GSH, mitochondrial

Botti B, Franceschini V, Tomasi A, et al. 1989. Mechanistic aspects of 1,2-dibromoethane-induced mitochondrial GSH depletion in vitro. Adv Biosci 76 99-105. 

GSH protection from APAP toxicity. Mitochondrial GSH depletion, peroxynitrite formation, and mitochondrial permeability transition appear to be critical for APAP hepatocellular necrosis. 

Mitochondrial oxidative stress and mitochondrial GSH defense affects transcription factor activation. Oxidant stress in mitochondria not only can promote the loss of mitochondrial GSH and mitochondrial functions, but also can promote extramito-chondrial activation of NF-kB and therefore may affect nuclear gene expression. Mitochondria are targets of cytokines leading to the overproduction of reactive oxygen species induced by ceramide, a lipid intermediate of cytokine action and closely associated with apoptosis. Chronic ethanol intake depletes liver mitochondrial glutathione due to an ethanol-induced defect in the transport of GSH from cytosol into the mitochondrial matirix. This sensitizes liver cells to the prooxidant effects of cytokines and prooxidants generated by the oxidative metabolism of ethanol. 

One of the main questions is whether this sudden collapse is closely associated with the loss of mitochondria structure and function, loss of energy production, protein synthesis, and the status of cytoplasmic and/or mitochondrial GSH. 

Mitochondria cannot synthesise GSH (see below). Thus, the mitochondrial GSH pool comes from cytosol GSH through a mitochondrial carrier. This GSH transporter identified in rat liver mitochondria is different from the canalicular and the sinusoidal carriers [68]. Chronic ethanol feeding impairs the mitochondrial GSH transport leading to mitochondrial GSH depletion [69]. An increase in microviscosity of mitochondrial membranes due to high cholesterol content appears to account for this impairment in GSH transport [70]. 

The mechanism by which JNK induces hepatocyte death following APAP involves a complex JNK-mitochondria signaling loop involving several steps (a) mitochondrial GSH depletion and ROS generation (b) redox changes and ASK-1 activation of JNK and (c) JNK modulation of bcl-2 family members (d) JNK translocation to mitochondria and inhibition of mitochondrial bioenergetics (Fig. 3). 

In rats chronically fed ethanol, type II cell mitochondrial GSH was depleted, and tumour necrosis factor-a-induced generation of mitochondrial reactive oxygen species and apoptosis were potentiated (Brown et al. 2001). When added to the ethanol diet, the GSH precursor (-)-2-oxo-4-thiazolidine-carboxyhc acid, but not N-acetylcysteine norma-hsed the type II cell mitochondrial GSH. Likewise, (-)-2-oxo-4-thiazolidinecarboxylic but not N-acetyl-cysteine normaUsed TNF-a-induced mitochondrial reactive oxygen species and apoptosis. 

In vitamin A-deficient rats, the mitochondrial GSH/GSSG ratio was significantly lower and the levels of malondialdehyde and 8-oxo-7,8-dihydro-2 -deoxyguanosine were higher when compared to control rats (Barber et al. 2000). These values were partially restored in re-fed rats. The mitochondrial membrane potential of vitamin A-deficient rats was significantly lower than in control rats and returned to normal levels in restored vitamin A rats. Two populations of mitochondria were found in vitamin A-deficient rats according to the composition of membrane lipids. One population showed a similar pattern to the control mitochondria and the second population had a higher membrane lipid content. 

It is mainly decomposed by microsomal catalase (HjOj H2O2 oxidoreductase), which contains Fe (haematin) as a cofactor or by cytoplasmic or mitochondrial GSH peroxidase (HjOj donor oxidoreductase) containing Se as a cofactor ... 

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