Effect of carnitine on the oxidation of α-oxoglutarate to succinate in the presence of acetoacetate or pyruvate

Hülsmann, W.C.; Siliprandi, D.; Ciman, M.; Siliprandi, N.

doi:10.1016/0304-4165(64)90271-5

Cited by 73 publications

(14 citation statements)

References 9 publications

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“…Because the addition of carnitine to hearts oxidizing acetoacetate failed to improve contractile function, as would be predicted by the mitochondrial studies cited earlier (4,5), it was important to determine whether carnitine altered the distribution ofC2 and C4 units between their CoA and carnitine derivatives. Despite the decline in contractile function for hearts perfused with carnitine, there was a 24% increase in the tissue level of acetylcarnitine and an eightfold increase in the level of 3-ketoacylcarnitine (including acetoacetylcarnitine) in hearts perfused with acetoacetate plus carnitine compared with hearts perfused with acetoacetate alone (Table II).…”

Section: Resultsmentioning

confidence: 99%

“…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 Receivedforpublication 25 June 1991 and in revisedform 4 October 1991. 1.…”

Section: Introductionmentioning

confidence: 99%

“…First, the relative distribution of CoA between nonesterified CoASH and esterified CoA (e.g., acetyl-CoA, fatty acyl-CoA) can be altered by the provision ofL-carnitine, which has been shown to result in the transfer of acetyl units from acetyl-CoA and acetoacetyl-CoA to carnitine via the action of the enzyme carnitine acetyltransferase (4,6), thereby forming acetylcarnitine and acetoacetylcarnitine while increasing the tissue content ofCoASH. This is supported by the observations that the addition ofcarnitine to isolated rat heart mitochondria oxidizing acetoacetate resulted in an increase in state 3 respiration (4,5) and that the incubation of isolated mitochondria with carnitine increases levels of intramitochondrial CoASH and decreases levels of acetyl-CoA (6). Because carnitine is readily transported across the sarcolemma (7), it may be possible to increase intracellular levels ofcarnitine in the intact heart in an attempt to "buffer" acetyl-CoA and acetoacetyl-CoA as the carnitine esters acetylcarnitine and acetoacetylcarnitine.…”

Section: Introductionmentioning

confidence: 99%

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Coenzyme A sequestration in rat hearts oxidizing ketone bodies.

Russell¹,

Taegtmeyer²

1992

J. Clin. Invest.

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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-

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Coenzyme A sequestration in rat hearts oxidizing ketone bodies.

Russell¹,

Taegtmeyer²

1992

J. Clin. Invest.

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“…The decrease in D-3-HB production in the normal state and the increase in the percent oxidation of acetoacetate in the diabetic state support such a suggestion, moreover, DNP enhances the utilization and oxidation of D-3-HB in isolated perfused heart in a concentration-dependent manner 14 , by decreasing myocyte NADH⁺ 29 , raising Ca⁺² cytosolic concentration, and AMP/ATP ratio 30,31 through stimulating AMPK/p38 MAPK 32 . The regeneration of NAD⁺ could enhance a-ketoglutarate dehydrogenase (a-KGDH) which is reported to be inhibited by acetoacetate 10 , and thereby the oxidation of ketone bodies is enhanced by providing succinyl CoA.…”

Section: Discussion:-mentioning

confidence: 99%

“…Propionate has been shown to enhance the utilization and oxidation of acetoacetate in the non-working heart 7 and improves heart contractile function in the working heart 8 , whereas propionate inhibits the utilization, but not the oxidation of D-3-HB 9 . Carnitine enhances the removal of acetoacetate in vivo and in vitro studies 10,11,12,13 , but has no effect on the removal of D-3-HB 12,13 . Ischemia-reperfusion stimulates myocardial D-3-HB utilization 14 .…”

Section: …………………………………………………………………………………………………… Introduction:-mentioning

confidence: 99%

The Effect of Diabetes on Acetoacetate Metabolism in Heart.

Ijar¹,

Sultan²,

Alturkistani³

et al. 2017

IJAR

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Background Aims: In this study, the effects of perfusion pressure, insulin, L-carnitine, propionate and 2,4-dinitrophenol on the utilization and oxidation of acetoacetate were investigated in the isolated nonworking perfused heart from normal and diabetic rats. Materials and Method: Hearts from Male Wistar albino rats were used. In the diabetic subgroup, Diabetes was induced by an intravenous injection of alloxan. The hearts were perfused at a perfusion pressure of 40 or 80 mmHg for 1 h with Krebs-Henseleit Medium, with the concentrations of calcium and magnesium halved, and oxygenated by equilibration with 5% carbon dioxide and 95% oxygen. Determination of acetoacetate and D-3-hydroxybutyrate levels were made by the method of Mellanby and Williamson and Williamson and Mellanby respectively, and comparison between groups was done using the twotailed Student's t-test for independent samples.

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Which way does the citric acid cycle turn during hypoxia? The critical role of α‐ketoglutarate dehydrogenase complex

Chinopoulos

2013

J of Neuroscience Research

110

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The citric acid cycle forms a major metabolic hub and as such it is involved in many disease states implicating energetic imbalance. In spite of the fact that it is being branded as a 'cycle', during hypoxia, when the electron transport chain does not oxidize reducing equivalents, segments of this metabolic pathway remain operational but exhibit opposing directionalities. This serves the purpose of harnessing high energy phosphates through matrix substrate-level phosphorylation in the absence of oxidative phosphorylation. In this mini-review these segments are appraised, pointing to the critical importance of the alpha-ketoglutarate dehydrogenase complex dictating their directionalities.

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Effect of carnitine on the oxidation of α-oxoglutarate to succinate in the presence of acetoacetate or pyruvate

Cited by 73 publications

References 9 publications

Coenzyme A sequestration in rat hearts oxidizing ketone bodies.

Coenzyme A sequestration in rat hearts oxidizing ketone bodies.

The Effect of Diabetes on Acetoacetate Metabolism in Heart.

Which way does the citric acid cycle turn during hypoxia? The critical role of α‐ketoglutarate dehydrogenase complex

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