene analysis from a dual CRISPR screen showed a buffering interaction between SLC25A39 and the iron transporter, SLC25A37 [ 87 ]. Together, the two studies suggest that GSH import into mitochondria is required to maintain proper activity and stability of iron-sulfur cluster containing proteins, although the precise mechanism through which mitochondrial GSH does so is yet to be uncovered [ 86 , 87 ].…”

Pathways Linking Nicotinamide Adenine Dinucleotide Phosphate Production to Endoplasmic Reticulum Protein Oxidation and Stress

“…GSH was thought to be exchanged between the mitochondrial intermembrane space and matrix by the 2-oxoglutarate and dicarboxylate carriers ( Chen and Lash, 1998 ; Chen et al, 2000 ), though this has since been challenged ( Booty et al, 2015 ). Recently, the mitochondrial solute carrier SLC25A39 was identified as a regulator of mitochondrial GSH import ( Wang et al, 2021 ), though it remains unclear how mitochondrial GSH is exported. Transport into and out of the ER is even less understood, with the only identified candidate for GSH transport being the Sec61 translocon in yeast ( Ponsero et al, 2017 ).…”