Glutathione in mammalian biology

Abstract

Glutathione (GSH) is a major antioxidant as well as a redox and cell-signaling regulator in living cells. Despite its exclusive synthesis in the cytosol, GSH is compartmentalized in different organelles, predominantly in nuclei, endoplasmic reticulum (ER), and mitochondria. The redox state and origin of GSH in these compartments differ. Unlike the ER in which GSH is mostly oxidized, nuclear GSH is in the reduced form and arises by passive diffusion via nuclear pores, playing a key role in preserving proteins involved in DNA repair and gene transcription. In contrast, GSH is distributed to the mitochondrial matrix through active transport systems. The transport of GSH to the mitochondria is dependent on the appropriate membrane dynamics. Although cholesterol is a critical component of membranes, increasing cholesterol or decreasing unsaturated fatty acids enhances membrane viscosity and diminishes GSH transport through the membrane resulting in mitochondrial GSH (mGSH) depletion. Mitochondria are the main source of ROS within cells as a consequence of the aerobic metabolism. Mitochondrial GSH preserves the mitochondrial integrity controlling mitochondrial ROS generation which promotes mitochondrial permeability transition pore opening, leading to mitochondrial dysfunction and cell death. A critical threshold of mGSH loss is necessary to trigger mitochondrial apoptotic signaling. Hence, reduced mGSH level correlates with apoptosis induced by exposure to aromatic hydrocarbons, hypoxia, and ethanol. Indeed, GSH regulates both the extrinsic and the intrinsic death pathways. Moreover, alterations in GSH homeostasis have been implicated in aging and the etiology and/or progression of multitude of human disorders. In fact, numerous pathologies are characterized by a consistent decrease in mGSH level. GSH plays a critical role in neuronal survival, suggesting therapies aimed at restoring brain GSH level as relevant for future therapeutic interventions. Thus, GSH represents a critical therapeutic target to control cell death and oxidative stress-related diseases.