Biphasic Modulation Of The Mitochondrial Electron Transport Chain In Myocardial Ischemia And Reperfusion
Cardiovascular System & Cardiology; cytochrome-c-oxidase; energy-metabolism; injury; nadh dehydrogenase; oxidative modification; oxygen-free-radicals; Physiology; postischemic myocardium; protein biosynthesis; rat-heart mitochondria; reactive oxygen species; transfer complex-i; translational control
Lee HL, Chen CL, Yeh ST, Zweier JL, Chen YR. Biphasic modulation of the mitochondrial electron transport chain in myocardial ischemia and reperfusion. Am J Physiol Heart Circ Physiol 302: H1410-H1422, 2012. First published January 20, 2012; doi: 10.1152/ajpheart.00731.2011.-Mitochondrial electron transport chain (ETC) is the major source of reactive oxygen species during myocardial ischemia-reperfusion (I/R) injury. Ischemic defect and reperfusion-induced injury to ETC are critical in the disease pathogenesis of postischemic heart. The properties of ETC were investigated in an isolated heart model of global I/R. Rat hearts were subjected to ischemia for 30 min followed by reperfusion for 1 h. Studies of mitochondrial function indicated a biphasic modulation of electron transfer activity (ETA) and ETC protein expression during I/R. Analysis of ETAs in the isolated mitochondria indicated that complexes I, II, III, and IV activities were diminished after 30 min of ischemia but increased upon restoration of flow. Immunoblotting analysis and ultrastructural analysis with transmission electron microscopy further revealed marked downregulation of ETC in the ischemic heart and then upregulation of ETC upon reperfusion. No significant difference in the mRNA expression level of ETC was detected between ischemic and postischemic hearts. However, reperfusion-induced ETC biosynthesis in myocardium can be inhibited by cycloheximide, indicating the involvement of translational control. Immunoblotting analysis of tissue homogenates revealed a similar profile in peroxisome proliferator-activated receptor-gamma coactivator-1 alpha expression, suggesting its essential role as an upstream regulator in controlling ETC biosynthesis during I/R. Significant impairment caused by ischemic and postischemic injury was observed in the complexes I-III. Analysis of NADH ferricyanide reductase activity indicated that injury of flavoprotein subcomplex accounts for 50% decline of intact complex I activity from ischemic heart. Taken together, our findings provide a new insight into the molecular mechanism of I/R-induced mitochondrial dysfunction.
Lee H L; Chen C L; Yeh S T; Zweier J L; Chen Y R
American Journal of Physiology-Heart and Circulatory Physiology
2012
2012-04
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1152/ajpheart.00731.2011" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00731.2011</a>
Increased Nitroxidative Stress Promotes Mitochondrial Dysfunction in Alcoholic and Nonalcoholic Fatty Liver Disease
aldehyde-dehydrogenase; ascorbate-dependent artifact; biotin-switch assay; Cell Biology; cytochrome-c-oxidase; hepatoma-cells; lipid-peroxidation; mediated oxidative stress; nitric-oxide; rat-liver; s-nitrosylation
Increased nitroxidative stress causes mitochondrial dysfunctions through oxidative modifications of mitochondrial DNA, lipids, and proteins. Persistent mitochondrial dysfunction sensitizes the target cells/organs to other pathological risk factors and thus ultimately contributes to the development of more severe disease states in alcoholic and nonalcoholic fatty liver disease. The incidences of nonalcoholic fatty liver disease continuously increase due to high prevalence of metabolic syndrome including hyperlipidemia, hypercholesterolemia, obesity, insulin resistance, and diabetes. Many mitochondrial proteins including the enzymes involved in fat oxidation and energy supply could be oxidatively modified (including S-nitrosylation/ nitration) under increased nitroxidative stress and thus inactivated, leading to increased fat accumulation and ATP depletion. To demonstrate the underlying mechanism(s) of mitochondrial dysfunction, we employed a redox proteomics approach using biotin-N-maleimide (biotin-NM) as a sensitive biotin-switch probe to identify oxidized Cys residues of mitochondrial proteins in the experimental models of alcoholic and acute liver disease. The aims of this paper are to briefly describe the mechanisms, functional consequences, and detection methods of mitochondrial dysfunction. We also describe advantages and limitations of the Cys-targeted redox proteomics method with alternative approaches. Finally, we discuss various applications of this method in studying oxidatively modified mitochondrial proteins in extrahepatic tissues or different subcellular organelles and translational research.
Song B J; Abdelmegeed M A; Henderson L E; Yoo S H; Wan J; Purohit V; Hardwick J P; Moon K H
Oxidative Medicine and Cellular Longevity
2013
2013
Journal Article
<a href="http://doi.org/10.1155/2013/781050" target="_blank" rel="noreferrer noopener">10.1155/2013/781050</a>
Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications
Biochemistry & Molecular Biology; cell death; cytochrome-c-oxidase; hepatic ischemia-reperfusion; induced liver-injury; Mitochondrial dysfunction; Mitochondrial proteins; nadp(+)-dependent isocitrate dehydrogenase; nitric-oxide; Nitroxidative stress; oxidative stress; Post-translational modifications; rat-liver; Redox; synthase; targeted antioxidant mitoq; terminal kinase; Tissue injury
Mitochondria are critically important in providing cellular energy ATP as well as their involvement in anfi-oxiclant defense, fat oxidation, intermediary metabolism and cell death processes lt is well-established that mitochondrial functions are suppressed when living cells or organisms are exposed to potentially toxic agents including alcohol, high fat diets, smoking and certain drugs or in many pathophysiological states through increased levels of oxidative/nitrative stress. Under elevated nitroxidative stress, cellular macromolecules proteins, DNA, and lipids can undergo different oxidative modifications, leading to disruption of their normal, sometimes critical, physiological functions. Recent reports also indicated that many mitochondrial proteins are modified via various post-translation modifications (PTMs) and primarily inactivated. Because of the recently-emerging information, in this review, we specifically focus on the mechanisms and roles of five major PTMs (namely oxidation, nitration, phosphorylation, acetylation, and adduct formation with lipid-peroxides, reactive metabolites, or advanced glycation end products) in experimental models of alcoholic and nonalcoholic fatty liver disease as well as acute hepatic injury caused by toxic compounds. We also highlight the role of the ethanol-inducible cytochrome P450-2E1 (CYP2E1) in some of these PTM changes. Finally, we discuss translational research opportunities with natural and/or synthetic anti-oxidants, which can prevent or delay the onset of mitochondial dysfunction, fat accumulation and tissue injury. Published by Elsevier B.V.
Song B J; Akbar M; Abdelmegeed M A; Byun K; Lee B; Yoon S K; Hardwick J P
Redox Biology
2014
2014
Journal Article
<a href="http://doi.org/10.1016/j.redox.2014.10.004" target="_blank" rel="noreferrer noopener">10.1016/j.redox.2014.10.004</a>