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

The 78-kDa glucose-regulated protein (GRP78) is ubiquitously expressed in many cell types. Its promoter contains multiple protein-binding sites and functional elements. In this study we examined a high affinity protein-binding site spanning bp -198 to -180 of the rat grp78 promoter, using nuclear extracts from both B-lymphoid and HeLa cells. This region contains a sequence TGACGTGA which, with the exception of one base, is identical to the cAMP-response element (CRE). Site-directed mutagenesis reveals that this sequence functions as a major basal level regulatory element in hamster fibroblast cells and is also necessary to maintain high promoter activity under stress-induced conditions. By gel mobility shift analysis, we detect two specific protein complexes. The major specific complex I, while immunologically distinct from the 42-kDa CRE-binding protein (CREB), binds most strongly to the grp site, but also exhibits affinity for the CRE consensus sequence. As such, complex I may consist of other members of the CREB/activating transcription factor protein family. The minor specific complex II consists of CREB or a protein antigenically related to it. A nonspecific complex III consists of the Ku autoantigen, an abundant 70- to 80-kDa protein complex in HeLa nuclear extracts. By cotransfection experiments, we demonstrate that in F9 teratocarcinoma cells, the grp78 promoter can be transactivated by the phosphorylated CREB or when the CREB-transfected cells are treated with the calcium ionophore A23187. The differential regulation of the grp78 gene by cAMP in specific cell types and tissues is discussed.
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PMID:A binding site for the cyclic adenosine 3',5'-monophosphate-response element-binding protein as a regulatory element in the grp78 promoter. 183 91

Parkinson's disease (PD) is an age-related disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra (SN) and corresponding motor deficits. Oxidative stress and mitochondrial dysfunction are implicated in the neurodegenerative process in PD. Although dietary restriction (DR) extends lifespan and reduces levels of cellular oxidative stress in several different organ systems, the impact of DR on age-related neurodegenerative disorders is unknown. We report that DR in adult mice results in resistance of dopaminergic neurons in the SN to the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP-induced loss of dopaminergic neurons and deficits in motor function were ameliorated in DR rats. To mimic the beneficial effect of DR on dopaminergic neurons, we administered 2-deoxy-D-glucose (2-DG; a nonmetabolizable analogue of glucose) to mice fed ad libitum. Mice receiving 2-DG exhibited reduced damage to dopaminergic neurons in the SN and improved behavioral outcome following MPTP treatment. The 2-DG treatment suppressed oxidative stress, preserved mitochondrial function, and attenuated cell death in cultured dopaminergic cells exposed to the complex I inhibitor rotenone or Fe2+. 2-DG and DR induced expression of the stress proteins heat-shock protein 70 and glucose-regulated protein 78 in dopaminergic cells, suggesting involvement of these cytoprotective proteins in the neuroprotective actions of 2-DG and DR. The striking beneficial effects of DR and 2-DG in models of PD, when considered in light of recent epidemiological data, suggest that DR may prove beneficial in reducing the incidence of PD in humans.
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PMID:Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson's disease. 1039 97

The histidine triad nucleotide-binding protein 2 (HINT-2) is a mitochondrial adenosine phosphoramidase expressed in hepatocytes. The phenotype of Hint2 knockout ( Hint2-/-) mice includes progressive hepatic steatosis and lysine hyperacetylation of mitochondrial proteins, which are features of respiratory chain malfunctions. We postulated that the absence of HINT-2 induces a defect in mitochondria bioenergetics. Isolated Hint2-/- hepatocytes produced less ATP and generated a lower mitochondrial membrane potential than did Hint2+/+ hepatocytes. In extracellular flux analyses with glucose, the basal, ATP-linked, and maximum oxygen consumption rates (OCRs) were decreased in Hint2-/- hepatocytes and in HepG2 cells lacking HINT-2. Conversely, in HINT-2 overexpressing SNU-449 and HepG2 cells, the basal, ATP-linked, and maximum OCRs were increased. Similarly, with palmitate, basal and maximum OCRs were decreased in Hint2-/- hepatocytes, but they were increased in HINT-2 overexpressing HepG2 cells. When assayed with radiolabeled substrate, palmitate oxidation was reduced by 25% in Hint2-/- mitochondria. In respirometry assays, complex I- and II-driven, coupled and uncoupled respirations and complex IV KCN-sensitive respiration were reduced in Hint2-/- mitochondria. Furthermore, HINT-2 associated with cardiolipin and glucose-regulated protein 75 kDa. Our study shows decreased electron transfer and oxidative phosphorylation capacity in the absence of HINT-2. The bioenergetics deficit accumulated over time in hepatocytes lacking HINT-2 likely leads to the secondary outcome of steatosis.-Rajasekaran, R., Felser, A., Nuoffer, J.-M., Dufour, J.-F., St-Pierre, M. V. The histidine triad nucleotide-binding protein 2 (HINT-2) positively regulates hepatocellular energy metabolism.
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PMID:The histidine triad nucleotide-binding protein 2 (HINT-2) positively regulates hepatocellular energy metabolism. 2991 63

DJ-1 was recently reported to be involved in the cardioprotection of hypoxic preconditioning (HPC) against hypoxia/reoxygenation (H/R)-induced oxidative stress damage, by preserving mitochondrial complex I activity and, subsequently, inhibiting mitochondrial reactive oxygen species (ROS) generation. However, the molecular mechanism by which HPC enables mitochondrial translocation of DJ-1, which has no mitochondria-targeting sequence, to preserve mitochondrial complex I, is largely unknown. In this study, co-immunoprecipitation data showed that DJ-1 was associated with glucose-regulated protein 75 (Grp75), and this association was significantly enhanced after HPC. Immunofluorescence imaging and Western blot analysis showed that HPC substantially enhanced the translocation of DJ-1 from cytosol to mitochondria in H9c2 cells subjected to H/R, which was mimicked by DJ-1 overexpression induced by pFlag-DJ-1 transfection. Importantly, knockdown of Grp75 markedly reduced the mitochondrial translocation of DJ-1 induced by HPC and pFlag-DJ-1 transfection. Moreover, HPC promoted the association of DJ-1 with mitochondrial complex I subunits ND1 and NDUFA4, improved complex I activity, and inhibited mitochondria-derived ROS production and subsequent oxidative stress damage after H/R, which was also mimicked by pFlag-DJ-1 transfection. Intriguingly, these effects of HPC and pFlag-DJ-1 transfection were also prevented by Grp75 knockdown. In conclusion, these results indicated that HPC promotes the translocation of DJ-1 from cytosol to mitochondria in a Grp75-dependent manner and Grp75 is required for DJ-1-mediated protection of HPC on H/R-induced mitochondrial complex I defect and subsequent oxidative stress damage.
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PMID:Molecular Mechanism Underlying Hypoxic Preconditioning-Promoted Mitochondrial Translocation of DJ-1 in Hypoxia/Reoxygenation H9c2 Cells. 3187 39