Calcium and 2‐oxoglutarate‐mediated control of aspartate formation by rat heart mitochondria

Scaduto, Russell C.

doi:10.1111/j.1432-1033.1994.tb19049.x

Cited by 21 publications

(16 citation statements)

References 36 publications

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“…The ensuing role of OGDHC in the degradation of glutamate, which is neurotoxic in excess, is in accordance with the known association between reduced OGDHC activity and neurodegeneration, both age‐related [2] and inborn [3,4]. Furthermore, 2‐oxoglutarate takes part in metabolic signaling [5–10], and therefore its degradation by OGDHC may affect signal transduction. Regulated by thioredoxin, OGDHC is at the intercept of not only energy production and glutamate turnover, but also mitochondrial production/scavenging of reactive oxygen species (ROS) [11].…”

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confidence: 66%

Novel isoenzyme of 2‐oxoglutarate dehydrogenase is identified in brain, but not in heart

et al. 2008

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The 2-oxoglutarate dehydrogenase complex (OGDHC) is a key regulator of a branch point in the tricarboxylic acid cycle. It belongs to the family of 2-oxo acid dehydrogenase complexes which comprise multiple copies of the three catalytic enzyme components: E1, thiamine diphosphate (ThDP)-dependent 2-oxo acid dehydrogenase (in OGDHC it is E1o); E2, dihydrolipoyl acyltransferase with the covalently bound lipoic acid 2-Oxoglutarate dehydrogenase (OGDH) is the first and rate-limiting component of the multienzyme OGDH complex (OGDHC) whose malfunction is associated with neurodegeneration. The essential role of this complex in the degradation of glucose and glutamate, which have specific significance in brain, raises questions about the existence of brain-specific OGDHC isoenzyme(s). We purified OGDHC from extracts of brain or heart mitochondria using the same procedure of poly(ethylene glycol) fractionation, followed by size-exclusion chromatography. Chromatographic behavior and the insufficiency of mitochondrial disruption to solubilize OGDHC revealed functionally significant binding of the complex to membrane. Components of OGDHC from brain and heart were identified using nanohigh performance liquid chromatography electrospray tandem mass spectrometry after trypsinolysis of the electrophoretically separated proteins. In contrast to the heart complex, where only the known OGDH was determined, the band corresponding to the brain OGDH component was found to also include the novel 2-oxoglutarate dehydrogenase-like (OGDHL) protein. The ratio of identified peptides characteristic of OGDH and OGDHL was preserved during purification and indicated comparable quantities of the two proteins in brain. Brain OGDHC also differed from the heart complex in the abundance of the components, lower apparent molecular mass and decreased stability upon size-exclusion chromatography. The functional competence of the novel brain isoenzyme and different regulation of OGDH and OGDHL by 2-oxoglutarate are inferred from the biphasic dependence of the overall reaction rate versus 2-oxoglutarate concentration. OGDHL may thus participate in brain-specific control of 2-oxoglutarate distribution between energy production and synthesis of the neurotransmitter glutamate.Abbreviations E1, 2-oxo acid dehydrogenase; E2, dihydrolipoyl acyl transferase; E3, dihydrolipoyl dehydrogenase; nanoLC-MS ⁄ MS, nano-high performance liquid chromatography-electrospray tandem mass spectrometry; OGDH (E1o), 2-oxoglutarate dehydrogenase; OGDHC, 2-oxoglutarate dehydrogenase complex; OGDHL, 2-oxoglutarate dehydrogenase-like protein; ROS, reactive oxygen species; ThDP, thiamin diphosphate.

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supporting

confidence: 66%

Novel isoenzyme of 2‐oxoglutarate dehydrogenase is identified in brain, but not in heart

et al. 2008

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“…The activity of citrin and aralar transfected into mammalian cells is stimulated by calcium ions on the external side of the inner mitochondrial membrane, where the calcium ion-binding domains of these proteins are located (Palmieri et al 2001). These results strongly suggest that calcium ion activation of the malate aspartate shuttle (Leverve et al 1986;Sugano et al 1988;Scaduto 1994) is based on the calcium-binding property of citrin and aralar as AGCs and that AGCs are one of the most important targets of calcium-mediating hormones.…”

Section: Citrin and Aralar As Aspartate Glutamate Carriersmentioning

confidence: 89%

Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD)

2002

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Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD) Abstract By using homozygosity mapping and positional cloning, we have shown that adult-onset type II citrullinemia (CTLN2) is caused by mutations of the SLC25A13 gene, which is localized on chromosome 7q21.3 and encodes a mitochondrial solute carrier protein named citrin. So far, we have reported nine mutations, most of which cause loss of citrin, and we have established several methods for DNA diagnosis. These methods have shown that more than 90% of the patients diagnosed as suffering from CTLN2 by enzymatic analysis carry SLC25A13 mutations in both alleles, indicating that CTLN2 is caused by citrin deficiency. Furthermore, by using the same DNA diagnosis methods, we discovered that 70 neonates or infants suffering from a particular type of neonatal hepatitis carry the same SLC25A13 mutations. Since the symptoms of the neonates are different from those of the more severe CTLN2 and usually ameliorate without special treatment, we designated the neonatal disease neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). We conclude that citrin deficiency causes NICCD in neonates and CTLN2 in adults through the additional effects of genetic or environmental modifiers. Since the function of citrin, together with that of an isoform, aralar, was found to be as a mitochondrial aspartate glutamate carrier, the various symptoms of NICCD and CTLN2 may be understood as caused by defective aspartate export from the mitochondria to the cytosol and defects in the malate aspartate shuttle. It is, however, still difficult to understand the cause of the hepatic deficiency of argininosuccinate synthetase protein in CTLN2.Received

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“…Mitochondrial isolation. The mitochondria were isolated from left ventricular tissue of normal heart as described previously (30). In brief, a portion of the ventricular tissue was removed, finely minced, and homogenized with a polytron homogenizer in isolation medium (300 mM sucrose, 10 mM MOPS, and 10 mM EGTA, pH 7.35 at 4°C).…”

Section: In Vitro Isolated Mitochondrial Analysismentioning

confidence: 99%

Antioxidant MCI-186 inhibits mitochondrial permeability transition pore and upregulates Bcl-2 expression

Rajesh

Sasaguri²,

Suzuki³

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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Reperfusion after a period of ischemia is associated with the formation of reactive oxygen species (ROS) and Ca2+ overload resulting in the opening of a nonspecific pore in the inner membrane of the mitochondria, called the mitochondrial permeability transition pore (PTP), leading to cell damage. Although endogenous antioxidants are activated because of oxidative stress following ischemia, their levels are not high enough to prevent reperfusion injury. Hence there is always a need for exogenous supplement of antioxidants, especially after acute ischemia. Here we demonstrated the effects of the antioxidant 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186) in preventing reperfusion injury of the heart by inhibition of PTP opening. Ischemia (30 min) by left coronary artery (LCA) occlusion and reperfusion (120 min) in Wistar rats after pretreatment with MCI-186 (10 mg/kg iv) infusion starting from 30 min before LCA occlusion resulted in 1) less area of myocardial infarction (19.2% vs. 61.6%), 2) well-maintained myocardial ATP content (P < 0.03 vs. control), 3) decreased mitochondrial swelling and reduced cytochrome c release, 4) increased expression of BCl-2, 5) lower prevalence of apoptotic cells (14.3% vs. 2.9%), and 6) reduced DNA fragmentation in the MCI-186-treated group. These cytoprotective effects of MCI-186 were inhibited on opening PTP before MCI-186 treatment with the PTP activators lonidamine (10 mg/kg iv) or atractyloside (5 mg/kg iv) but failed to inhibit the protective effects exerted by another antioxidant, allopurinol, suggesting that the PTP inhibiting property is specific for MCI-186. These results demonstrate that the radical scavenger MCI-186, by inhibiting the opening of the PTP, prevents necrosis and cytochrome c release and hence pathological apoptosis.

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Calcium and 2‐oxoglutarate‐mediated control of aspartate formation by rat heart mitochondria

Cited by 21 publications

References 36 publications

Novel isoenzyme of 2‐oxoglutarate dehydrogenase is identified in brain, but not in heart

Novel isoenzyme of 2‐oxoglutarate dehydrogenase is identified in brain, but not in heart

Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD)

Antioxidant MCI-186 inhibits mitochondrial permeability transition pore and upregulates Bcl-2 expression

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