Haem oxygenase 1 gene induction by glucose deprivation is mediated by reactive oxygen species via the mitochondrial electron-transport chain.
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.
Chang
Se-Ho
SH
Division of Nephrology, Hypertension & Transplantation, Department of Medicine, University of Florida, Box 100224 JHMHC, 1600 SW Archer Road, Gainesville, FL 32610, USA.
Garcia
Jairo
J
Melendez
J Andres
JA
Kilberg
Michael S
MS
Agarwal
Anupam
A
D002374:Catalase / Q000378:metabolism; D004579:Electron Transport; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D006801:Humans; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species; D015533:Transcriptional Activation
D016328:NF-kappa B; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D002374:Catalase; D006419:Heme Oxygenase (Decyclizing); D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D005947:Glucose