The capacity of reducing‐equivalent shuttles limits glycolysis during ethanol oxidation

Berry, Michael N.; Gregory, Roland B.; Grivell, Anthony R.; Phillips, John W.; SchÖN, Arne

doi:10.1111/j.1432-1033.1994.00557.x

Cited by 28 publications

(22 citation statements)

References 36 publications

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“…By investigating the effects of Aralar1 overexpression in INS-1E cells, our data show a direct relationship between changes in NAD(P)H levels, mitochondrial activation, and insulin secretion. Activity of NADH shuttles may limit glycolysis (29,30). Here, Aralar1 overexpression enhanced glucose evoked NAD(P)H generation, electron transport chain activity, and ATP generation, correlating with elevation of glucose oxidation, thereby demonstrating increased mitochondrial metabolism.…”

Section: Discussionmentioning

confidence: 99%

The Malate-Aspartate NADH Shuttle Member Aralar1 Determines Glucose Metabolic Fate, Mitochondrial Activity, and Insulin Secretion in Beta Cells

Rubı́¹,

Arco

Bartley³

et al. 2004

Journal of Biological Chemistry

109

104

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The NADH shuttle system, which transports reducing equivalents from the cytosol to the mitochondria, is essential for the coupling of glucose metabolism to insulin secretion in pancreatic beta cells. Aralar1 and citrin are two isoforms of the mitochondrial aspartate/ glutamate carrier, one key constituent of the malateaspartate NADH shuttle. Here, the effects of Aralar1 overexpression in INS-1E beta cells and isolated rat islets were investigated for the first time. We prepared a recombinant adenovirus encoding for human Aralar1 (AdCA-Aralar1), tagged with the small FLAG epitope. Transduction of INS-1E cells and isolated rat islets with AdCA-Aralar1 increased aralar1 protein levels and immunostaining revealed mitochondrial localization. Compared with control INS-1E cells, overexpression of Aralar1 potentiated metabolism secretion coupling stimulated by 15 mM glucose. In particular, there was an increase of NAD(P)H generation, of mitochondrial membrane hyperpolarization, ATP levels, glucose oxidation, and insulin secretion (؉45%, p < 0.01). Remarkably, this was accompanied by reduced lactate production. Rat islets overexpressing Aralar1 secreted more insulin at 16.7 mM glucose (؉65%, p < 0.05) compared with controls. These results show that aspartate-glutamate carrier capacity limits glucose-stimulated insulin secretion and that Aralar1 overexpression enhances mitochondrial metabolism.Glucose metabolism, through glycolysis and mitochondria, drives stimulation of insulin secretion in pancreatic beta cells (1, 2). According to low lactate dehydrogenase activity in beta cells, glycolysis-derived electrons carried by NADHϩH ϩ are mostly transferred to mitochondria through the NADH shuttle system. Therefore, NADH shuttles couple glycolysis to activation of mitochondrial energy metabolism, leading to insulin secretion. Moreover, low activity of NADH shuttles in beta cells has been found in type 2 diabetes models (3) and is also the cause of impaired glucose-stimulated insulin secretion (GSIS) 1 in fetal islets (4).In beta cells, the NADH shuttle system is composed essentially of the glycerophosphate and the malate-aspartate shuttles (5). The respective importance of these shuttles is illustrated in pancreatic islets of mice with abrogation of NADH shuttle activities. Mice lacking mitochondrial glycerol-phosphate dehydrogenase exhibit normal GSIS (6). However, additional inhibition of the malate-aspartate shuttle with aminooxyacetate strongly impairs the secretory response to glucose (6). This suggested that the malate-aspartate shuttle might play a key role in both mitochondrial metabolism and cytosolic redox state. Besides glycerophosphate and malate-aspartate shuttles, pyruvate-citrate shuttle also regenerates NAD ϩ necessary to maintain glycolysis. Pyruvate-citrate shuttle (7) contributes to the formation of malonyl-CoA and cytosolic NADPH, two molecules proposed as candidate coupling factors in GSIS (8, 9).In the mitochondria, NADH electrons are transferred to the electron transport chain, which in turn supplies th...

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Section: Discussionmentioning

confidence: 99%

The Malate-Aspartate NADH Shuttle Member Aralar1 Determines Glucose Metabolic Fate, Mitochondrial Activity, and Insulin Secretion in Beta Cells

Rubı́¹,

Arco

Bartley³

et al. 2004

Journal of Biological Chemistry

109

104

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“…AOA, an inhibitor of various aminotransferases, is widely used to block the malate-aspartate shuttle in islets and other tissues (17,29,41,42). At the concentration of 5 mM, AOA inhibed glucose-induced insulin secretion by 50 -60% in normal rat islets (17,29).…”

Section: Discussionmentioning

confidence: 99%

The Oscillatory Behavior of Pancreatic Islets from Mice with Mitochondrial Glycerol-3-phosphate Dehydrogenase Knockout

Ravier¹,

Eto²,

Jonkers³

et al. 2000

Journal of Biological Chemistry

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] i on the exocytotic process (6 -8). Both pathways require glucose metabolism and appear to depend on a rise in the ATP/ADP ratio (9).Glucose metabolism in ␤ cells essentially occurs through aerobic glycolysis (10 -12). An increase in the glucose concentration is followed by an acceleration of glycolysis and an even greater stimulation of mitochondrial oxidative events, in which Ca 2ϩ may play an important role. Thus, the elevation of [Ca 2ϩ ] i is paralleled by an increase in mitochondrial Ca 2ϩ (13) that may then activate the three Ca 2ϩ -sensitive intramitochondrial dehydrogenases and promote ATP synthesis (14). Another feature of the ␤ cell metabolic organization is a low activity of lactate dehydrogenase (12,15). Cytosolic NADH formed during glycolysis is re-oxidized (and ATP synthesis concomitantly stimulated) by transfer of the reducing equivalents into mitochondria through the glycerol phosphate shuttle and the malate-aspartate shuttle (16, 17). The rate-limiting enzyme of the former shuttle, mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) is located on the outer face of the mitochondrial membrane and can be activated by increases in cytosolic [Ca 2ϩ ] i (18,19). The importance of the NADH shuttles for glucose-induced insulin secretion (20) has received strong support from a recent study using islets from mice with a targeted disruption of mGPDH (21).Many ␤ cell responses to glucose are oscillatory. Oscillations of the membrane potential drive oscillations of [Ca 2ϩ ] i , leading to oscillations of insulin secretion that can be amplified by metabolic oscillations (4,(22)(23)(24)(25)(26). It is still unclear whether oscillations of glucose metabolism are intrinsic and initiate the whole chain of other pulsatile events or are entrained by the oscillations of [Ca 2ϩ ] i (27). The Ca 2ϩ sensitivity of mGPDH makes the enzyme a possible key site of the interplay between glucose metabolism and [Ca 2ϩ ] i oscillations. Thus, imposed oscillations of free Ca 2ϩ in islet mitochondrial extracts induced oscillations of mGPDH activity (28). If the hypothesis is correct, the oscillatory behavior of stimulus secretion coupling should be perturbed by mGPDH defects. The present study addressed this question with islets isolated from mGPDH knock-out (mG-PDH Ϫ/Ϫ ) mice (21). We compared the oscillations of ␤ cell

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“…It is well established that acute and chronic ethanol consumption increases the malate-aspartate shuttle in rat liver [10]. The capacity of the malate-aspartate shuttle to function as a key factor limiting the rate of glycolysis during ethanol oxidation was also demonstrated [11]. Some reports showed the increases of MDH activities in myocardium [12], liver, and blood [13] of ethanoltreated rats.…”

Section: Introductionmentioning

confidence: 95%

Ethanol‐induced redox imbalance in rat kidneys

Nechifor

Dinu

2010

J Biochem & Molecular Tox

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This study reports the effects of long-term ethanol consumption on kidney redox status, in terms of enzymatic mechanisms involved in regulating the cytosolic [NADH]/[NAD(+) ] balance. Wistar rats were treated with ethanol (2 g/kg body weight/24 h) via intragastric intubation for 10 and 30 weeks, respectively. Ethanol administration induced an enhancement of alcohol dehydrogenase activities and affected the capacity of the kidney to prevent NADH accumulation in the cytosol. After 10 weeks, the excess of NADH was balanced by increased activities of malate dehydrogenase and aspartate transaminase. In the event of a longer period of ethanol intake, the kidney was not able to balance the NADH excess, even though an increase in malate dehydrogenase, lactate dehydrogenase, aspartate transaminase, and alanine transaminase activities was noted. The electrophoretic analysis of alcohol dehydrogenase, lactate dehydrogenase, and malate dehydrogenase isoforms revealed differences between control and ethanol-treated animals. The results suggest that rat kidneys have a multicomponent metabolic response to the same daily dose of ethanol that functions to maintain the redox status and which varies with the length of the administration period.

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The capacity of reducing‐equivalent shuttles limits glycolysis during ethanol oxidation

Cited by 28 publications

References 36 publications

The Malate-Aspartate NADH Shuttle Member Aralar1 Determines Glucose Metabolic Fate, Mitochondrial Activity, and Insulin Secretion in Beta Cells

The Malate-Aspartate NADH Shuttle Member Aralar1 Determines Glucose Metabolic Fate, Mitochondrial Activity, and Insulin Secretion in Beta Cells

The Oscillatory Behavior of Pancreatic Islets from Mice with Mitochondrial Glycerol-3-phosphate Dehydrogenase Knockout

Ethanol‐induced redox imbalance in rat kidneys

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