Biochimica et Biophysica Acta (BBA) - General Subjects
Review
Mitochondrial glutathione: Features, regulation and role in disease☆
Highlights
► Role of mitochondrial GSH in oxidative stress and mitochondrial physiology. ► Description and features of mitochondrial GSH transport carriers. ► Role and mechanisms of mitochondrial GSH in cell death pathways. ► Contribution of mitochondrial GSH in neurodegeneration and liver diseases.
Introduction
Despite its exclusive synthesis in the cytosol, GSH is distributed in intracellular organelles, including endoplasmic reticulum (ER), nucleus and mitochondria. The compartmentalization of GSH in separate redox pools is critical to control compartment-specific needs and functions [1], [2]. In the nucleus, GSH maintains critical protein sulphydryls that are necessary for DNA repair and expression [3] and functions also as a hydrogen donor in ribonucleotide reductase-catalyzed reduction of ribonucleotides to deoxyribonucleotides, thus playing a contributory role in DNA synthesis [4]. Intracellularly GSH is predominantly found in its reduced form except in the ER, where it exists mainly as oxidized glutathione (GSSG), GSSG being the main source of oxidizing equivalents to provide the adequate environment necessary for disulphide bond formation and proper folding of nascent proteins [5]. In mitochondria, however, GSH is mainly found in reduced form and represents a minor fraction of the total GSH pool (10–15%). Considering the volume of the mitochondrial matrix, the concentration of mitochondrial GSH (mGSH) is similar to that of cytosol (10–14 mM) [1], [2], [6], [7].
Mitochondria are an excellent example of subcellular organelles whose function is closely linked to maintenance of redox balance. The mitochondria are the primary intracellular site of oxygen consumption and the major source of reactive oxygen species (ROS), most of them originating from the mitochondrial respiratory chain. Associated with this constant flow of ROS generation mitochondria are a target for the damaging effects of oxygen radicals [8], [9], [10]. Although normal electron transport in mitochondria involves four-electron reduction of molecular oxygen to water, partial reduction reactions occur even under physiological conditions, causing release of superoxide anion (O∙2 −) and hydrogen peroxide. In accordance with this, it has been estimated that the steady-state concentration of O∙2 − in the mitochondrial matrix is five- to tenfold higher than in the cytosol [11].
In addition to the ROS generated under physiological settings, toxic or pathological conditions that lead to an impairment of mitochondrial function can increase the release of ROS. Therefore, although mitochondria are exposed to the constant generation of oxidant species, the organelle remains functional due to the existence of an antioxidant defense system, of which mGSH is a critical component, aimed to prevent or repair oxidative damage generated during normal aerobic metabolism. This review summarizes current knowledge on the physiology and function of mGSH and its role in cell death regulation and pathological states.
Section snippets
Mitochondrial oxidative stress and defense
The primary function of mitochondria is to transduce oxygen consumption in the electron transport chain (ETC.) into energy required for myriad cell functions. Although the process is highly efficient, a small fraction of electrons are transferred directly to molecular oxygen, resulting in the generation of O2∙−, which can give rise to other potent ROS as well as reactive nitrogen species (RNS). Therefore, a fine equilibrium between ROS production and removal will determine the physiological vs.
mGSH transport
Despite the high GSH concentration existing in mitochondrial matrix, GSH is not synthesized de novo as mitochondria lack the enzymes required for the synthesis of GSH from its constituent aminoacids. Therefore, mitochondrial GSH arises from the cytosol GSH by the activity of specific carriers [7]. Furthermore, GSH has an overall negative charge at physiological pH and mitochondria exhibit a large negative membrane potential; consequently, although GSH can cross easily the mitochondrial outer
mGSH and cell death
Mitochondria play a central role in various forms of cell death, which are characterized by differential biochemical features, with predominant forms including apoptosis (caspase-dependent and independent), or necrosis. Besides amplifying and mediating extrinsic apoptotic pathways, mitochondria also play a central role in the integration and propagation of death signals originating from inside the cell such as DNA damage, oxidative stress, starvation, as well as those induced by radiation or
mGSH in pathology
Examples for the contribution of mGSH to different diseases have increased over the years. In many pathological settings mGSH depletion is both the consequence of disease progression and the cause of organ failure, and in most cases related to cholesterol-mediated changes in membrane dynamics. Indeed, mitochondrial cholesterol has emerged as an important modulator of MOMP in response to apoptotic stimuli, underlying the importance of this lipid in disease pathogenesis, including alcoholic and
Final remarks
Mitochondria play an essential role in maintaining cells alive by providing the energy needed for multiple signaling cascades and functions. The consumption of molecular oxygen in the respiratory chain is not only the driving force for the ATP synthesis required for cell viability, but also the source of ROS that target mitochondrial and extramitochondrial processes. Mitochondrial GSH plays a critical role to control the damaging effects of mitochondrial generated ROS, and hence its regulation
Acknowledgments
The work was supported by grants: SAF2009-11417, SAF2010-15760, and SAF2011-23031 (Plan Nacional de I + D), Proyectos de Investigación en Salud PI10/02114 and PS09/00056 (Instituto de Salud Carlos III), P50-AA-11999 (Research Center for Liver and Pancreatic Diseases, US National Institute on Alcohol Abuse and Alcoholism) and by CIBEREHD from the Instituto de Salud Carlos III. We want to thank the valuable contributions of Drs. Anna Fernandez, Joan Montero, Francisco Caballero and Gorka Basañez to
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This article is part of a Special Issue entitled Cellular functions of glutathione.