The Key Role of Anaplerosis and Cataplerosis for Citric Acid Cycle Function

Owen, Oliver E.; Kalhan, Satish C.; Hanson, Richard W.

doi:10.1074/jbc.r200006200

Cited by 1,000 publications

(854 citation statements)

References 22 publications

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“…leak out of the TCA cycle. GDH is one of the major cataplerotic enzymes [48] and can form glutamate from the TCA cycle intermediate, α-ketoglutarate. Downstream of mitochondrial activation, glutamate might play a role in exocytosis, together with permissive cytosolic Ca 2+ levels, by acting on secretory granules [13,17,49,50].…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, muscle is an important reservoir from which the glutamine pool can be mobilised during acute exercise [63]. Moreover, following an overnight fast, there is a net release of amino acids from skeletal muscle, glutamine being quantitatively most prominent [48]. Acute exercise as well as an overnight fast are both physiological states in which insulin secretion must be avoided.…”

Section: Discussionmentioning

confidence: 99%

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Insulin secretion profiles are modified by overexpression of glutamate dehydrogenase in pancreatic islets

Carobbio¹,

Ishihara²,

Fernández-Pascual

et al. 2004

Diabetologia

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Aims/hypothesis. Glutamate dehydrogenase (GDH) is a mitochondrial enzyme playing a key role in the control of insulin secretion. However, it is not known whether GDH expression levels in beta cells are ratelimiting for the secretory response to glucose. GDH also controls glutamine and glutamate oxidative metabolism, which is only weak in islets if GDH is not allosterically activated by L-leucine or (+/−)-2-aminobicyclo-[2,2,1]heptane-2-carboxylic acid (BCH). Methods. We constructed an adenovirus encoding for GDH to overexpress the enzyme in the beta-cell line INS-1E, as well as in isolated rat and mouse pancreatic islets. The secretory responses to glucose and glutamine were studied in static and perifusion experiments. Amino acid concentrations and metabolic parameters were measured in parallel.Results. GDH overexpression in rat islets did not change insulin release at basal or intermediate glucose (2.8 and 8.3 mmol/l respectively), but potentiated the secretory response at high glucose concentrations (16.7 mmol/l) compared to controls (+35%). Control islets exposed to 5 mmol/l glutamine at basal glucose did not increase insulin release, unless BCH was added with a resulting 2.5-fold response. In islets overexpressing GDH glutamine alone stimulated insulin secretion (2.7-fold), which was potentiated 2.2-fold by adding BCH. The secretory responses evoked by glutamine under these conditions correlated with enhanced cellular metabolism. Conclusions/interpretation. GDH could be rate-limiting in glucose-induced insulin secretion, as GDH overexpression enhanced secretory responses. Moreover, GDH overexpression made islets responsive to glutamine, indicating that under physiological conditions this enzyme acts as a gatekeeper to prevent amino acids from being inappropriate efficient secretagogues. [Diabetologia (2004) 47:266-276]

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Insulin secretion profiles are modified by overexpression of glutamate dehydrogenase in pancreatic islets

Carobbio¹,

Ishihara²,

Fernández-Pascual

et al. 2004

Diabetologia

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“…Principle anaplerotic molecules feeding into the TCA cycle include pyruvate, glutamate, and precursors of propionyl-CoA. Two important cataplerotic enzymes that help remove excess TCA intermediates are aspartate aminotransferase and citrate lyase (Owen et al, 2002). We propose that Asp-NAT also plays a cataplerotic role in neuronal mitochondria.…”

Section: Integrating Various Naa Functions In the Cnsmentioning

confidence: 96%

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

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1,126

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The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research will be required to more fully understand the biochemical functions served by NAA in CNS development and activity, and additional functions are likely to be discovered.

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“…In addition to adaptation to anaerobic conditions, enhanced glycolysis is an energetic boost to the cells, rapidly generating ATP in the cytosol. Moreover, enhanced glucose breakdown provides building blocks for the synthesis of nucleotides (via the pentose phosphate pathway), and amino and fatty acids (from glycolytic and TCA cycle intermediates) (Figure 1) (Owen et al, 2002). Even under conditions in which the TCA cycle is not fully functional, as is the case for SDH-and FH-deficient tumours, the anaplerotic reaction catalysed by pyruvate carboxylase, which converts pyruvate to oxaloacetate, can operate to replenish TCA cycle intermediates (Figure 1).…”

Section: Mechanisms Linking Loss Of Mitochondrial Tumour Suppressorsmentioning

confidence: 99%

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

2006

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The phenomenon of enhanced glycolysis in tumours has been acknowledged for decades, but biochemical evidence to explain it is only just beginning to emerge. A significant hint as to the triggers and advantages of enhanced glycolysis in tumours was supplied by the recent discovery that succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tumour suppressors and which associated, for the first time, mitochondrial enzymes and their dysfunction with tumorigenesis. Further steps forward showed that the substrates of SDH and FH, succinate and fumarate, respectively, can mediate a 'metabolic signalling' pathway. Succinate or fumarate, which accumulate in mitochondria owing to the inactivation of SDH or FH, leak out to the cytosol, where they inhibit a family of prolyl hydroxylase enzymes (PHDs). Depending on the PHD inhibited, two newly recognized pathways that support tumour maintenance may ensue: affected cells become resistant to certain apoptotic signals and/or activate a pseudohypoxic response that enhances glycolysis and is conveyed by hypoxia-inducible factor.

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The Key Role of Anaplerosis and Cataplerosis for Citric Acid Cycle Function

Cited by 1,000 publications

References 22 publications

Insulin secretion profiles are modified by overexpression of glutamate dehydrogenase in pancreatic islets

Insulin secretion profiles are modified by overexpression of glutamate dehydrogenase in pancreatic islets

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

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