THE EFFECT OF RESPIRATORY-CHAIN IMPAIRMENT ON 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; Latipaa (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 (CO2)-C-14 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 gener ated under these conditions showed that there was a progressive decrea se in the amounts of chain-shortened saturated acyl esters with increa sing amounts of myxothiazol. The concentrations of 3-hydroxyacyl and 2 -enoyl esters, however, were increased between 0 and 0.2 mu M myxothia zol but were lowered at higher myxothiazol concentrations. More hexade canoyl-CoA and hexadecanoyl-carnitine were present with increasing con centrations of myxothiazol. We conclude that 3-hydroxyacyl-CoA dehydro genase and acyl-CoA dehydrogenase activities are inhibited by reductio n of the ubiquinone pool, and that this explains the confusion over wh ich esters of CoA and carnitine accumulate during cardiac ischaemia. F urthermore these studies demonstrate that the site of the control exer ted by the respiratory chain over beta-oxidation is shifted depending on the extent of the inhibition of the respiratory chain.