Modulation of adenine nucleotide translocase activity during myocardial ischemia.
Preliminary studies have shown that high levels of free fatty acids, which elevate LCACAE and lower levels of free carnitine, are much more harmful to the heart after repeated periods of ischemia and reperfusion than after exposure to continuous ischemia and reperfusion. These observations appear to support our hypothesis that LCACAE inhibition of the mitochondrial ANT during ischemia potentiates free radical mediated damage to the inner mitochondrial membrane during reperfusion. These and related findings by others have led us to hypothesize that the mechanisms of ischemic injury to the heart involve the following sequence of events: (1) exposure to high levels of FFA during ischemia and reperfusion results in permanently elevated LCACAE and low free carnitine levels; (2) LCACAE-ANT binding increases and ANT activity decreases; (3) mitochondrial swelling occurs because of decreased ADP/ATP transport and oxidative phosphorylation; (4) complex III activity is altered (superoxide formation increases), and swelling of mitochondrial membranes exposes C = C bonds that are required for lipid peroxidation, which can lead to inner mitochondrial membrane damage. We further hypothesize that LCACAE-ANT inhibition-induced free radical damage causes the loss of mitochondrial matrix components (22), eventually leading to lesions of the sarcolemmal membrane and cell necrosis (22). Studies now in progress support this hypothesis and indicate that inhibition of ANT in isolated rat heart mitochondria by carboxyatractyloside or palmitoyl CoA stimulates free radical formation, probably at the complex III loci.(ABSTRACT TRUNCATED AT 250 WORDS)
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William S. Middleton Memorial VA Hospital, Madison.
Subramanian
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D000818:Animals; D003065:Coenzyme A / Q000378:metabolism; D003326:Coronary Circulation; D003327:Coronary Disease / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D004285:Dogs; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism; D000226:Mitochondrial ADP, ATP Translocases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009713:Nucleotidyltransferases / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D005230:Fatty Acids, Nonesterified; D000226:Mitochondrial ADP, ATP Translocases; D009713:Nucleotidyltransferases; D003065:Coenzyme A