Coenzyme A sequestration in rat hearts oxidizing ketone bodies.

Abstract

Previous studies have indicated that ketone body-mediated contractile failure in rat hearts is due to inhibition of 2-oxoglutarate dehydrogenase, and it has been speculated that this inhibition is due to the sequestration of intramitochondrial CoA as acetoacetyl-CoA and acetyl-CoA. These studies were performed to determine whether oxidation of acetoacetate by isolated rat heart mitochondria results in a fall in intramitochondrial nonesterified CoA ICoASHI and whether increasing the available CoA improves contractile performance in hearts oxidizing acetoacetate. The oxidation of acetoacetate by isolated rat heart mitochondria resulted in depressed state 3 respiration as well as in a decrease in ICoASHI. Increasing the tissue content of CoASH in perfused hearts by providing the precursors for CoA relieved inhibition of 2-oxoglutarate dehydrogenase and improved the contractile performance of isolated working hearts. In contrast, the addition ofcarnitine increased the tissue content of CoASH but did not improve function. These findings suggest the presence of two different pools of CoASH. We conclude that ketone body-mediated inhibition of 2-oxoglutarate dehydrogenase is due to decreased intramitochondrial CoASH and that this inhibition of the citric acid cycle is a plausible mechanism for concomitant contractile failure. (J. Clin. Invest. 1992. 89:968-973.) Key words: acetoacetate *2-oxoglutarate dehydrogenase * citric acid cycle * rat heart Introduction Oxidation of ketone bodies as a sole substrate by the isolated working rat heart results in reversible contractile failure (1, 2), despite the ability ofmammalian hearts to utilize ketone bodies as fuel for respiration (3). We (1) and others (4, 5) have previously suggested that the failure results from inhibition of the citric acid cycle at the level of 2-oxoglutarate dehydrogenase through the sequestration of the required cofactor nonesterified CoA (CoASH)1 as the thioesters acetoacetyl-CoA and ace-

Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I

“…Increased ketone body utilization was previously shown to sequester free CoA and cause accumulation of α-ketoglutarate, since free CoA is a limiting substrate for α-ketoglutarate dehydrogenase (17). Depletion of α-ketoglutarate with acetyl-CoA accumulation in Gcdh -/-mice suggests a different mechanism, involving glutaric acid accumulation and resulting in CoA sequestration.…”

“…accumulation of glutaryl-CoA, which may result in sequestration of intramitochondrial free CoA. Alternatively, increased ketone body utilization leads to acetyl-CoA accumulation, which can also reduce free CoA levels (17,18). Therefore, we measured acetyl-CoA, glutaryl-CoA, free CoA, ATP, phosphocreatine, and α-ketoglutarate in the brain of weanling and adult Gcdh -/-mice or heterozygote controls with normal and lysine diet exposure ( Figure 5, A-D).…”

Short‐chain 3‐hydroxyacyl‐CoA dehydrogenase is a negative regulator of insulin secretion in response to fuel and non‐fuel stimuli in INS832/13 β‐cells

“…32,33 It can be hypothesized that knockdown of HADHSC activity could lead to the accumulation of short-chain acyl-CoAs, with the resultant inhibition of a-KGDH and efflux of a-ketoglutarate (a-KG) from the mitochondria, used in transamination reactions.…”

Competition between acetate and oleate for the formation of malonyl-CoA and mitochondrial acetyl-CoA in the perfused rat heart

“…The trapping of mitochondrial CoA into esters plays a role in a number of physiological and pathological processes, such as the oxidation of acetoacetate in isolated heart mitochondria [34] and perfused hearts [35], propionate metabolism in the heart [27,28], inborn errors of longchain fatty acid oxidation [36], valproate intoxication [37,38], etc. Stanley et al showed that a moderate elevation of β-hydroxybutyrate suppressed palmitate oxidation in pig hearts [39], without changes in concentrations of malonyl-CoA, acetyl-CoA, or free CoA.…”