Pyruvate Carboxylation in Different Model Systems Studied by 13C MRS

Sonnewald, Ursula; Rae, Caroline

doi:10.1007/s11064-010-0257-5

Cited by 35 publications

(25 citation statements)

References 60 publications

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“…Pyruvate carboxylation is the major anaplerotic pathway in the brain and is exclusively glial (for review Sonnewald and Rae ). Triheptanoin did not affect the extent of anaplerosis from [1,2‐ 13 C]glucose in glutamate and glutamine but reduced it in aspartate in both the sham as well as SE groups (Fig.…”

Section: Discussionmentioning

confidence: 99%

Triheptanoin partially restores levels of tricarboxylic acid cycle intermediates in the mouse pilocarpine model of epilepsy

Hadera

Smeland

McDonald

et al. 2013

Journal of Neurochemistry

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Triheptanoin, the triglyceride of heptanoate, is anticonvulsant in various epilepsy models. It is thought to improve energy metabolism in the epileptic brain by re-filling the tricarboxylic acid (TCA) cycle with C4-intermediates (anaplerosis). Here, we injected mice with [1,2-13 C]glucose 3.5-4 weeks after pilocarpine-induced status epilepticus (SE) fed either a control or triheptanoin diet. Amounts of metabolites and incorporations of 13 C were determined in extracts of cerebral cortices and hippocampal formation and enzyme activity and mRNA expression were quantified. The percentage enrichment with two 13 C atoms in malate, citrate, succinate, and GABA was reduced in hippocampal formation of control-fed SE compared with control mice. Except for succinate, these reductions were not found in triheptanoin-fed SE mice, indicating that triheptanoin prevented a decrease of TCA cycle capacity. Compared to those on control diet, triheptanoin-fed SE mice showed few changes in most other metabolite levels and their 13 C labeling. Reduced pyruvate carboxylase mRNA and enzyme activity in forebrains and decreased [2,3-13 C]aspartate amounts in cortex suggest a pyruvate carboxylation independent source of C-4 TCA cycle intermediates. Most likely anaplerosis was kept unchanged by carboxylation of propionyl-CoA derived from heptanoate. Further studies are proposed to fully understand triheptanoin's effects on neuroglial metabolism and interaction.

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Section: Discussionmentioning

confidence: 99%

Triheptanoin partially restores levels of tricarboxylic acid cycle intermediates in the mouse pilocarpine model of epilepsy

Hadera

Smeland

McDonald

et al. 2013

Journal of Neurochemistry

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“…Succinate can be the end-product of a 'backflux' citric acid cycle (Brekke et al 2012), commencing from pyruvate that is converted to oxaloacetate by pyruvate carboxylase. Pyruvate carboxylase is mostly expressed in liver and kidneys being part of gluconeogenesis, but it is also found in the astrocytes of the brain (Shank et al 1985;Yu et al 1983), playing an important role in lipogenesis and synthesis of neurotransmitters (Wallace et al 1998;Sonnewald and Rae 2010).…”

Section: Discussionmentioning

confidence: 99%

Exclusive neuronal expression of SUCLA2 in the human brain

et al. 2013

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SUCLA2 encodes the ATP-forming b subunit (A-SUCL-b) of succinyl-CoA ligase, an enzyme of the citric acid cycle. Mutations in SUCLA2 lead to a mitochondrial disorder manifesting as encephalomyopathy with dystonia, deafness and lesions in the basal ganglia. Despite the distinct brain pathology associated with SUCLA2 mutations, the precise localization of SUCLA2 protein has never been investigated. Here, we show that immunoreactivity of A-SUCL-b in surgical human cortical tissue samples was present exclusively in neurons, identified by their morphology and visualized by double labeling with a fluorescent Nissl dye. A-SUCL-b immunoreactivity colocalized [99 % with that of the d subunit of the mitochondrial F 0 -F 1 ATP synthase. Specificity of the anti-A-SUCL-b antiserum was verified by the absence of labeling in fibroblasts from a patient with a complete deletion of SUCLA2. A-SUCL-b immunoreactivity was absent in glial cells, identified by antibodies directed against the glial markers GFAP and S100. Furthermore, in situ hybridization histochemistry demonstrated that SUCLA2 mRNA was present in Nissl-labeled neurons but not glial cells labeled with S100. Immunoreactivity of the GTP-forming b subunit (G-SUCL-b) encoded by SUCLG2, or in situ hybridization histochemistry for SUCLG2 mRNA could not be demonstrated in either neurons or astrocytes. Western blotting of post mortem brain samples revealed minor G-SUCL-b immunoreactivity that was, however, not upregulated in samples obtained from diabetic versus nondiabetic patients, as has been described for murine brain. Our work establishes that SUCLA2 is expressed exclusively in neurons in the human cerebral cortex.

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“…The PC/PDH ratio was calculated using the formula [2,3 13 C 2 ] glutamate (or glutamine)/[4,5 13 C 2 ] glutamate (or glutamine) [reviewed in (Sonnewald and Rae, 2010)]. An increase in the PC/PDH ratio reflects either an increase in PC activity or a decrease in PDH activity.…”

Section: Methodsmentioning

confidence: 99%

Metabolic fate of glucose in rats with traumatic brain injury and pyruvate or glucose treatments: A NMR spectroscopy study

Shijo

Sutton

Ghavim

et al. 2017

Neurochemistry International

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Administration of sodium pyruvate (SP; 9.08 μmol/kg, i.p.), ethyl pyruvate (EP; 0.34 μmol/kg, i.p.) or glucose (GLC; 11.1 μmol/kg, i.p.) to rats after unilateral controlled cortical impact (CCI) injury has been reported to reduce neuronal loss and improve cerebral metabolism. In the present study these doses of each fuel or 8% saline (SAL; 5.47 nmoles/kg) were administered immediately and at 1, 3, 6 and 23 h post-CCI. At 24 h all CCI groups and non-treated Sham injury controls were infused with [1,2 13C] glucose for 68 min 13C nuclear magnetic resonance (NMR) spectra were obtained from cortex + hippocampus tissues from left (injured) and right (contralateral) hemispheres. All three fuels increased lactate labeling to a similar degree in the injured hemisphere. The amount of lactate labeled via the pentose phosphate and pyruvate recycling (PPP + PR) pathway increased in CCI-SAL and was not improved by SP, EP, and GLC treatments. Oxidative metabolism, as assessed by glutamate labeling, was reduced in CCI-SAL animals. The greatest improvement in oxidative metabolism was observed in animals treated with SP and fewer improvements after EP or GLC treatments. Compared to SAL, all three fuels restored glutamate and glutamine labeling via pyruvate carboxylase (PC), suggesting improved astrocyte metabolism following fuel treatment. Only SP treatments restored the amount of [4 13C] glutamate labeled by the PPP + PR pathway to sham levels. Milder injury effects in the contralateral hemisphere appear normalized by either SP or EP treatments, as increases in the total pool of 13C lactate and labeling of lactate in glycolysis, or decreases in the ratio of PC/PDH labeling of glutamine, were found only for CCI-SAL and CCI-GLC groups compared to Sham. The doses of SP, EP and GLC examined in this study all enhanced lactate labeling and restored astrocyte-specific PC activity but differentially affected neuronal metabolism after CCI injury. The restoration of astrocyte metabolism by all three fuel treatments may partially underlie their abilities to improve cerebral glucose utilization and to reduce neuronal loss following CCI injury.

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Pyruvate Carboxylation in Different Model Systems Studied by 13C MRS

Cited by 35 publications

References 60 publications

Triheptanoin partially restores levels of tricarboxylic acid cycle intermediates in the mouse pilocarpine model of epilepsy

Triheptanoin partially restores levels of tricarboxylic acid cycle intermediates in the mouse pilocarpine model of epilepsy

Exclusive neuronal expression of SUCLA2 in the human brain

Metabolic fate of glucose in rats with traumatic brain injury and pyruvate or glucose treatments: A NMR spectroscopy study

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