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Haem oxygenase 1 gene induction by glucose deprivation is mediated by reactive oxygen species via the mitochondrial electron-transport chain.

ABSTRACT: Glucose depletion results in cellular stress and reactive oxygen species (ROS) production, which evokes adaptive and protective responses. One such protective response is the induction of haem oxygenase 1 (HO-1), which catalyses the rate-limiting step in haem degradation, liberating iron, CO and biliverdin. The present study evaluated the role of ROS and the mitochondrial electron-transport chain in the induction of HO-1 by glucose deprivation in HepG2 hepatoma cells. Either N-acetylcysteine, an antioxidant, or deferoxamine, an iron chelator, resulted in a dose-dependent inhibition of HO-1 mRNA and protein induction during glucose deprivation, suggesting a redox- and iron-dependent mechanism. Inhibitors of electron-transport chain complex III, antimycin A and myxothiazol, the ATP synthase inhibitor oligomycin and ATP depletion with 2-deoxyglucose or glucosamine also blocked HO-1 induction. To address the involvement of ROS further, specifically H(2)O(2), we showed that overexpression of catalase completely blocked HO-1 activation by glucose deprivation. In contrast, inhibition of nuclear factor kappa B, mitogen-activated protein kinase (MAPK), protein kinase A, protein kinase C, phosphoinositide 3-kinase, cyclo-oxygenase or cytosolic phospholipase A(2), did not prevent HO-1 induction. These results demonstrate that activation of the HO-1 gene by glucose deprivation is mediated by a 'glucose metabolic response' pathway via generation of ROS and that the pathway requires a functional electron-transport chain.

SUBMITTER: Chang SH

PROVIDER: S-EPMC1223354 | biostudies-other | 2003 May

REPOSITORIES: biostudies-other

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Project description:HO-1 (haem oxygenase 1) is an essential antioxidant enzyme in the cell that exerts its effects through removal of pro-oxidant haem groups and the formation of antioxidant molecules and carbon monoxide. The electrophilic cyclopentenone 15d-PGJ2 (15-deoxy-Delta(12,14)-prostaglandin J2) induces the expression of HO-1 protein through the covalent modification of protein thiols. It has been shown that specific thiol residues of the redox-sensor Keap1 (Kelch-like ECH-associated protein 1) are modified by 15d-PGJ2, leading to activation of the transcription factor Nrf-2 (nuclear factor-erythroid 2 p45 subunit-related factor 2) and up-regulation of genes under control of the electrophile-response element, including HO-1. However, 15d-PGJ2 has also been shown to modify other proteins which comprise the electrophile-responsive proteome. Since 15d-PGJ2 has been shown to localize to the mitochondria in endothelial cells, we hypothesized that mitochondrial protein modification may also be important in Keap1/Nrf-2 signal transduction, leading to HO-1 up-regulation. In order to determine the role of mitochondrial protein thiol modification in HO-1 induction, we used the mitochondrial-targeted thiol-reactive compound IBTP [(4-iodobutyl)triphenylphosphonium]. IBTP had no effect on basal HO-1 levels, but effectively blocked HO-1 induction by a variety of reagents including haemin, iodoacetamide and 15d-PGJ2. Mechanistically, IBTP did not prevent the covalent modification of Keap1 by 15d-PGJ2. However, IBTP prevented the 15d-PGJ2-dependent increases in HO-1 mRNA and protein. Furthermore, IBTP prevented the nuclear accumulation of Nrf-2, suggesting cross-talk between mitochondria and antioxidant-response signal transduction. This effect was independent of reactive oxygen species formation or mitochondrial membrane potential. In addition, IBTP significantly enhanced the toxicity of high concentrations of 15d-PGJ2, suggesting that loss of mitochondrial control of HO-1 leads to increased susceptibility to electrophilic stress in endothelial cells. The implications for these studies in understanding the balance between cytoprotection and cytotoxicity in the context of diseases such as atherosclerosis is discussed.

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Haem oxygenase 1 gene induction by glucose deprivation is mediated by reactive oxygen species via the mitochondrial electron-transport chain.

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