Dataset Information

Isolated rat heart mitochondria are able to metabolize pent-4-enoate to tricarboxylic acid-cycle intermediates.

ABSTRACT: The metabolism of four short-chain odd-number-carbon fatty acids, pentanoate, pent-4-enoate, propionate and acrylate, was studied in isolated rat heart mitochondria incubated in [14C]bicarbonate buffer. Under these conditions pentanoate was metabolized with a concomitant accumulation of malate and incorporation of 14CO2 into non-volatile compounds. The metabolism of propionate to tricarboxylic acid-cycle intermediates required the addition of ATP and oligomycin. After addition of a small amount of rotenone to the incubation medium, pent-4-enoate was metabolized with an increase in malate from less than 3 nmol/mg of protein to 34.0 +/- 1.5 nmol/mg in 40 min, during which time the amount of 14CO2 fixed in acid-stable compounds increased from 1.56 +/- 0.30 to 41.1 +/- 2.6 nmol/mg of protein. Acrylate was not metabolized under any of the conditions tested. The results show that cardiac mitochondria must have an enzyme system that is capable of reducing the double bond of either pent-4-enoate or its metabolities. That the metabolism of pent-4-enoate occurs through a reductive step and energy-dependent carboxylation is evident from the requirement for NAD+ reduction by partial inhibition of the mitochondrial respiratory chain and the presence of ATP and CO2. The results do not enable us to say whether the compound reduced is pent-4-enoyl-CoA or acryloyl-CoA.

SUBMITTER: Hiltunen JK

PROVIDER: S-EPMC1161954 | biostudies-other | 1980 Jun

REPOSITORIES: biostudies-other

ACCESS DATA

Similar Datasets

Project description:The metabolic effects of pent-4-enoate were studied in beating and potassium-arrested perfused rat hearts. The addition of 0.8mm-pent-4-enoate to the fluid used to perfuse a potassium-arrested heart resulted in a 70% increase in the O(2) consumption and a 66% decrease in the glycolytic flux as measured in terms of the de-tritiation of [3-(3)H]glucose, although the proportion of the O(2) consumption attributable to glucose oxidation decreased from an initial 30% to 10%. The pent-4-enoate-induced increase in O(2) consumption was only 15% in the beating heart. In the potassium-arrested heart, pent-4-enoate stimulated palmitate oxidation by more than 100% when measured in terms of the production of (14)CO(2) from [1-(14)C]palmitate, but in the beating heart palmitate oxidation was inhibited. Perfusion of the heart with pent-4-enoate had no effect on the proportion of pyruvate dehydrogenase found in the active form, in spite of large changes in the CoASH and acetyl-CoA concentrations and changes in their concentration ratios. The effects of pent-4-enoate on the cellular redox state were dependent on the ATP consumption of the heart. In the beating heart, pent-4-enoate caused a rapid mitochondrial NAD(+) reduction that subsequently faded out, so that the final state was more oxidized than the initial state. The arrested heart, however, remained in a more reduced state than initially, even after the partial re-oxidation that followed the initial rapid NAD(+) reduction. The ability of pent-4-enoate to increase or decrease fatty acid oxidation can be explained on the basis of the differential effects of pent-4-enoate on the concentration of citric acid-cycle intermediates under conditions of high or low ATP consumption of the myocardial cell. The proportion of the fatty acids in the fuel consumed by the heart is probably primarily determined by the regulatory mechanisms of glycolysis. When pent-4-enoate causes an increase in the citric acid-cycle intermediates, feedback inhibition of glycolysis results in an increase in the oxidation of fatty acids.

Project description:BackgroundTricarboxylic acid (TCA) cycle deregulation may predispose to cardiovascular diseases, but the role of TCA cycle-related metabolites in the development of atrial fibrillation (AF) and heart failure (HF) remains unexplored. This study sought to investigate the association of TCA cycle-related metabolites with risk of AF and HF.MethodsWe used two nested case-control studies within the PREDIMED study. During a mean follow-up for about 10 years, 512 AF and 334 HF incident cases matched by age (±5 years), sex and recruitment center to 616 controls and 433 controls, respectively, were included in this study. Baseline plasma levels of citrate, aconitate, isocitrate, succinate, malate and d/l-2-hydroxyglutarate were measured with liquid chromatography-tandem mass spectrometry. Multivariable conditional logistic regression models were fitted to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for metabolites and the risk of AF or HF. Potential confounders included smoking, family history of premature coronary heart disease, physical activity, alcohol intake, body mass index, intervention groups, dyslipidemia, hypertension, type 2 diabetes and medication use.ResultsComparing extreme quartiles of metabolites, elevated levels of succinate, malate, citrate and d/l-2-hydroxyglutarate were associated with a higher risk of AF [ORQ4 vs. Q1 (95% CI): 1.80 (1.21-2.67), 2.13 (1.45-3.13), 1.87 (1.25-2.81) and 1.95 (1.31-2.90), respectively]. One SD increase in aconitate was directly associated with AF risk [OR (95% CI): 1.16 (1.01-1.34)]. The corresponding ORs (95% CI) for HF comparing extreme quartiles of malate, aconitate, isocitrate and d/l-2-hydroxyglutarate were 2.15 (1.29-3.56), 2.16 (1.25-3.72), 2.63 (1.56-4.44) and 1.82 (1.10-3.04), respectively. These associations were confirmed in an internal validation, except for aconitate and AF.ConclusionThese findings underscore the potential role of the TCA cycle in the pathogenesis of cardiac outcomes.

Dataset Information

Isolated rat heart mitochondria are able to metabolize pent-4-enoate to tricarboxylic acid-cycle intermediates.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets