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Review
. 2011 Nov;278(22):4243-51.
doi: 10.1111/j.1742-4658.2011.08358.x. Epub 2011 Oct 12.

Dual localization of glutathione S-transferase in the cytosol and mitochondria: implications in oxidative stress, toxicity and disease

Haider Raza  1
Affiliations
Review

Dual localization of glutathione S-transferase in the cytosol and mitochondria: implications in oxidative stress, toxicity and disease

Haider Raza. FEBS J. 2011 Nov.

Abstract

Glutathione (GSH) conjugating enzymes, glutathione S-transferases (GSTs), are present in different subcellular compartments including cytosol, mitochondria, endoplasmic reticulum, nucleus and plasma membrane. The regulation and function of GSTs have implications in cell growth, oxidative stress as well as disease progression and prevention. Of the several mitochondria localized forms, GSTK (GST kappa) is mitochondria-specific since it contains N-terminal canonical and cleavable mitochondria targeting signals. Other forms like GST alpha, mu and pi purified from mitochondria are similar to the cytosolic molecular forms or 'echoproteins'. Altered GST expression has been implicated in hepatic, cardiac and neurological diseases. Mitochondria-specific GSTK has also been implicated in obesity, diabetes and related metabolic disorders. Studies have shown that silencing the GSTA4 (GST alpha) gene resulted in mitochondrial dysfunction, as was also seen in GSTA4 null mice, which could contribute to insulin resistance in type 2 diabetes. This review highlights the significance of the mitochondrial GST pool, particularly the mechanism and significance of dual targeting of GSTA4-4 under in vitro and in vivo conditions. GSTA4-4 is targeted in the mitochondria by activation of the internal cryptic signal present at the C-terminus of the protein by protein-kinase-dependent phosphorylation and cytosolic heat shock protein (Hsp70) chaperone. Mitochondrial GST pi, on the other hand, has been shown to have two uncleaved cryptic signals rich in positively charged amino acids at the N-terminal region. Both physiological and pathophysiological implications of GST translocation to mitochondria are discussed in the review.

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Figures

Figure 1
Figure 1. Bimodal targeting of GSTA4-4 in the cytosol and mitochondria
Model showing Ser189/Thr193 protein kinase-dependent phosphorylation of GST A4-4 has increased affinity for chaperon Hsp70 which activates mitochondrial competent import signals for GSTA4-4. Nonphosphorylated form is retained in the cytosol.Increased oxidative stress and activated protein kinase enhances mitochondrial import of GSTA4-4.
Figure 2a
Figure 2a
Mitochondrial oxygen metabolism and electron leakage in ROS production and toxicity
Figure 2b
Figure 2b
Mitochondrial GSH/GST pools implicated in the protection of oxidative stress related complications
See this image and copyright information in PMC

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