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

• Published in: The FEBS journal Vol. 278; no. 22; pp. 4243 - 4251
• Main Author: Raza, Haider
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.11.2011
• Subjects: Animals; Cell growth; Cellular biology; chemical toxicity; cryptic mitochondrial signal; Cytoplasm - enzymology; Diabetes Mellitus - enzymology; dual localization of GSTs; Enzymes; glutathione S‐transferase; Glutathione Transferase - metabolism; Hsp70 chaperone; Humans; Inactivation, Metabolic; Mice; Mitochondria; Mitochondria - enzymology; N‐terminal signal region; Oxidative Stress; PKA phosphorylation; Protein Transport; Proteins
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/j.1742-4658.2011.08358.x

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. This paper is part of a minireview series on bimodal targeting of proteins in the mitochondria and other compartments. Glutathione S‐transferases (GSTs) are a family of enzymes present in the cytosol, mitochondria, endoplasmic reticulum, nucleus and plasma membrane. They play a significant role in cell growth and toxicity. Both physiological and pathophysiological implications of GST compartmentalization have been discussed