The effect of respiratory chain impairment of beta-oxidation in rat heart mitochondria.
Cardiac ischaemia leads to an inhibition of beta-oxidation flux and an accumulation of acyl-CoA and acyl-carnitine esters in the myocardium. However, there remains some uncertainty as to which esters accumulate during cardiac ischaemia and therefore the site of inhibition of beta-oxidation [Moore, Radloff, Hull and Sweely (1980) Am. J. Physiol. 239, H257-H265; Latipää (1989) J. Mol. Cell. Cardiol. 21, 765-771]. When beta-oxidation of hexadecanoyl-CoA in state III rat heart mitochondria was inhibited by titration of complex III activity, flux measured as 14CO2 release, acid-soluble radioactivity or as acetyl-carnitine was progressively decreased. Low concentrations of myxothiazol caused reduction of the ubiquinone pool whereas the NAD+/NADH redox state was less responsive. Measurement of the CoA and carnitine esters generated under these conditions showed that there was a progressive decrease in the amounts of chain-shortened saturated acyl esters with increasing amounts of myxothiazol. The concentrations of 3-hydroxyacyl and 2-enoyl esters, however, were increased between 0 and 0.2 microM myxothiazol but were lowered at higher myxothiazol concentrations. More hexadecanoyl-CoA and hexadecanoyl-carnitine were present with increasing concentrations of myxothiazol. We conclude that 3-hydroxyacyl-CoA dehydrogenase and acyl-CoA dehydrogenase activities are inhibited by reduction of the ubiquinone pool, and that this explains the confusion over which esters of CoA and carnitine accumulate during cardiac ischaemia. Furthermore these studies demonstrate that the site of the control exerted by the respiratory chain over beta-oxidation is shifted depending on the extent of the inhibition of the respiratory chain.
Sir James Spence Institute of Child Health, Royal Victoria Infirmary, Newcastle-upon-Tyne, U.K.
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Eaton
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Pourfarzam
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Bartlett
D000108:Acetylcarnitine / Q000378:metabolism*; D000214:Acyl Coenzyme A / Q000378:metabolism*; D000818:Animals; D004579:Electron Transport; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar
D000214:Acyl Coenzyme A; D009243:NAD; D000108:Acetylcarnitine