Acyl-CoA inhibition of adenine nucleotide translocation in ischemic myocardium

Shug, AL; Shrago, Earl; Bittar, Neville; Jd, Folts; Koke,

doi:10.1152/ajplegacy.1975.228.3.689

Cited by 258 publications

(72 citation statements)

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“…These results showed a dramatic upregulation of MTE-1 mRNA, protein expression, and activity by diabetes, which was largely mimicked by pharmacological stimulation of PPARa, suggesting that increased plasma fatty acids in diabetes upregulate MTE-I via ligand activation of PPARa. Upregulation of MTE-I activity in cardiac mitochondria may help prevent the lipotoxic cardiomyopathy that can develop in diabetes (12,13), as it would reduce the accumulation of toxic long-chain acyl-CoA in the mitochondrial matrix and facilitate the export of fatty acid anions (7,11,(23)(24)(25). Upregulation of MTE-1 in diabetes should also prevent depletion of the free CoA pool and thus help maintain the oxidation of pyruvate and a-ketoglutarate.…”

Section: Discussionmentioning

confidence: 99%

“…Altered mitochondrial respiration in liver, skeletal muscle, and heart has been observed in response to perturbations that alter UCP3 and/or MTE-I expression (e.g., treatment with fenofibrate or thyroid hormone, caloric restriction, fasting, or diabetes) (3,(16)(17)(18)(19)(20)(21)(22). Induction of MTE-I should facilitate the export of fatty acid anions and reduce the accumulation of toxic longchain acyl-CoAs (3,7,(23)(24)(25) and thus might help prevent the lipotoxic cardiomyopathy that can develop in diabetes (12,13), with accelerated lipid uptake or impaired fatty acid metabolism (26)(27)(28)(29).…”

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confidence: 99%

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Diabetes or peroxisome proliferator-activated receptor α agonist increases mitochondrial thioesterase I activity in heart

King

Young

Kerner

et al. 2007

Journal of Lipid Research

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Peroxisome proliferator-activated receptor a (PPARa) is a transcriptional regulator of the expression of mitochondrial thioesterase I (MTE-I) and uncoupling protein 3 (UCP3), which are induced in the heart at the mRNA level in response to diabetes. Little is known about the regulation of protein expression of MTE-I and UCP3 or about MTE-I activity; thus, we investigated the effects of diabetes and treatment with a PPARa agonist on these parameters. Rats were either made diabetic with streptozotocin (55 mg/kg ip) and maintained for 10-14 days or treated with the PPARa agonist fenofibrate (300 mg/kg/day) for 4 weeks. MTE-I and UCP3 protein expression, MTE-1 activity, palmitate export, and oxidative phosphorylation were measured in isolated cardiac mitochondria. Diabetes and fenofibrate increased cardiac MTE-I mRNA, protein, and activity (?4-fold compared with controls). This increase in activity was matched by a 6-fold increase in palmitate export in fenofibrate-treated animals, despite there being no effect in either group on UCP3 protein expression. Both diabetes and fenofibrate caused significant decreases in state III respiration of isolated mitochondria with pyruvate 1 malate as the substrate, but only diabetes reduced state III rates with palmitoylcarnitine. Both diabetes and specific PPARa activation increased MTE-I protein, activity, and palmitate export in the heart, with little effect on UCP3 protein expres-

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Diabetes or peroxisome proliferator-activated receptor α agonist increases mitochondrial thioesterase I activity in heart

King

Young

Kerner

et al. 2007

Journal of Lipid Research

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“…A specific interaction between acyl-CoA and bovine mitochondrial ANT was demonstrated using an "#&I-labelled photoreactive acyl-CoA [21]. Ligating the anterior coronary artery to produce ischaemia resulted in a clear correlation between the increase in the intracellular acyl-CoA level and the decrease in translocase activity in itro [22]. Under these conditions the mitochondrial acyl-CoA concentration was reported to be increased to 1 mM [23].…”

Section: Long-chain Acyl-coa Esters As Regulators Of Energy Metabolismmentioning

confidence: 99%

Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling

Færgeman¹,

Knudsen²

1997

Biochemical Journal

629

477

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The intracellular concentration of free unbound acyl-CoA esters is tightly controlled by feedback inhibition of the acyl-CoA synthetase and is buffered by specific acyl-CoA binding proteins. Excessive increases in the concentration are expected to be prevented by conversion into acylcarnitines or by hydrolysis by acyl-CoA hydrolases. Under normal physiological conditions the free cytosolic concentration of acyl-CoA esters will be in the low nanomolar range, and it is unlikely to exceed 200 nM under the most extreme conditions. The fact that acetyl-CoA carboxylase is active during fatty acid synthesis (Ki for acyl-CoA is 5 nM) indicates strongly that the free cytosolic acyl-CoA concentration is below 5 nM under these conditions. Only a limited number of the reported experiments on the effects of acyl-CoA on cellular functions and enzymes have been carried out at low physiological concentrations in the presence of the appropriate acyl-CoA-buffering binding proteins. Re-evaluation of many of the reported effects is therefore urgently required. However, the observations that the ryanodine-senstitive Ca2+-release channel is regulated by long-chain acyl-CoA esters in the presence of a molar excess of acyl-CoA binding protein and that acetyl-CoA carboxylase, the AMP kinase kinase and the Escherichia coli transcription factor FadR are affected by low nanomolar concentrations of acyl-CoA indicate that long-chain acyl-CoA esters can act as regulatory molecules in vivo. This view is further supported by the observation that fatty acids do not repress expression of acetyl-CoA carboxylase or Δ9-desaturase in yeast deficient in acyl-CoA synthetase.

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“…It is well known that these esters are potent inhibitors of ANT [1]. It has been proposed that inhibition of adenine nucleotide transport by acyl-CoA is one of the steps in role in disturbance of the energy metabolism of the ischemic myocardial cell [2]. At the same time, data exist which at first glance seem to contradict the above-mentioned hypothesis.…”

Section: Introductionmentioning

confidence: 99%

The role of long‐chain acyl‐CoA in the damage of oxidative phosphorylation in heart mitochondria

Borutait¹,

Mildaz̆ien²,

Ivanovien³

et al. 1989

FEBS Letters

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The aim of this investigation was to study the effect of intramitochondrial acyl-CoA on the respiration of rabbit heart mitochondria over the whole range of stationary respiratory rates between States 4 and 3. The creatine phosphokinase system was used for stabilization of extramitoehondrial adenine nueleotide concentration. It was shown that acyl-CoA depressed respiration more effectively in the intermediate range of respiration between States 4 and 3. The effect of acylCoA was negligible near State 4 and in State 3. These data are in line with our previous results concerning the dependence of the adenine nucleotide transloeator control coefficient on the rate of mitochondrial respiration. Thus, our data suggest that long-chain acyl-CoA may regulate oxidative phosphorylation in heart mitochondria in vivo.Adenine nucleotide translocator; Long-chain acyl-CoA; Oxidative phosphorylation; (Heart mitochondria)

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Acyl-CoA inhibition of adenine nucleotide translocation in ischemic myocardium

Cited by 258 publications

References 0 publications

Diabetes or peroxisome proliferator-activated receptor α agonist increases mitochondrial thioesterase I activity in heart

Diabetes or peroxisome proliferator-activated receptor α agonist increases mitochondrial thioesterase I activity in heart

Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling

The role of long‐chain acyl‐CoA in the damage of oxidative phosphorylation in heart mitochondria

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