Carnitine-acylcarnitine translocase in ischemia: evidence for sulfhydryl modification.
After coronary occlusion and reflow, carbohydrate catabolism is enhanced, whereas fatty acid utilization is delayed. To test the hypothesis that "stunning" of fatty acid use by ischemic heart reflects reduced fatty acid transport into the mitochondria, two activities involved in the transport were examined: carnitine-acylcarnitine translocase and carnitine palmitoyltransferase II (CPT II). The maximal velocity for carnitine exchange of the translocase is reduced 55% in mitochondria isolated from ischemic canine heart (60-min left circumflex occlusion). Mitochondria from ischemic heart show 50% depletion in total matrix glutathione, a 200% increase in glutathione disulfide (GSSG), and an 80% decrease in the ratio of reduced glutathione (GSH) to GSSG, suggesting that the loss of translocase activity may be a consequence of protein sulfhydryl modifications. In support of this, treatment of these mitochondria with the sulfhydryl-reducing agents, GSH or dithiothreitol, restores carnitine exchange to control. Partial return of mitochondrial GSH and a decrease in GSSG are observed with a 20-min reperfusion of the ischemic myocardium. Continued depression in carnitine exchange with reperfusion suggests that other mechanisms may prevent restoration of activity. Import of palmitoylcarnitine on the translocase is coupled to palmitoyl-CoA production by CPT II. Mitochondria from ischemic heart with decreased coupling activity also have the lowest palmitoylcarnitine-supported respiratory rates, suggesting that in severely ischemic tissue the translocation-transesterification sequence may become rate limiting to fatty acid oxidation.
D000818:Animals; D001692:Biological Transport; D002331:Carnitine / Q000378:metabolism; D002333:Carnitine Acyltransferases; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D003326:Coronary Circulation; D003327:Coronary Disease / Q000201:enzymology*; D004229:Dithiothreitol / Q000378:metabolism; D004285:Dogs; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D019803:Glutathione Disulfide; D007511:Ischemia; D007700:Kinetics; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D010172:Palmitoylcarnitine / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D014166:Transferases / Q000378:metabolism*
D013438:Sulfhydryl Compounds; D010172:Palmitoylcarnitine; D014166:Transferases; D002333:Carnitine Acyltransferases; D002334:Carnitine O-Palmitoyltransferase; D005978:Glutathione; D002331:Carnitine; D004229:Dithiothreitol; D019803:Glutathione Disulfide