title: Biphasic modulation of the mitochondrial electron transport chain in myocardial ischemia and reperfusion.
abstract: 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-γ coactivator-1α 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.
authors.affiliation: Davis Heart and Lung Research Institute, College of Medicine, Ohio State University, Columbus, USA.
authors.forename: Hsin-Ling
authors.initials: HL
authors.lastname: Lee
authors.forename: Chwen-Lih
authors.initials: CL
authors.lastname: Chen
authors.forename: Steve T
authors.initials: ST
authors.lastname: Yeh
authors.forename: Jay L
authors.initials: JL
authors.lastname: Zweier
authors.forename: Yeong-Renn
authors.initials: YR
authors.lastname: Chen
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology; D004579:Electron Transport / Q000187:drug effects / Q000502:physiology*; D014450:Electron Transport Complex III / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D006339:Heart Rate / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D046529:Microscopy, Electron, Transmission; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D009245:NADH Dehydrogenase / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left / Q000502:physiology
chemical_list: D005609:Free Radicals; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D000244:Adenosine Diphosphate; D003513:Cycloheximide; D009245:NADH Dehydrogenase; D014450:Electron Transport Complex III