Mitochondrial Glutathione: Recent Insights and Role in Disease

Abstract

Mitochondria are the main source of reactive oxygen species (ROS), most of them deriving from the mitochondrial respiratory chain. Among the numerous enzymatic and non-enzymatic antioxidant systems present in mitochondria, mitochondrial glutathione (mGSH) emerges as the main line of defense for maintaining the appropriate mitochondrial redox environment. mGSH's ability to act directly or as a co-factor in reactions catalyzed by other mitochondrial enzymes makes its presence essential to avoid or to repair oxidative modifications that can lead to mitochondrial dysfunction and subsequently to cell death. Since mitochondrial redox disorders play a central part in many diseases, harboring optimal levels of mGSH is vitally important. In this review, we will highlight the participation of mGSH as a contributor to disease progression in pathologies as diverse as Alzheimer's disease, alcoholic and non-alcoholic steatohepatitis, or diabetic nephropathy. Furthermore, the involvement of mitochondrial ROS in the signaling of new prescribed drugs and in other pathologies (or in other unmet medical needs, such as gender differences or coronavirus disease of 2019 (COVID-19) treatment) is still being revealed; guaranteeing that research on mGSH will be an interesting topic for years to come.

Keywords: Alzheimer; aging; antioxidant; diabetic nephropathy; glutathione; mitochondria; oxidative stress; steatohepatitis.

Figure 1

(A) Glutathione (GSH) synthesis in cytosol. GSH is synthesized by the concerted action of two enzymes. The first reaction is the formation of γ-glutamylcysteine from glutamate and cysteine by the enzyme γ-glutamylcysteine synthetase (GCS). The last step in GSH synthesis is regulated by GSH synthetase (GS). GCS and Cysteine (in yellow) are the limiting factors in GSH synthesis. (B) Chemical structure of reduced (GSH) and oxidized (GSSG) glutathione.

Figure 2

Sources of reactive oxygen species (ROS) in the electron transport chain. During mitochondrial respiration partial reduction reactions occur, mainly from complexes I and III that cause the accumulation of superoxide and hydrogen peroxide mainly in the mitochondrial matrix.

Figure 3

Mitochondrial control of ROS. Different reactions that take place in the mitochondria to eliminate superoxide and hydrogen peroxide. GSH peroxidase (GPx); GSSG-reductase (GR); GSSG, glutaredoxin-2 (Grx2); Mn-dependent superoxide dismutase (MnSOD); thioredoxin-2 (Trx2); Trx-reductase (TrxR); peroxiredoxin-4 (Prx3).

Figure 4

GSH transport to mitochondria. Once GSH is synthesized in the cytosol it can be transported to the mitochondria by specific IMM carriers: 2-oxoglutarate carrier (OGC; SLC25A11) and dicarboxylate carrier (DIC; SLC25A10), although the presence of unknown carriers cannot be discarded at present. In addition, S-d-lactoylglutathione (SLG), a stable intermediate product of the glyoxalase (GLO1) system which catalyzes the conversion of methylglyoxal (MG) into d-lactic acid (Lact), can enter the mitochondria and by the action of mitochondrial glyoxalase II (GLO2), be hydrolyzed to lactate and mGSH.

Figure 5

The balance between mGSH levels and reactive oxygen species (ROS) present in the mitochondrial milieu determines cellular susceptibility to death stimuli. Under physiological conditions or even in the continuous presence of increased ROS production survival is guaranteed due to upregulation of GSH-related antioxidant mechanisms. Mitochondrial death only arises when the production of ROS is high and/or the levels of mGSH are compromised due to minor synthetic capabilities or problems with mGSH transport.