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)

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor that regulates transcriptional activation of several genes that are responsive to oxygen lack, including erythropoietin, vascular endothelial growth factor, various glycolytic enzymes and the GLUT-1 glucose transporter. Because mitochondria have been postulated to be involved in the regulation of HIF-1, we tested the effects of mitochondrial electron transport chain complex I inhibitors, rotenone and 1-methyl-4-phenylpiridinium (MPP(+)), on hypoxic-induced accumulation of HIF-1 alpha, the regulated component of the dimer. We found, consistent with our previous observations in Cath.a and PC12 cells, that rotenone and MPP(+) attenuated the HIF-1 alpha hypoxic response. Thus, it can be concluded that an intact, functional mitochondrial respiratory chain is required for HIF-1 alpha accumulation.
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PMID:Inhibitors of mitochondrial complex I attenuate the accumulation of hypoxia-inducible factor-1 during hypoxia in Hep3B cells. 1206 97

Cytokine-mediated regulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) non-hypoxic stabilization, translocation and activation is not well characterized. Furthermore, evidence that reactive oxygen species (ROS) signaling mediates interleukin (IL)-1 beta-dependent regulation of HIF-1 alpha has yet to be ascertained in alveolar epithelial cells. Recombinant human IL-1 beta induced, in a time-dependent manner, the nuclear translocation of HIF-1 alpha, an effect associated with up-regulating the activity of this transcription factor under normoxic conditions. In addition, analysis of the mode of action of IL-1 beta revealed a novel induction of intracellular ROS, including hydrogen peroxide (H(2)O(2)), the superoxide anion (O(2)(-*)) and the hydroxyl radical (*OH). The antioxidants, dimethyl sulfoxide (DMSO) and 1,3-dimethyl-2-thiourea (DMTU), purported to be prototypical scavengers of H2O2 and *OH, attenuated, in a dose-dependent manner, IL-1 beta-induced HIF-1 alpha nuclear translocation and activation. The NADPH-oxidase inhibitor, 4'-hydroxy-3'-methoxy-acetophenone (HMAP), which may affect mitochondrial ROS production, attenuated IL-1 beta-mediated nuclear translocation and activation of HIF-1 alpha. Inhibition of the mitochondrion complex I nicotinamide adenine dinucleotide phosphate-dependent oxidase by diphenylene iodonium (DPI), which blocks the conversion of ubiquinone --> ubiquinol, abrogated IL-1 beta-dependent nuclear translocation and activation of HIF-1 alpha. Similarly, interrupting the respiratory chain with potassium cyanide reversed the excitatory effect of IL-1 beta on HIF-1 alpha nuclear translocation and activation. These results indicate that a non-hypoxic pathway mediates cytokine-dependent regulation of HIF-1 alpha translocation and activation in a ROS-sensitive mechanism.
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PMID:Recombinant human interleukin (IL)-1 beta-mediated regulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) stabilization, nuclear translocation and activation requires an antioxidant/reactive oxygen species (ROS)-sensitive mechanism. 1210 Oct 82

Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a transcription factor that activates the transcription of genes and is responsible for progression of cell survival and proliferation. The synthesis of HIF-1 alpha can be stimulated via oxygen (O(2))-independent mechanisms; whereas, the degradation of HIF-1 alpha is regulated via Fe(2+) and/or O(2)-dependent enzyme prolyl hydroxylase (PHD). Aberrant iron accumulation, mitochondrial dysfunction and impairment of protein degradation system, such as autophagy, have been implicated in the pathogenesis of Parkinson's disease, among which, iron and mitochondrial dysfunction may enhance the enzyme activity of prolyl hydroxylase and cause the decrease of HIF-1 alpha. Recent reports have indicated that HIF-1 alpha may induce autophagy under hypoxic condition. Considering the metabolic characteristics of HIF-1 alpha under the pathogenesis of Parkinson's disease, we speculated that compounds that might stabilize HIF-1 alpha could prevent neuronal injury caused by excessive iron or mitochondrial injury under normoxic condition. Deferoxamine is one of iron chelators that may accumulate HIF-1 alpha due to the decreased degradation of HIF-1 alpha via inhibition of prolyl hydroxylase activity. In this study, we showed that the protein level of HIF-1 alpha was decreased in rotenone or MPP(+)-treated SH-SY5Y cell models of Parkinson's disease. We demonstrated that deferoxamine caused accumulation of HIF-1 alpha accompanied by the enhancement of autophagy in SH-SY5Y cells. When HIF-1 alpha gene was inhibited, deferoxamine-induced autophagy was suppressed accordingly, indicating that deferoxamine-induced autophagy was dependent on the expression of HIF-1 alpha. Our results also showed that deferoxamine attenuated rotenone-induced apoptosis, which was blocked when HIF-1 alpha or autophagy related gene Beclin 1 was suppressed. In summary, the present study indicated that the level of HIF-1 alpha was decreased under the situation when mitochondrial complex I was inhibited, and the neuroprotective role of deferoxamine in rotenone-induced apoptosis could be partially explained by its effects on the accumulation of HIF-1 alpha and HIF-1 alpha-mediated induction of autophagy.
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PMID:Neuroprotection of deferoxamine on rotenone-induced injury via accumulation of HIF-1 alpha and induction of autophagy in SH-SY5Y cells. 2054 14

The anti-diabetic drug metformin regulates T-cell responses to immune activation and is proposed to function by regulating the energy-stress-sensing adenosine-monophosphate-activated protein kinase (AMPK). However, the molecular details of how metformin controls T cell immune responses have not been studied nor is there any direct evidence that metformin acts on T cells via AMPK. Here, we report that metformin regulates cell growth and proliferation of antigen-activated T cells by modulating the metabolic reprogramming that is required for effector T cell differentiation. Metformin thus inhibits the mammalian target of rapamycin complex I signalling pathway and prevents the expression of the transcription factors c-Myc and hypoxia-inducible factor 1 alpha. However, the inhibitory effects of metformin on T cells did not depend on the expression of AMPK in T cells. Accordingly, experiments with metformin inform about the importance of metabolic reprogramming for T cell immune responses but do not inform about the importance of AMPK.
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PMID:Adenosine-mono-phosphate-activated protein kinase-independent effects of metformin in T cells. 2518 Oct 53