Phosphoenolpyruvate shuttle ‐ transport of energy from mitochondria to cytosol

Drahota, Z; Rauchová, Hana; Miková, M; Kaul, P P; Bass, A

doi:10.1016/0014-5793(83)80573-0

Cited by 12 publications

(10 citation statements)

References 13 publications

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“…The role of mitochondrial PEPCK in tissues that do not exhibit gluconeogenesis remains to be defined. Possibilities include the regulation of intramitochondrial concentrations of 4-carbon citric acid cycle intermediates [14] and export of energy to the cytosol [5].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial phosphoenolpyruvate carboxykinase deficiency

et al. 1986

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A 3-month-old girl presented with anorexia, failure to thrive and drowsiness. She was mildly icteric with hepatomegaly and peripheral oedema. Disordered liver function tests were associated with the biopsy appearances of a giant cell hepatitis and with a Fanconi syndrome. At the age of 16 weeks she collapsed with profound hypoglycaemia. Fasting also provoked hypoglycaemia with lactic acidaemia. She became increasingly irritable and hypotonic and, although initially liver and renal function improved, she deteriorated and died of hepatocellular failure and septicaemia. A post-mortem revealed massive fatty degeneration of the liver. The activity of phosphoenolpyruvate carboxykinase in her cultured skin fibroblasts was 16% of controls. Her brother died at the age of 4 weeks of sudden infant death syndrome.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial phosphoenolpyruvate carboxykinase deficiency

et al. 1986

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“…Drahota et al identified very high specific activities of PEPCK-M in brown adipose [40]. In addition, they reported high rates of PEP export from mitochondria supplied with malate and alpha-ketoglutarate.…”

Section: Sensing Tca Cycle Fluxmentioning

confidence: 99%

The mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) and glucose homeostasis: Has it been overlooked?

Stark

Kibbey

2014

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background Plasma glucose levels are tightly regulated within a narrow physiologic range. Insulin-mediated glucose uptake by tissues must be balanced by the appearance of glucose from nutritional sources, glycogen stores, or gluconeogenesis. In this regard, a common pathway regulating both glucose clearance and appearance has not been described. The metabolism of glucose to produce ATP is generally considered to be the primary stimulus for insulin release from beta-cells. Similarly, gluconeogenesis from phosphoenolpyruvate (PEP) is believed to be the primarily pathway via the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C). These models cannot adequately explain the regulation of insulin secretion or gluconeogenesis. Scope of review A metabolic sensing pathway involving mitochondrial GTP (mtGTP) and PEP synthesis by the mitochondrial isoform of PEPCK (PEPCK-M) is associated with glucose-stimulated insulin secretion from pancreatic beta-cells. Here we examine whether there is evidence for a similar mtGTP-dependent pathway involved in gluconeogenesis. In both islets and the liver, mtGTP is produced at the substrate level by the enzyme succinyl CoA synthetase (SCS-GTP) with a rate proportional to the TCA cycle. In the beta-cell PEPCK-M then hydrolyzes mtGTP in the production of PEP that, unlike mtGTP, can escape the mitochondria to generate a signal for insulin release. Similarly, PEPCK-M and mtGTP might also provide a significant source of PEP in gluconeogenic tissues for the production of glucose. This review will focus on the possibility that PEPCK-M, as a sensor for TCA cycle flux, is a key mechanism to regulate both insulin secretion and gluconeogenesis suggesting conservation of this biochemical mechanism in regulating multiple aspects of glucose homeostasis. Moreover, we propose that this mechanism may be more important for regulating insulin secretion and gluconeogenesis compared to canonical nutrient sensing pathways. Major conclusions PEPCK-M, initially believed to be absent in islets, carries a substantial metabolic flux in beta-cells. This flux is intimately involved with the coupling of glucose-stimulated insulin secretion. PEPCK-M activity may have been similarly underestimated in glucose producing tissues and could potentially be an unappreciated but important source of gluconeogenesis. General Significance The generation of PEP via PEPCK-M may occur via a metabolic sensing pathway important for regulating both insulin secretion and gluconeogenesis.

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“…The latter reaction would increase the adenylate charge and could be a part of "pyruvate cycling," the rate of which can exceed by severalfold the rate of flux through the citric acid cycle and the synthesis of glucose (18). Rather than being an energy-wasting, futile cycle, such cycling of P-enolpyruvate and pyruvate may be a mechanism for transferring phosphorylation potential from mitochondria to cytosol (19).…”

Section: Table II Specific Activities Of A-scs and G-scs Inmentioning

confidence: 99%

Expression of Two Succinyl-CoA Synthetases with Different Nucleotide Specificities in Mammalian Tissues

Lambeth

Tews

Adkins

et al. 2004

Journal of Biological Chemistry

121

109

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We suggest that both succinyl-CoA synthetases catalyze the reverse reaction in the citric acid cycle in which the ADP-forming enzyme augments ATP production, whereas the GDP-forming enzyme supports GTPdependent anabolic processes. Widely accepted shuttle mechanisms are invoked to explain how transport of P-enolpyruvate across mitochondrial membranes can transfer high energy phosphate between the cytosol and mitochondrial matrix.

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Phosphoenolpyruvate shuttle ‐ transport of energy from mitochondria to cytosol

Cited by 12 publications

References 13 publications

Mitochondrial phosphoenolpyruvate carboxykinase deficiency

Mitochondrial phosphoenolpyruvate carboxykinase deficiency

The mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) and glucose homeostasis: Has it been overlooked?

Expression of Two Succinyl-CoA Synthetases with Different Nucleotide Specificities in Mammalian Tissues

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