Rat hepatic coenzyme A is redistributed in response to mitochondrial acyl-coenzyme A accumulation.
Coenzyme A without an acyl-thioester (CoASH) is required for numerous cellular reactions, and sequestration of CoASH as acyl-CoAs may impair metabolic function. Increased total CoA protects the cell from acyl-CoA accumulation, and enhanced CoA biosynthesis may represent a compensatory response in metabolic disease. To test the hypothesis that cellular CoA is redistributed from the cytosol to the mitochondria in response to mitochondrial acyl-CoA accretion, the subcellular distribution of hepatic CoA was determined by differential centrifugation and measurement of the mitochondrial marker enzyme citrate synthase. Liver from control, clofibrate-treated and hydroxycobalamin[c-lactam] (HCCL)-treated rats were used. Clofibrate increased total hepatic CoA concentration 2.2-fold, whereas HCCL (which causes inhibition of L-methylmalonyl-CoA mutase and consequent propionyl- and methylmalonyl-CoA accumulation) increased it threefold. However, clofibrate did not affect the percentage of total CoA in the mitochondria (control: 44 +/- 3%, clofibrate: 49 +/- 5%), and HCCL-treatment induced a marked redistribution of CoA into the mitochondria (HCCL: 78 +/- 8%). Redistribution of total CoA was also induced acutely by incubation of hepatocytes from control rats with 10 mmol/L propionate. Thus, redistribution of the cellular CoA pool can help maintain CoASH availability as mitochondrial acyl-CoA accumulation occurs and may be an important compensatory response to metabolic injury.
Brass
E P
EP
Department of Medicine, Case Western Reserve University, Cleveland, OH 44106.
Ruff
L J
LJ
D000214:Acyl Coenzyme A / Q000378:metabolism*; D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology; D002478:Cells, Cultured; D002950:Citrate (si)-Synthase / Q000032:analysis; D002994:Clofibrate / Q000494:pharmacology; D003065:Coenzyme A / Q000032:analysis*; D003600:Cytosol / Q000201:enzymology; D006879:Hydroxocobalamin / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000214:Acyl Coenzyme A; D002950:Citrate (si)-Synthase; D002994:Clofibrate; D006879:Hydroxocobalamin; D003065:Coenzyme A