scholarly journals Mitochondrial electron-transport-chain inhibitors of complexes I and II induce autophagic cell death mediated by reactive oxygen species

2007 ◽  
Vol 120 (23) ◽  
pp. 4155-4166 ◽  
Author(s):  
Y. Chen ◽  
E. McMillan-Ward ◽  
J. Kong ◽  
S. J. Israels ◽  
S. B. Gibson
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Electron Transport ◽  
Electron Transport Chain ◽  
Reactive Oxygen ◽  
Autophagic Cell Death ◽  
Oxygen Species ◽  
Mitochondrial Electron Transport Chain ◽  
Transport Chain

scholarly journals A Chemogenomic Screen in Saccharomyces cerevisiae Uncovers a Primary Role for the Mitochondria in Farnesol Toxicity and Its Regulation by the Pkc1 Pathway

2006 ◽  
Vol 282 (7) ◽  
pp. 4868-4874 ◽  
Author(s):  
Gregory D. Fairn ◽  
Kendra MacDonald ◽  
Christopher R. McMaster
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Electron Transport ◽  
Signaling Pathway ◽  
Electron Transport Chain ◽  
Reactive Oxygen ◽  
Complex Iii ◽  
Oxygen Species ◽  
Transport Chain

The isoprenoid farnesol has been shown to preferentially induce apoptosis in cancerous cells; however, the mode of action of farnesol-induced death is not established. We used chemogenomic profiling using Saccharomyces cerevisiae to probe the core cellular processes targeted by farnesol. This screen revealed 48 genes whose inactivation increased sensitivity to farnesol. The gene set indicated a role for the generation of oxygen radicals by the Rieske iron-sulfur component of complex III of the electron transport chain as a major mediator of farnesol-induced cell death. Consistent with this, loss of mitochondrial DNA, which abolishes electron transport, resulted in robust resistance to farnesol. A genomic interaction map predicted interconnectedness between the Pkc1 signaling pathway and farnesol sensitivity via regulation of the generation of reactive oxygen species. Consistent with this prediction (i) Pkc1, Bck1, and Mkk1 relocalized to the mitochondria upon farnesol addition, (ii) inactivation of the only non-essential and non-redundant member of the Pkc1 signaling pathway, BCK1, resulted in farnesol sensitivity, and (iii) expression of activated alleles of PKC1, BCK1, and MKK1 increased resistance to farnesol and hydrogen peroxide. Sensitivity to farnesol was not affected by the presence of the osmostabilizer sorbitol nor did farnesol affect phosphorylation of the ultimate Pkc1-responsive kinase responsible for controlling the cell wall integrity pathway, Slt2. The data indicate that the generation of reactive oxygen species by the electron transport chain is a primary mechanism by which farnesol kills cells. The Pkc1 signaling pathway regulates farnesol-mediated cell death through management of the generation of reactive oxygen species.

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

2003 ◽  
Vol 371 (3) ◽  
pp. 877-885 ◽  
Author(s):  
Se-Ho CHANG ◽  
Jairo GARCIA ◽  
J. Andres MELENDEZ ◽  
Michael S. KILBERG ◽  
Anupam AGARWAL
Keyword(s):  
Reactive Oxygen Species ◽  
Electron Transport ◽  
Protein Kinase ◽  
Electron Transport Chain ◽  
Reactive Oxygen ◽  
Glucose Deprivation ◽  
Oxygen Species ◽  
Mitochondrial Electron Transport Chain ◽  
Transport Chain ◽  
Haem Oxygenase

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 H2O2, we showed that overexpression of catalase completely blocked HO-1 activation by glucose deprivation. In contrast, inhibition of nuclear factor κB, mitogen-activated protein kinase (MAPK), protein kinase A, protein kinase C, phosphoinositide 3-kinase, cyclo-oxygenase or cytosolic phospholipase A2, 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.

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