Citrate release by perfused rat hearts: a window on mitochondrial cataplerosis

Vincent, Geneviève; Comte, Blandine; Poirier, Myriame; Rosiers, Christine Des

doi:10.1152/ajpendo.2000.278.5.e846

Cited by 36 publications

(74 citation statements)

References 35 publications

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“…The combined data of Groups 1 and 2 show that the contributions of exogenous oleate, lactate plus pyruvate, and glucose to mitochondrial acetyl-CoA, 81, 4, and 18%, respectively, add up to close to 100%. These results, which concur with previous ones (16,19), indicate that there is little if any contribution of endogenous substrates to mitochondrial acetyl-CoA.…”

Section: Table I Conditions Of Perfusion Of Isolated Rat Heartssupporting

confidence: 93%

“…Since peroxisomal oxidation contributes at least one-half of the acetyl-CoA used for malonyl-CoA synthesis, the latter could be supported by a rate of peroxisomal oxidation of about 2.5 (nmol acetyl)⅐min Ϫ1 ⅐g of wet weight Ϫ1 . This rate is 100 times lower than the rate of acetyl-CoA produced from mitochondrial ␤-oxidation of long-chain fatty acids in hearts perfused with a mixture of substrates including 0.4 mM oleate (19). Therefore, a very low rate of peroxisomal fatty acid oxidation is sufficient to sustain the turnover of heart malonylCoA.…”

Section: Discussionmentioning

confidence: 94%

“…This difference can be explained by the following considerations. The transfer of label from [16-13 C]palmitate to mitochondrial acetyl-CoA is only partial because of the combined effects of (i) the incomplete isotopic equilibrium of the mitochondrial acetoacetyl-CoA thiolase reaction (34,35) and (ii) the reversibility of the mitochondrial 3-oxoacid-CoA transferase reaction that converts acetoacetyl-CoA to acetoacetate (19,35). In the reversible acetoacetyl-CoA thiolase reaction, the exchange of the C 3 ϩ 4 acetyl of acetoacetyl-CoA with the free acetyl-CoA pool is much slower than the exchange of the C 1 ϩ 2 acetyl (34).…”

Section: Discussionmentioning

confidence: 99%

“…Although the activity of ATP-citrate lyase in the heart is low, it could sustain the rates of increase in malonyl-CoA concentration measured in perfused rat hearts following the addition of substrates that raise malonyl-CoA concentration (16). Also, the physiological release of citrate by the heart (18,19) implies that citrate is available to cytosolic ATP-citrate lyase after transport from the mitochondria (20). Using a new gas chromatography-mass spectrometry technique (21), we showed that [ 13 C]oleate contributes carbon to the acetyl moiety of malonyl-CoA (16).…”

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confidence: 99%

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Peroxisomal Fatty Acid Oxidation Is a Substantial Source of the Acetyl Moiety of Malonyl-CoA in Rat Heart

Reszko

Kasumov

Jobbins

et al. 2004

Journal of Biological Chemistry

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Little is known about the sources of acetyl-CoA used for the synthesis of malonyl-CoA, a key regulator of mitochondrial fatty acid oxidation in the heart. In perfused rat hearts, we previously showed that malonylCoA is labeled from both carbohydrates and fatty acids. This study was aimed at assessing the mechanisms of incorporation of fatty acid carbons into malonyl-CoA. Rat hearts were perfused with glucose, lactate, pyruvate, and a fatty acid (palmitate, oleate or docosanoate). In each experiment, substrates were 13 C-labeled to yield singly or/and doubly labeled acetyl-CoA. The mass isotopomer distribution of malonyl-CoA was compared with that of the acetyl moiety of citrate, which reflects mitochondrial acetyl-CoA. In the presence of labeled glucose or lactate/pyruvate, the 13 C labeling of malonylCoA was up to 2-fold lower than that of mitochondrial acetyl-CoA. However, in the presence of a fatty acid labeled in its first acetyl moiety, the 13 C labeling of malonyl-CoA was up to 10-fold higher than that of mitochondrial acetyl-CoA. The labeling of malonyl-CoA and of the acetyl moiety of citrate is compatible with peroxisomal ␤-oxidation forming C 12 and C 14 acyl-CoAs and contributing >50% of the fatty acid-derived acetyl groups that end up in malonyl-CoA. This fraction increases with the fatty acid chain length. By supplying acetyl-CoA for malonyl-CoA synthesis, peroxisomal ␤-oxidation may participate in the control of mitochondrial fatty acid oxidation in the heart. In addition, this pathway may supply some acyl groups used in protein acylation, which is increasingly recognized as an important regulatory mechanism for many biochemical processes.Malonyl-CoA is an intermediate of fatty acid synthesis in lipogenic organs. It is also a key regulator of mitochondrial long-chain fatty acid oxidation in most mammalian tissues because it modulates the activity of carnitine palmitoyltransferase-I (1-4). Malonyl-CoA is formed by cytosolic acetyl-CoA carboxylase (ACC) 1 and is disposed off either by lipogenesis or via malonyl-CoA decarboxylase, which reforms acetyl-CoA. Alterations in malonyl-CoA metabolism and regulation have been associated with insulin resistance and obesity (5). Mice lacking ACC␤, the predominant ACC isoform in cardiac and skeletal muscle, show not only decreased malonyl-CoA levels and increased fatty acid oxidation but also major alterations in systemic energy balance with decreased body fat despite increased food intake (6). The above data emphasize the crucial role of malonyl-CoA in fat metabolism and energy balance. In the heart, much work has been conducted on the control of malonyl-CoA metabolism, emphasizing the mechanisms of regulation of ACC␤ and malonyl-CoA decarboxylase. This includes acute changes in activity through phosphorylation via cAMPdependent protein kinase or AMP kinase (for recent reviews, see Refs. 5 and 7-10), as well as chronic regulation through gene expression involving peroxisomal proliferator-activated receptor (11,12). However, little is known about the origin of ac...

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Section: Table I Conditions Of Perfusion Of Isolated Rat Heartssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Peroxisomal Fatty Acid Oxidation Is a Substantial Source of the Acetyl Moiety of Malonyl-CoA in Rat Heart

Reszko

Kasumov

Jobbins

et al. 2004

Journal of Biological Chemistry

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“…Plasma concentrations of glucose and lactate were quantified using enzymatic assays and ketone bodies by GC-MS as previously described (19,48).…”

Section: Analytical Proceduresmentioning

confidence: 99%

Alterations in carbohydrate metabolism and its regulation in PPARα null mouse hearts

Gélinas¹,

Labarthe²,

Bouchard³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Although a shift from fatty acids (FAs) to carbohydrates (CHOs) is considered beneficial for the diseased heart, it is unclear why subjects with FA ␤-oxidation defects are prone to cardiac decompensation under stress conditions. The present study investigated potential alterations in the myocardial utilization of CHOs for energy production and anaplerosis in 12-wkold peroxisome proliferator-activating receptor-␣ (PPAR␣) null mice (a model of FA ␤-oxidation defects). Carbon-13 methodology was used to assess substrate flux through energy-yielding pathways in hearts perfused ex vivo at two workloads with a physiological substrate mixture mimicking the fed state, and real-time RT-quantitative polymerase chain reaction was used to document the expression of selected metabolic genes. When compared with that from control C57BL/6 mice, isolated working hearts from PPAR␣ null mice displayed an impaired capacity to withstand a rise in preload (mimicking an increased venous return as it occurs during exercise) as reflected by a 20% decline in the aortic flow rate. At the metabolic level, beyond the expected shift from FA (5-fold down) to CHO (1.5-fold up; P Ͻ 0.001) at both preloads, PPAR␣ null hearts also displayed 1) a significantly greater contribution of exogenous lactate and glucose and/or glycogen (2-fold up) to endogenous pyruvate formation, whereas that of exogenous pyruvate remained unchanged and 2) marginal alterations in citric acid cycle-related parameters. The lactate production rate was the only measured parameter that was affected differently by preloads in control and PPAR␣ null mouse hearts, suggesting a restricted reserve for the latter hearts to enhance glycolysis when the energy demand is increased. Alterations in the expression of some glycolysis-related genes suggest potential mechanisms involved in this defective CHO metabolism. Collectively, our data highlight the importance of metabolic alterations in CHO metabolism associated with FA oxidation defects as a factor that may predispose the heart to decompensation under stress conditions even in the fed state. isolated working mouse heart perfusion; citric acid cycle; 13 C isotopomer analysis; glycolysis; ATP-citrate lyase; peroxisome proliferator-activated receptor-␣ IN THE HEALTHY adult heart, the concerted regulation of longchain fatty acid (LCFA) and carbohydrate (CHO) metabolism ensures optimal energy production, in which LCFAs are often considered to be the predominant energy substrate under most conditions. This contrasts with the hypertrophied and/or failing heart, which displays a shift from LCFAs toward CHOs utilization that has been attributed, at least in part, to the deactivation of peroxisome proliferator-activated receptor-␣ (PPAR␣) (5,12,28,36,41). This nuclear transcription factor, which is highly expressed in the heart, is known to be activated by fatty acids (FAs) and to regulate the expression of genes encoding for LCFA uptake and oxidation (7). Although this shift from LCFAs to CHOs for energy production has been shown to be benef...

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Activation of mitochondrial lactate uptake by flavone induces apoptosis in human colon cancer cells

Wenzel

Schoberl

Lohner

et al. 2004

Journal Cellular Physiology

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Lactate production from glucose even in the presence of oxygen is a characteristic of cancer cell metabolism and an important feature for tumor progression. Here, we describe that an increased uptake of lactate into mitochondria of HT-29 human colon cancer cells by treatment of cells with the flavonoid flavone is associated with an increased production of mitochondrial superoxide anions and apoptotic cell death. In search of the mitochondrial transporter that could promote enhanced lactate uptake and energetic flow through the electron transport chain, we used fluorescein as a model substrate. Flavone increased fluorescein uptake at pH 7.4 into mitochondria of HT-29 cells almost tenfold while lactate inhibited uptake significantly. Uptake of fluorescein in the absence or presence of flavone was strongly increased by lowering pH from 7.4 to 6.0 and almost abolished by the protonophore carbonyl cyanide m-chlorophenylhydrazone (CCCP). The lactate-sensitive part of fluorescein transport was completely blocked by p-chloromercuribenzenesulfonic acid (pCMBS), a specific inhibitor of the monocarboxylate transporter-1 (MCT-1) that by Western blotting and immunofluorescence was identified in mitochondria of HT-29 cells. Finally, lactate increased and pCMBS inhibited the flavone-induced generation of mitochondrial O2-* radicals and in turn blunted the apoptotic response. In conclusion, our studies provide evidence that flavone reverts the metabolic phenotype of transformed colonocytes towards a phenotype characteristic for normal cells. Transformed colonocytes, however, seem especially vulnerable to O2-*, produced in mitochondria as a consequence of these metabolic alterations, and respond with the induction of apoptosis.

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Citrate release by perfused rat hearts: a window on mitochondrial cataplerosis

Cited by 36 publications

References 35 publications

Peroxisomal Fatty Acid Oxidation Is a Substantial Source of the Acetyl Moiety of Malonyl-CoA in Rat Heart

Peroxisomal Fatty Acid Oxidation Is a Substantial Source of the Acetyl Moiety of Malonyl-CoA in Rat Heart

Alterations in carbohydrate metabolism and its regulation in PPARα null mouse hearts

Activation of mitochondrial lactate uptake by flavone induces apoptosis in human colon cancer cells

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