Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the yeast Saccharomyces cerevisiae, the two most important systems for conveying excess cytosolic NADH to the mitochondrial respiratory chain are external NADH dehydrogenase (Nde1p/Nde2p) and the glycerol-3-phosphate dehydrogenase shuttle. In the latter system, NADH is oxidized to NAD+ and dihydroxyacetone phosphate is reduced to glycerol 3-phosphate by the cytosolic Gpd1p; glycerol 3-phosphate gives two electrons to the respiratory chain via mitochondrial glycerol-3-phosphate dehydrogenase (Gut2p)-regenerating dihydroxyacetone phosphate. Both Nde1p/Nde2p and Gut2p are located in the inner mitochondrial membrane with catalytic sites facing the intermembranal space. In this study, we showed kinetic interactions between these two enzymes. First, deletion of either one of the external dehydrogenases caused an increase in the efficiency of the remaining enzyme. Second, the activation of NADH dehydrogenase inhibited the Gut2p in such a manner that, at a saturating concentration of NADH, glycerol 3-phosphate is not used as respiratory substrate. This effect was not a consequence of a direct action of NADH on Gut2p activity because both NADH dehydrogenase and its substrate were needed for Gut2p inhibition. This kinetic regulation of the activity of an enzyme as a function of the rate of another having a similar physiological function may be allowed by their association into the same supramolecular complex in the inner membrane. The physiological consequences of this regulation are discussed.
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PMID:Kinetic regulation of the mitochondrial glycerol-3-phosphate dehydrogenase by the external NADH dehydrogenase in Saccharomyces cerevisiae. 1203 56

Keeping a cytosolic redox balance is a prerequisite for living cells in order to maintain a metabolic activity and enable growth. During growth of Saccharomyces cerevisiae, an excess of NADH is generated in the cytosol. Aerobically, it has been shown that the external NADH dehydrogenase, Nde1p and Nde2p, as well as the glycerol-3-phosphate dehydrogenase shuttle, comprising the cytoplasmic glycerol-3-phosphate dehydrogenase, Gpdlp, and the mitochondrial glycerol-3-phosphate dehydrogenase, Gut2p, are the most important mechanisms for mitochondrial oxidation of cytosolic NADH. In this review we summarize the recent results showing (i) the contribution of each of the mechanisms involved in mitochondrial oxidation of the cytosolic NADH, under different physiological situations; (ii) the kinetic and structural properties of these metabolic pathways in order to channel NADH from cytosolic dehydrogenases to the inner mitochondrial membrane and (iii) the organization in supramolecular complexes and, the peculiar ensuing kinetic regulation of some of the enzymes (i.e. Gut2p inhibition by external NADH dehydrogenase activity) leading to a highly integrated functioning of enzymes having a similar physiological function. The cell physiological consequences of such an organized and regulated network are discussed.
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PMID:Organization and regulation of the cytosolic NADH metabolism in the yeast Saccharomyces cerevisiae. 1497 71

In the yeast Saccharomyces cerevisiae, the most important systems for conveying excess cytosolic NADH to the mitochondrial respiratory chain are the external NADH dehydrogenases (Nde1p and Nde2p) and the glycerol-3-phosphate dehydrogenase shuttle. In the latter system, NADH is oxidized to NAD+ and dihydroxyacetone phosphate is reduced to glycerol 3-phosphate by the cytosolic Gpd1p. Subsequently, glycerol 3-phosphate donates electrons to the respiratory chain via mitochondrial glycerol-3-phosphate dehydrogenase (Gut2p). At saturating concentrations of NADH, the activation of external NADH dehydrogenases completely inhibits glycerol 3-phosphate oxidation. Studies on the functionally isolated enzymes demonstrated that neither Nde1p nor Nde2p directly inhibits Gut2p. Thus, the inhibition of glycerol 3-phosphate oxidation may be caused by competition for the entrance of electrons into the respiratory chain. Using single deletion mutants of Nde1p or Nde2p, we have shown that glycerol 3-phosphate oxidation via Gut2p is inhibited fully when NADH is oxidized via Nde1p, whereas only 50% of glycerol 3-phosphate oxidation is inhibited when Nde2p is functioning. By comparing respiratory rates with different respiratory substrates, we show that electrons from Nde1p are favored over electrons coming from Ndip (internal NADH dehydrogenase) and that when electrons come from either Nde1p or Nde2p and succinodehydrogenase, their use by the respiratory chain is shared to a comparable extent. This suggests a very specific competition for electron entrance into the respiratory chain, which may be caused by the supramolecular organization of the respiratory chain. The physiological consequences of such regulation are discussed.
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PMID:Competition of electrons to enter the respiratory chain: a new regulatory mechanism of oxidative metabolism in Saccharomyces cerevisiae. 1555 39

Mitochondrial respiratory chain enzyme Complexes are present in placenta at proportion similar to other tissues with exception of glycerophosphate dehydrogenase (mGPDH) which is expressed at a very high rate. As shown by Western blot quantification and respiratory chain enzyme activity measurements, the specific content of mGPDH is similar to that of succinate dehydrogenase or NADH dehydrogenase. Using fluorometric probe dichlorodihydrofluorescein diacetate we found that placental mitochondria display high rate of glycerophosphate-dependent hydrogen peroxide production. This was confirmed by oxygraphic detection of glycerophosphate-induced, KCN- or antimycin A-insensitive oxygen uptake. Hydrogen peroxide production by mGPDH was highly activated by one-electron acceptor, potassium ferricyanide and it was depressed by inhibitors of mGPDH and by cytochrome c. Our results indicate that mGPDH should be considered as an additional source of reactive oxygen species participating in induction of oxidative stress in placenta.
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PMID:Specific properties of heavy fraction of mitochondria from human-term placenta - glycerophosphate-dependent hydrogen peroxide production. 1594 44

Although, metformin is a drug of the first choice in the treatment of type 2 diabetes mellitus, its molecular action is not fully determined. It is widely accepted that the antihyperglycemic effect of metformin is a result of a decrease in hepatic glucose production, and several cellular targets of the drug have been proposed. The reduction of gluconeogenesis evoked by metformin may be a result of an energy deficit evoked through the inhibition of mitochondrial respiratory chain complex I and/or increased cytosolic redox state and decreased mitochondrial redox state elicited by the inhibition of mitochondrial glycerophosphate dehydrogenase (mGPD). Metformin mediated reduction of hepatic gluconeogenesis was found to be AMP-activated protein kinase (AMPK) dependent and independent, including the inhibition of gluconeogenesis gene expression and allosteric regulation of key gluconeogenesis enzymes. Recently, it was reported that inhibition of mGPD by metformin decreases the level of dihydroxyacetone phosphate and reduces the conversion of lactate to pyruvate, that in consequence diminishes the utilization of glycerol and lactate for gluconeogenesis. The purpose of this paper is to discus molecular mechanisms responsible for the metabolic action of metformin.
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PMID:Molecular action of metformin in hepatocytes: an updated insight. 2580 33

Mitochondria can utilize different fuels according to physiological and nutritional conditions to promote cellular homeostasis. However, during nutrient overload metabolic inflexibility can occur, resulting in mitochondrial dysfunctions. High-fat diets (HFDs) are usually used to mimic this metabolic inflexibility in different animal models. However, how mitochondria respond to the duration of a HFD exposure is still under debate. In this study, we investigated the dynamic of the mitochondrial and physiological functions in Drosophila melanogaster at several time points following an exposure to a HFD. Our results showed that after two days on the HFD, mitochondrial respiration as well as ATP content of thorax muscles are increased, likely due to the utilization of carbohydrates. However, after four days on the HFD, impairment of mitochondrial respiration at the level of complex I, as well as decreased ATP content were observed. This was associated with an increased contribution of complex II and, most notably of the mitochondrial glycerol-3-phosphate dehydrogenase (mG3PDH) to mitochondrial respiration. We suggest that this increased mG3PDH capacity reflects the occurrence of metabolic inflexibility, leading to a loss of homeostasis and alteration of the cellular redox status, which results in senescence characterized by decreased climbing ability and premature death.
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PMID:Dynamic mitochondrial responses to a high-fat diet in Drosophila melanogaster. 3087 5

Incidence of endocrine cancers is rising every year. Over the last decade, evidence has accumulated that demonstrates the anti-cancer effects of an anti-diabetic drug, metformin, in endocrine malignancies. We performed a literature review utilizing the PubMed, Medline and clinicaltrials.gov databases using the keyword 'metformin' plus the following terms: 'thyroid cancer', 'thyroid nodules', 'parathyroid', 'hyperparathyroidism', 'adrenal adenoma', 'Cushing syndrome', 'hyperaldosteronism', 'adrenocortical cancer', 'neuroendocrine tumor (NET)', 'pancreatic NET (pNET)', 'carcinoid', 'pituitary adenoma', 'pituitary neuroendocrine tumor (PitNET)', 'prolactinoma', 'pheochromocytoma/paraganglioma'. We found 37 studies describing the preclinical and clinical role of metformin in endocrine tumors. The available epidemiological data show an association between exposure of metformin and lower incidence of thyroid cancer and pNETs in diabetic patients. Metformin treatment has been associated with better response to cancer therapy in thyroid cancer and pNETs. Preclinical evidence suggests that the primary direct mechanisms of metformin action include inhibition of mitochondrial oxidative phosphorylation via inhibition of both mitochondrial complex I and mitochondrial glycerophosphate dehydrogenase, leading to metabolic stress. Decreased ATP production leads to an activation of a cellular energy sensor, AMPK, and subsequent downregulation of mTOR signaling pathway, which is associated with decreased cellular proliferation. We also describe several AMPK-independent mechanisms of metformin action, as well as the indirect mechanisms targeting insulin resistance. Overall, repositioning of metformin has emerged as a promising strategy for adjuvant therapy of endocrine tumors. The mechanisms of synergy between metformin and other anti-cancer agents need to be elucidated further to guide well-designed prospective trials on combination therapies in endocrine malignancies.
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PMID:The role of an anti-diabetic drug metformin in the treatment of endocrine tumors. 3130 11

The antidiabetic drug phenformin displays potent anticancer activity in different tumors, but its mechanism of action remains elusive. Using Shh medulloblastoma as model, we show here that at clinically relevant concentrations, phenformin elicits a significant therapeutic effect through a redox-dependent but complex I-independent mechanism. Phenformin inhibits mitochondrial glycerophosphate dehydrogenase (mGPD), a component of the glycerophosphate shuttle, and causes elevations of intracellular NADH content. Inhibition of mGPD mimics phenformin action and promotes an association between corepressor CtBP2 and Gli1, thereby inhibiting Hh transcriptional output and tumor growth. Because ablation of CtBP2 abrogates the therapeutic effect of phenformin in mice, these data illustrate a biguanide-mediated redox/corepressor interplay, which may represent a relevant target for tumor therapy.
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PMID:Phenformin Inhibits Hedgehog-Dependent Tumor Growth through a Complex I-Independent Redox/Corepressor Module. 3204 7