Reversible inhibition of adenine nucleotide translocation by long chain fatty acyl coenzyme A esters in liver mitochondria of diabetic and hibernating animals.

The sluggish respiratory response to chondria of alloxan diabetic rats and ADP in liver mitohibernating ground squirrels was overcome by addition of uncouplers of oxidative phosphorylation, suggesting that poor penetration of ADP prevented maximum oxygen consumption. The in uivo depression of adenine nucleotide translocation through the inner mitochondrial membrane was confirmed directly by measurements of [14C]ADP translocase and 32Pi-ATP exchange reactions. The inhibition of adenine nucleotide penetration was considered to be a consequence of increased hepatic lipid content, particularly long chain acyl-CoA esters, which occur in diabetes and hibernation. Demonstrated changes in the pattern of mitochondrial long chain fatty acids may be responsible for the altered spectral characteristics of the cytochromes observed in these animals. The inhibition of adenine nucleotide translocation could be reproduced in vitro with normal rat liver mitochondria by production of, or upon addition of certain esters of long chain fatty acids. Simultaneous addition of pyruvate or o-ketoglutarate with the free fatty acid prevented formation of the acyl-CoA ester and inhibition of translocation. Selective reversal of the inhibition by carnitine provided strong evidence implicating the acyl-CoA ester rather than the free fatty acid as the inhibitory agent. From these results, it is postulated that certain long chain acyl-CoA esters, acting as natural effecters of adenine nucleotide translocation, can perform a physiological role in the regulation of mitochondrial metabolism.