Glutathione and mitochondria

Abstract

Glutathione (GSH) is the main non-protein thiol in cells whose functions are dependent on the redox-active thiol of its cysteine moiety that serves as a cofactor for a number of antioxidant and detoxifying enzymes. While synthesized exclusively in the cytosol from its constituent amino acids, GSH is distributed in different compartments, including mitochondria where its concentration in the matrix equals that of the cytosol. This feature and its negative charge at physiological pH imply the existence of specific carriers to import GSH from the cytosol to the mitochondrial matrix, where it plays a key role in defense against respiration-induced reactive oxygen species and in the detoxification of lipid hydroperoxides and electrophiles. Moreover, as mitochondria play a central strategic role in the activation and mode of cell death, mitochondrial GSH has been shown to critically regulate the level of sensitization to secondary hits that induce mitochondrial membrane permeabilization and release of proteins confined in the intermembrane space that once in the cytosol engage the molecular machinery of cell death. In this review, we summarize recent data on the regulation of mitochondrial GSH and its role in cell death and prevalent human diseases, such as cancer, fatty liver disease, and Alzheimer’s disease.

Redox Imaging Using Cardiac Myocyte-Specific Transgenic Biosensor Mice

“…15%), the mitochondrial glutathione concentration is similar to that found in the cytosol. 34 The high ratio of GSH:GSSG in the mitochondria is maintained by the mitochondrial reducing equivalent of NADPH, generated in the Krebs cycle 38 and based on our data is indeed capable of maintaining a high degree of GSH reduction under normal conditions. Maintenance of an appropriate redox balance in mitochondria is of particular importance in the heart, which is an organ that is highly dependent on proper mitochondrial function.…”

“…33 Nevertheless, mitochondria are apparently well equipped with reducing defense systems, including coenzyme Q, cytochrome c, superoxide dismutase, catalase, peroxiredoxin, and glutathione peroxidase. [34][35][36] Glutathione peroxidase inactivates peroxides using GSH as a source of reducing equivalents. GSH resides in the mitochondria although produced exclusively in the cytosol from its constituent amino acids by the sequential action of γ-glutamylcysteine synthase and GSH synthase.…”

ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

“…There has recently been extensive focus on exploring ways to exploit the altered redox state of tumor cells through the use of pro-oxidant therapies, thus far with limited success, at least as monotherapy (35)(36)(37). Mitochondria are the major source of ROS in most cells and are highly dependent on mitochondrial antioxidant defenses, such as glutathione peroxidase (about one third of glutathione peroxidase is mitochondrial) to avoid their deleterious effects (38). Given our data showing that FLT3 inhibition causes a severe decrease in glutathione levels in AML cells, it is not surprising that this results in a severe increase in ROS in the mitochondria.…”

Reduced Glutathione Promotes Implants Osseointegration in Rabbits with Diabetes Mellitus: An Experimental Study

“…It plays an important role in cell signaling of reactive oxygen species under oxidative stress and prevents the oxidative stress response by adjusting the Ca 2+ concentration in mitochondria. Reduced GSH can prevent Ca 2+ overload in neurons and activate glutamate receptors in neurodegenerative diseases 8) . At present, reduced GSH has been widely applied in the drug treatment and adjuvant therapy of a variety of multi-system, multi-organ diseases such as those associated with liver and kidney damage, eye diseases, and cardiovascular diseases 9) .…”