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Rat Hepatic Coenzyme A is Redistributed in Response to Mitochondrial Acyl-Coenzyme A Accumulation^1,2,

Departments of Medicine and Pharmacology, Division of Clinical Pharmacology, Case Western Reserve University, Cleveland, OH 44106

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.

KEY WORDS: • rats • coenzyme A • cobalamin • propionate • clofibrate

¹ Presented at 1992 FASEB meeting, Anaheim, CA [Brass, E. P. & Ruff, L. J. (1992) Redistribution of hepatic coenzyme A in response to mitochondrial acyl-CoA accumulation. FASEB J. 6: A1519 (abs.)].

² This work was supported by NIH DK36069. Eric Paul Brass is a Burroughs Wellcome Scholar in Clinical Pharmacology.

Manuscript received 10 April 1992. Revision accepted 26 June 1992.