The metabolism of malate by cultured rat brain astrocytes

McKenna, Mary C.; Tildón, J. Tyson; Couto, R.; Stevenson, J.H.; Caprio, F.J.

doi:10.1007/bf01208582

Cited by 43 publications

(68 citation statements)

References 40 publications

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“…Since lactate has been proposed to have a role in metabolic trafficking from astrocytes to neurons in brain [3][4][5][6][7][8][9], we determined the effect of other compounds which are released by brain cells and/or thought to be involved in trafficking [33,41] on the rate of lactate uptake by synaptosomes (table 2). Addition of the amino acids glutamate, glutamine and aspartate had little or no effect on the rate of lactate uptake by synaptosomes.…”

Section: Uptake Of L-[u-14 C]lactate In the Presence Of Added Effectorsmentioning

confidence: 99%

“…A number of competition experiments were done since our group and others have demonstrated that both the uptake [20,25,26] and metabolism [7,26,[33][34][35] of energy substrates in brain tissue are regulated in part by the relative concentration of other key metabolites in the Values with asterisks are significantly different from the control value: * p ! 0.05; ** p !…”

Section: Uptake Of L-[u-14 C]lactate In the Presence Of Added Effectorsmentioning

confidence: 99%

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Lactate Transport by Cortical Synaptosomes from Adult Rat Brain: Characterization of Kinetics and Inhibitor Specificity

et al. 1998

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Since lactate released by glial cells may be a key substrate for energy in neurons, the kinetics for the uptake of L-[U-¹⁴C]lactate by cortical synaptic terminals from 7- to 8-week-old rat brain were determined. Lactate uptake was temperature-dependent, and increased by 64.9% at pH 6.2, and decreased by 43.4% at pH 8.2 relative to uptake at pH 7.3. Uptake of monocarboxylic acids was saturable with increasing substrate concentration. Eadie-Hofstee plots of the data gave evidence of two carrier-mediated uptake mechanisms with a high-affinity K_m of 0.66 mM and V_max of 3.66 mM for pyruvate, and a low-affinity system with a K_m of 9.9 mM for both lactate and pyruvate and V_max values of 16.6 and 23.1 nmol/30 s/mg protein for lactate and pyruvate, respectively. Saturable uptake was seen in the presence of 10 mM α-cyano-4-hydroxycinnamate. Lactate transport by synaptic terminals was much more sensitive to inhibition by sulfhydryl reagents than transport in astrocytes. Addition of 0.5 and 2 mM mersalyl decreased the uptake of 1 mM lactate by synaptic terminals by 59.3 and 66.37%, respectively. Pyruvate moderately decreased lactate transport, whereas 3-hydroxybutyrate had little effect. Quercetin, an inhibitor of lactate release, had little effect on the content of ¹⁴C lactate in synaptic terminals, supporting the concept that the majority of lactate produced within brain is from glial cells. Oxidation of L-[U-¹⁴C]lactate by synaptosomes was saturable, and yielded a K_m of 1.23 mM and a V_max of 116 nmol/h/mg protein. Overall the studies show that synaptic terminals from adult brain have a high capacity for transport and oxidation of lactate, consistent with the proposed role for this compound in metabolic trafficking in brain. Furthermore, the data provide kinetic evidence of two carrier-mediated mechanisms for monocarboxylic acid transport by synaptosomes and demonstrate that uptake of lactate by synaptic terminals is regulated differently than transport by astrocytes. Uptake of lactate by synaptic terminals also has differences from the systems described for neurons.

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Section: Uptake Of L-[u-14 C]lactate In the Presence Of Added Effectorsmentioning

confidence: 99%

Section: Uptake Of L-[u-14 C]lactate In the Presence Of Added Effectorsmentioning

confidence: 99%

Lactate Transport by Cortical Synaptosomes from Adult Rat Brain: Characterization of Kinetics and Inhibitor Specificity

et al. 1998

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“…It has been shown that malate can be oxidized as an energy source by cultured mouse brain astrocytes and to a lesser extent by neurons [1]. Furthermore, McKenna et al [2] proposed that the oxidation of malate in astrocytes occurs in multiple compartments and is significantly affected by a number of metabolites. The high rate of oxidative metabolism in the brain requires a very active glycolysis closely coupled to the TCA cycle, so that the reducing equivalents of NADH, generated during glycolysis, are transported across the mitochondrial membrane [3].…”

Section: Introductionmentioning

confidence: 99%

Metabolism of 3-<sup>13</sup>C-Malate in Primary Cultures of Mouse Astrocytes

et al. 2000

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Malate, specifically labeled with carbon 13 on C₃, was synthesized by chemical means and used to study malate metabolism by primary cultures of mouse cortical astrocytes. 3-¹³C-Malate in combination with glucose as well as 3-¹³C-malate alone were used as substrates; the effect of 3-nitropropionic acid, an inhibitor of succinate dehydrogenase and fumarase was also examined. The consumption of malate was only 0.26 μmol/mg of protein, approx. 25-fold lower than the consumption of glucose. Besides lactate, glutamine and fumarate were the two major metabolites released to the medium. Very low and similar levels of isotopic enrichment were detected on C₂ and C₃ of lactate; glutamine was labeled on C₂ and C₃ to a similar extent as well and labeling on C₄ was only detected when glucose was not added. These labeling studies suggest that cytosolic malic enzyme is not active in primary astrocytes and support the occurrence of pyruvate recycling in astrocytes.

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“…In vitro studies have documented uptake and oxidation of 14 C-labeled glycerol (McKenna et al 1986a), lactate (Brandt et al 1984;McKenna et al 1994), glutamine/glutamate (Yu et al 1984;McKenna et al 1994), citrate (Westergaard et al 1994), malate (McKenna et al 1994(McKenna et al , 1990, b-hydroxybutyrate (bHB) (Edmond et al 1987;McKenna et al 1994), acetoacetate (Lopes-Cardozo et al 1986;Waniewski and Martin 1998), as well as octanoate and palmitate (Edmond et al 1987). However, ketone bodies such as bHB are the only endogenously circulating alternative substrates that have been shown significantly to supplement cerebral metabolism (Owen et al 1967;Hawkins et al 1971;Dahlquist and Persson 1976).…”

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confidence: 99%

Increased cerebral uptake and oxidation of exogenous βHB improves ATP following traumatic brain injury in adult rats

Prins

Lee

Fujima

et al. 2004

Journal of Neurochemistry

101

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There is growing evidence of the brain's ability to increase its reliance on alternative metabolic substrates under conditions of energy stress such as starvation, hypoxia and ischemia. We hypothesized that following traumatic brain injury (TBI), which results in immediate changes in energy metabolism, the adult brain increases uptake and oxidation of the alternative substrate b-hydroxybutyrate (bHB). Arterio-venous differences were used to determine global cerebral uptake of bHB and production of 14 CO 2 from [ 14 C]3-bHB 3 h after controlled cortical impact (CCI) injury. Quantitative bioluminescence was used to assess regional changes in ATP concentration. As expected, adult sham and CCI animals with only endogenously available bHB showed no significant increase in cerebral uptake of bHB or 14 CO 2 production. Increasing arterial bHB concentrations 2.9-fold with 3 h of bHB infusion failed to increase cerebral uptake of bHB or 14 CO 2 production in adult sham animals. Only CCI animals that received a 3-h bHB infusion showed an 8.5-fold increase in cerebral uptake of bHB and greater than 10.7-fold increase in 14 CO 2 production relative to sham bHB-infused animals. The TBI-induced 20% decrease in ipsilateral cortical ATP concentration was alleviated by 3 h of bHB infusion beginning immediately after CCI injury. Keywords: alternative substrates, b-hydroxybutyrate, metabolism, traumatic brain injury. Although glucose remains the primary cerebral metabolic substrate under normal conditions, there are many physiological states during which the brain's reliance on glucose shifts to alternative substrates (Owen et al. 1967;Hawkins et al. 1971;Dahlquist and Persson 1976;Kries and Ross 1992;Vannucci and Vannucci 2000). In vitro studies have documented uptake and oxidation of 14 C-labeled glycerol (McKenna et al. 1986a) (Edmond et al. 1987). However, ketone bodies such as bHB are the only endogenously circulating alternative substrates that have been shown significantly to supplement cerebral metabolism (Owen et al. 1967;Hawkins et al. 1971;Dahlquist and Persson 1976). In normally fed adult mammals bHB metabolism comprises less than 3% of total cerebral metabolism and bHB is present in low circulating concentrations (0.1 mM) with negligible uptake into the brain (Hawkins et al. 1971). However, upon increasing bHB arterial concentrations by starvation for 2 days or more, cerebral uptake is significantly enhanced (Hawkins et al. 1971). Increased cerebral uptake of bHB has also been shown during development (Hawkins et al. 1971;Dahlquist and Persson 1976), following starvation (Owen et al. 1967) and in diabetes (Kries and Ross 1992). The brain's ability to increase its reliance on bHB appears to be a common form of cerebral metabolic adaptation under conditions of insufficient glucose availability and developmental increases in cerebral energy demand.The evidence for the use of bHB by the brain under conditions of cerebral metabolic stress suggests a role for this alternative substrate in cerebral metabolism after ...

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The metabolism of malate by cultured rat brain astrocytes

Cited by 43 publications

References 40 publications

Lactate Transport by Cortical Synaptosomes from Adult Rat Brain: Characterization of Kinetics and Inhibitor Specificity

Lactate Transport by Cortical Synaptosomes from Adult Rat Brain: Characterization of Kinetics and Inhibitor Specificity

Metabolism of 3-<sup>13</sup>C-Malate in Primary Cultures of Mouse Astrocytes

Increased cerebral uptake and oxidation of exogenous βHB improves ATP following traumatic brain injury in adult rats

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