Influence of NAD-linked dehydrogenase activity on flux through oxidative phosphorylation

Moreno‐Sánchez, Rafael; Hogue, Barbara A.; Hansford, Richard G.

doi:10.1042/bj2680421

Cited by 90 publications

(59 citation statements)

References 62 publications

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“…This study demonstrates that hyperoxia-induced alveolar developmental arrest is strongly associated with inhibition of mitochondrial phosphorylating respiration, the most effective pathway in generation of ATP in mammalian cells. In vivo control over the rate of phosphorylating respiration is shared between (1) the reactions generating electrochemical proton gradient (DmH 1 ) (depends on the activity of proton-pumping electron chain complexes), (2) the reactions of substrate dehydrogenases (supplying reducing equivalents for the respiratory chain), and (3) the reactions consuming the DmH 1 (such as ATP-ase and ADP/ATP translocator) (22,23). In the presence of saturating concentrations of NAD-linked substrates and phosphate, the maximum respiration rate in State 3 is not limited by the activity of ATP-phosphorylating system (24) or substrate dehydrogenases (25).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Dysfunction Contributes to Alveolar Developmental Arrest in Hyperoxia-Exposed Mice

Ratner¹,

Starkov²,

Matsiukevich³

et al. 2009

Am J Respir Cell Mol Biol

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This study investigated whether mitochondrial dysfunction contributes to alveolar developmental arrest in a mouse model of bronchopulmonary dysplasia (BPD). To induce BPD, 3-day-old mice were exposed to 75% O 2 . Mice were studied at two time points of hyperoxia (72 h or 2 wk) and after 3 weeks of recovery in room air (RA). A separate cohort of mice was exposed to pyridaben, a complex-I (C-I) inhibitor, for 72 hours or 2 weeks. Alveolarization was quantified by radial alveolar count and mean linear intercept methods. Pulmonary mitochondrial function was defined by respiration rates, ATP-production rate, and C-I activity. At 72 hours, hyperoxic mice demonstrated significant inhibition of C-I activity, reduced respiration and ATP production rates, and significantly decreased radial alveolar count compared with controls. Exposure to pyridaben for 72 hours, as expected, caused significant inhibition of C-I and ADP-phosphorylating respiration. Similar to hyperoxic littermates, these pyridaben-exposed mice exhibited significantly delayed alveolarization compared with controls. At 2 weeks of exposure to hyperoxia or pyridaben, mitochondrial respiration was inhibited and associated with alveolar developmental arrest. However, after 3 weeks of recovery from hyperoxia or 2 weeks after 72 hours of exposure to pyridaben alveolarization significantly improved. In addition, there was marked normalization of C-I and mitochondrial respiration. The degree of hyperoxia-induced pulmonary simplification and recovery strongly (r 2 5 0.76) correlated with C-I activity in lung mitochondria. Thus, the arrest of alveolar development induced by either hyperoxia or direct inhibition of mitochondrial oxidative phosphorylation indicates that bioenergetic failure to maintain normal alveolar development is one of the fundamental mechanisms responsible for BPD.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Dysfunction Contributes to Alveolar Developmental Arrest in Hyperoxia-Exposed Mice

Ratner¹,

Starkov²,

Matsiukevich³

et al. 2009

Am J Respir Cell Mol Biol

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“…A clear conclusion offered by these results is that though a-KGDH is less sensitive to H 2 O 2 than aconitase, because it is inhibited at higher oxidant concentrations and is never inactivated by 100%, yet this is the key enzyme that limits the generation of NAD(P)H in the Krebs cycle under acute exposure to oxidative stress. a-KGDH, as discussed above, is one of the key regulatory enzymes, which, together with citrate synthase and isocitrate dehydrogenase, is thought to determine the overall rate of the Krebs cycle (Cooney et al 1981;McCormack et al 1990;Moreno-Sanchez et al 1990). Nonetheless, it has to be resolved how the Krebs cycle can function and generate NAD(P)H when one of the enzymes, aconitase, even though not ratelimiting, is completely blocked.…”

Section: A-kgdh Is a Crucial Target Of Reactive Oxygen Species In Thementioning

confidence: 99%

Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress

Tretter

Ádám-Vizi

2005

Phil. Trans. R. Soc. B

351

282

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Alpha-ketoglutarate dehydrogenase (a-KGDH) is a highly regulated enzyme, which could determine the metabolic flux through the Krebs cycle. It catalyses the conversion of a-ketoglutarate to succinylCoA and produces NADH directly providing electrons for the respiratory chain. a-KGDH is sensitive to reactive oxygen species (ROS) and inhibition of this enzyme could be critical in the metabolic deficiency induced by oxidative stress. Aconitase in the Krebs cycle is more vulnerable than a-KGDH to ROS but as long as a-KGDH is functional NADH generation in the Krebs cycle is maintained. NADH supply to the respiratory chain is limited only when a-KGDH is also inhibited by ROS. In addition being a key target, a-KGDH is able to generate ROS during its catalytic function, which is regulated by the NADH/NAD C ratio. The pathological relevance of these two features of a-KGDH is discussed in this review, particularly in relation to neurodegeneration, as an impaired function of this enzyme has been found to be characteristic for several neurodegenerative diseases.

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“…Activation of pyruvate dehydrogenase, isocitrate dehydrogenase, and ␣-ketoglutarate dehydrogenase by calcium has been described in several tissues, including heart, liver, and some endocrine tissues (42)(43)(44)(45), and occurs at [Ca 2ϩ ] m in the approximate range of 0.1-2.0 mol/l (46 -48). The peak [Ca 2ϩ ] m achieved in the present study in glucose-and glucose plus CGP37157-treated cells was within this range, consistent with our conclusion that the elevated [Ca 2ϩ ] m was responsible for the enhanced Krebs cycle flux and oxidative ATP production that we observed.…”

Section: Diabetes Vol 52 April 2003mentioning

confidence: 99%

Inhibition of Mitochondrial Na+-Ca2+ Exchanger Increases Mitochondrial Metabolism and Potentiates Glucose-Stimulated Insulin Secretion in Rat Pancreatic Islets

Lee¹,

Miles²,

Vargas³

et al. 2003

Diabetes

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؉ . We show that inhibition of the mNCE enhances mitochondrial oxidative metabolism and increases glucose-stimulated insulin secretion in rat islets and INS-1 cells. The benzothiazepine CGP37157 inhibited mNCE activity in INS-1 cells (50% inhibition at IC 50 ‫؍‬ 1.5 mol/l) and increased the glucose-induced rise in mitochondrial Ca 2؉ ([Ca 2؉ ] m ) 2.1 times. Cellular ATP content was increased by 13% in INS-1 cells and by 49% in rat islets by CGP37157 (1 mol/l). Krebs cycle flux was also stimulated by CGP37157 when glucose was present. Insulin secretion was increased in a glucosedependent manner by CGP37157 in both INS-1 cells and islets. In islets, CGP37157 increased insulin secretion dose dependently (half-maximal efficacy at EC 50 ‫؍‬ 0.06 mol/l) at 8 mmol/l glucose and shifted the glucose dose response curve to the left. In perifused islets, mNCE inhibition had no effect on insulin secretion at 2.8 mmol/l glucose but increased insulin secretion by 46% at 11 mmol/l glucose. The effects of CGP37157 could not be attributed to interactions with the plasma membrane sodium calcium exchanger, L-type calcium channels, ATP-sensitive K ؉ channels, or [Ca 2؉ ] m uniporter. In hyperglycemic clamp studies of Wistar rats, CGP37157 increased plasma insulin and C-peptide levels only during the hyperglycemic phase of the study. These results illustrate the potential utility of agents that affect mitochondrial metabolism as novel insulin secretagogues. Diabetes 52:965-973, 2003 M itochondrial oxidative metabolism plays an important role in the insulin secretory process in pancreatic ␤-cells. Stimulus-secretion coupling in the ␤-cell depends on the metabolism of glucose and the subsequent mitochondrial oxidative phosphorylation that generates ATP. ATP closes ATPsensitive K ϩ (K ATP ) channels, causing depolarization of the ␤-cell membrane, opening of voltage-dependent calcium channels, and Ca 2ϩ influx (1,2). Although two main processes, glycolysis and oxidative phosphorylation, are responsible for ATP synthesis during glucose metabolism, oxidative phosphorylation is the predominant pathway in the pancreatic ␤-cell (3,4). Insulin secretion induced by other secretagogues, such as leucine and glyceraldehydes, is also mediated by the production of ATP (5,6). The critical regulatory role of oxidative ATP production in glucose-stimulated insulin secretion (GSIS) is underscored by the observation that disrupting mitochondrial oxidative metabolism blocks nutrient-mediated insulin secretion. For example, inhibition of oxidative phosphorylation (7,8), blockade of NADH transport into mitochondria (9,10), or elimination of mitochondrial DNA from ␤-cells in vitro (11-15) or in vivo (16) all prevent GSIS. We tested the hypothesis that enhancing oxidative ATP production in response to glucose can increase insulin secretion. The normal feed-forward regulatory role of mitochondrial Ca 2ϩ ([Ca 2ϩ ] m ) in the ␤-cell was exploited to enhance oxidative metabolism.The influx of calcium into the cytoplasm of the ␤-cell in response to a nutrient l...

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Influence of NAD-linked dehydrogenase activity on flux through oxidative phosphorylation

Cited by 90 publications

References 62 publications

Mitochondrial Dysfunction Contributes to Alveolar Developmental Arrest in Hyperoxia-Exposed Mice

Mitochondrial Dysfunction Contributes to Alveolar Developmental Arrest in Hyperoxia-Exposed Mice

Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress

Inhibition of Mitochondrial Na+-Ca2+ Exchanger Increases Mitochondrial Metabolism and Potentiates Glucose-Stimulated Insulin Secretion in Rat Pancreatic Islets

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