Glutathione: subcellular distribution and membrane transport

Abstract

Glutathione (γ-glutamylcysteinylglycine) is a small tripeptide found at millimolar concentrations in nearly all eukaryotes as well as many prokaryotic cells. Glutathione synthesis is restricted to the cytosol in animals and fungi and to the cytosol and plastids in plants. Nonetheless, glutathione is found in virtually all subcellular compartments. This implies that transporters must exist, which facilitate glutathione transport into and out of the various subcellular compartments. Glutathione may also be exported and imported across the plasma membrane in many cells. However, in most cases, the molecular identity of these transporters remains unclear. Whilst glutathione transport is essential for the supply and replenishment of subcellular glutathione pools, recent evidence supports a more active role for glutathione transport in the regulation of subcellular glutathione redox homeostasis. However, our knowledge of glutathione redox homeostasis at the level of specific subcellular compartments remains remarkably limited and the role of glutathione transport remains largely unclear. In this review we discuss how new tools and techniques have begun to yield insights into subcellular glutathione distribution and glutathione redox homeostasis. In particular, we discuss the known and putative glutathione transporters and examine their contribution to the regulation of subcellular glutathione redox homeostasis.

ACADSB regulates ferroptosis and affects the migration, invasion, and proliferation of colorectal cancer cells

“…GSH is a tripeptide compound composed by glutamic acid, cysteine, and glycine. It is the most important antioxidant and free radical scavenger in cells by combining with free radicals and heavy metals to form harmless substances (Oestreicher & Morgan, 2019).…”

Role of Glutathione in Cancer: From Mechanisms to Therapies

“…These organelles generally have similar concentrations of GSH as in the cytosol, although their redox ratio (reduced GSH to oxidized GSSG) may vary [ 71 ]. Mitochondria, for example, contain 10–15% of the total cellular GSH content [ 72 ], where the OXPHOS-mediated generation of ROS results in a large demand for GSH. The influx of GSH into mitochondria requires passing through both the outer and inner mitochondrial membranes (OMM and IMM, respectively), however movement across the OMM is kept in equilibrium with the cytosol for small molecules such as GSH via free movement of small molecules (<5 kDa) through porin proteins in the OMM [ 73 ].…”

Mitochondrial Glutathione: Recent Insights and Role in Disease

“…The first reaction, the formation of γ-glutamylcysteine from glutamate and cysteine by the enzyme γ-glutamylcysteine synthetase (GCS), is rate-limiting due to the usually low availability of cysteine. Of note, the inhibition of this reaction by GSH constitutes a regulatory step for maintaining a proper GSH concentration intracellularly [ 1 , 2 ]. The last step in GSH synthesis, regulated by GSH synthetase (GS), requires γ-glutamylcysteine and glycine as substrates ( Figure 1 A) [ 3 ].…”

“…GSH is synthesized exclusively in the cytosol; nonetheless it is found present at different intracellular organelles such as the endoplasmic reticulum (ER), nucleus, and mitochondria. This compartmentation results in separate redox pools of GSH, where it performs specific functions [ 2 ]. The independence of these separate GSH pools, for example, is supported by the observation that treatment with L-buthionine-SR-sulfoximine (BSO), an inhibitor of GSH synthesis, does not result in a complete reduction in the nuclear GSH, as compared to cytosolic GSH [ 14 ].…”