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)

Heme oxygenase-1 (HO-1) is a cytoprotective enzyme activated by various phytochemicals and we examined the ability of Epigallocatechin-3-gallate (EGCG), the major constituent of green tea, to upregulate HO-1 expression in endothelial cells (ECs). We demonstrate that EGCG induces HO-1 expression in a concentration- and time-dependent manner. Furthermore, EGCG-mediated HO-1 induction was abrogated in the presence of actinomycin D and cycloheximide, indicating that this upregulation of HO-1 occurred at the transcriptional level. EGCG also upregulates Nrf2 levels in nuclear extracts and increases ARE-luciferase activity. Furthermore, EGCG is the most potent inducer of HO-1 expression of the different green tea constituents that we analyzed, but had no detectable cytotoxic effects over the 25-100 microM dosage range. The inhibition of intracellular ROS production by N-acetylcysteine (NAC), glutathione (GSH), superoxide dismutase (SOD), catalase and the mitochondrial complex I inhibitor, rotenone, results in a decrease in EGCG-dependent HO-1 expression. In addition, we determined that tyrosine kinase is involved in EGCG induction of HO-1 as this is abrogated by genistein. ECs treated with EGCG exhibit activation of Akt and ERK1/2. In addition, pharmacological inhibitors of phosphatidylinositol 3-kinase and MEK1/2, which are upstream of Akt and ERK1/2, respectively, attenuate EGCG-induced HO-1 expression. On the other hand, pretreatment of these cells with EGCG exerts significant cytoprotective effects against H2O2, suggesting that the induction of HO-1 is an important component in the protection against oxidative stress. Hence, EGCG is a novel phytochemical inducer of HO-1 expression and we further identify the principal underlying mechanisms involved in this process.
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PMID:Upregulation of heme oxygenase-1 by Epigallocatechin-3-gallate via the phosphatidylinositol 3-kinase/Akt and ERK pathways. 1637 25

Previously, we showed that oxidant exposure in renal proximal tubular cells (RPTC) induces mitochondrial dysfunction mediated by PKC-epsilon. This study examined the role of ERK1/2 in mitochondrial dysfunction induced by oxidant injury and whether PKC-epsilon mediates its effects on mitochondrial function through the Raf-MEK1/2-ERK1/2 pathway. Sublethal injury produced by tert-butylhydroperoxide (TBHP) resulted in three- to fivefold increase in phosphorylation of ERK1/2 and p38 but not JNK. This was followed by decreases in basal and uncoupled respirations (41%), state 3 respiration and ATP production coupled to complex I (46%), and complex I activity (42%). Oxidant exposure decreased aconitase activity 30% but not pyruvate, alpha-ketoglutarate, and malate dehydrogenase activities. Inhibition of ERK1/2 restored basal and state 3 respirations, DeltaPsi(m), ATP production, and complex I activity but not aconitase activity. In contrast, activation of ERK1/2 by expression of constitutively active MEK1 suppressed basal, uncoupled, and state 3 respirations in noninjured RPTC to the levels observed in TBHP-injured RPTC. MEK1/2 inhibition did not change Akt or p38 phosphorylation, demonstrating that the protective effect of MEK1/2 inhibitor was not due to activation of Akt or inhibition of p38 pathway. Inhibition of PKC-epsilon did not block TBHP-induced ERK1/2 phosphorylation in whole RPTC or in mitochondria. We conclude that 1) oxidant-induced activation of ERK1/2 but not p38 or JNK reduces mitochondrial respiration and ATP production by decreasing complex I activity and substrate oxidation through complex I, 2) citric acid cycle dehydrogenases are not under control of the ERK1/2 pathway in oxidant-injured RPTC, 3) the protective effects of ERK1/2 inhibition are not due to activation of Akt, and 4) ERK1/2 and PKC-epsilon mediate oxidant-induced mitochondrial dysfunction through independent pathways.
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PMID:Activation of ERK1/2 pathway mediates oxidant-induced decreases in mitochondrial function in renal cells. 1670 47

Aldosterone (Aldo) stimulates glomerular mesangial cell (MC) proliferation, in part, through an ERK1/2-dependent pathway. In this study, we examined whether Aldo activation of ERK1/2 in MC is mediated through redox-dependent EGF receptor (EGFR) transactivation, as well as the involvement of other signaling mechanisms in Aldo-induced MC proliferation. Aldo increased human MC proliferation, as determined by [(3)H]thymidine incorporation and cell counts. This increase in proliferation was blocked by inhibition of the mineralocorticoid receptor (MR). Continuing our observations downstream in the signaling pathway, we examined the ability of Aldo to activate both the Ras/MAPK and the PI3K signaling pathways. Aldo increased Ki-RasA and Ki-RasA:GTP levels, and sequentially phosphorylated c-Raf, MAPK kinase (MEK1/2), and ERK1/2. Ki-RasA small interfering RNA (siRNA), the c-Raf inhibitor GW5074, and the MEK1/2 inhibitor PD98059 reduced Aldo-induced cell proliferation by approximately 65%. Aldo also increased phosphorylation of PI3K, Akt, the mammalian target of rapamycin (mTOR), and the 70-kDa ribosomal S6 kinase (p70S6K1). Inhibition of the PI3K pathways by the selective PI3K inhibitor LY 294002, an Akt inhibitor, or the mTOR inhibitor rapamycin reduced cell proliferation by 51%. Combining LY 294002 and PD98059 completely blocked Aldo-induced MC proliferation. Next, we confirmed that Aldo exerts its effect on MAPK and PI3K activation, as well as on cell proliferation, by activating the EGFR. Pretreatment with the EGFR antagonist AG1478 inhibited MC proliferation, as well as the activation of Ras/MAPK and PI3K/Akt, suggesting that Ras/MAPK and PI3K/Akt activation occur downstream of EGFR activation. Finally, we examined the role of reactive oxygen species (ROS) in Aldo-induced transactivation of the EGFR. Aldo-induced ROS were predominantly generated by mitochondria. Pretreatment with the antioxidant N-acetyl-l-cysteine, catalase, SOD, mitochondrial respiratory chain complex I inhibitor rotenone (Rot), NADPH oxidase inhibitor apocynin, and DPI significantly inhibited Aldo-stimulated MC proliferation as well as EGFR transactivation. However, Rot reduced MC proliferation more potently than apocynin and DPI. In conclusion, Aldo stimulated cell proliferation through MR-mediated, redox-sensitive EGFR transactivation, which was dependent on the Ki-RasA/c-Raf/MEK/ERK and PI3K/Akt/mTOR/p70S6K1 signaling pathways in human MCs.
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PMID:Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation. 1933 32

The regulation of mitochondrial quality has emerged as a central issue in neurodegeneration, diabetes, and cancer. We utilized repeated low-dose applications of the complex I inhibitor 1-methyl-4-phenylpyridinium (MPP(+)) over 2 weeks to study cellular responses to chronic mitochondrial stress. Chronic MPP(+) triggered depletion of functional mitochondria resulting in diminished capacities for aerobic respiration. Inhibiting autophagy/mitophagy only partially restored mitochondrial content. In contrast, inhibiting activation of extracellular signal-regulated protein kinases conferred complete cytoprotection with full restoration of mitochondrial functional and morphological parameters, enhancing spare respiratory capacity in MPP(+) co-treated cells above that of control cells. Reversal of mitochondrial injury occurred when U0126 was added 1 week after MPP(+), implicating enhanced repair mechanisms. Chronic MPP(+) caused a >90% decrease in complex I subunits, along with decreases in complex III and IV subunits. Decreases in respiratory complex subunits were reversed by co-treatment with U0126, ERK1/2 RNAi or transfection of dominant-negative MEK1, but only partially restored by degradation inhibitors. Chronic MPP(+) also suppressed the de novo synthesis of mitochondrial DNA-encoded proteins, accompanied by decreased expression of the mitochondrial transcription factor TFAM. U0126 completely reversed each of these deficits in mitochondrial translation and protein expression. These data indicate a key, limiting role for mitochondrial biogenesis in determining the outcome of injuries associated with elevated mitophagy.
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PMID:Impaired mitochondrial biogenesis contributes to depletion of functional mitochondria in chronic MPP+ toxicity: dual roles for ERK1/2. 2262 31

The Ras-MEK1/2-ERK1/2 kinase signaling pathway regulates proliferation, survival, and differentiation and, because it is often aberrant in tumors, is a popular target for small molecule inhibition. A novel metabolic analysis that measures the real-time oxidation state of NAD(H) and the hemes of the electron transport chain and oxygen consumption within intact, living cells found that structurally distinct MEK1/2 inhibitors had an immediate, dose-dependent effect on mitochondrial metabolism. The inhibitors U0126, MIIC and PD98059 caused NAD(H) reduction, heme oxidation, and decreased oxygen consumption, characteristic of complex I inhibition. PD198306, an orally active MEK1/2 inhibitor, acted as an uncoupler. Each MEK1/2 inhibitor depleted phosphorylated ERK1/2 and inhibited proliferation, but the most robust antiproliferative effects always correlated with the metabolic failure which followed mitochondrial inhibition rather than inhibition of MEK1/2. This warrants rethinking the role of ERK1/2 in proliferation and emphasizes the importance of mitochondrial function in this process.
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PMID:Acute mitochondrial inhibition by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) 1/2 inhibitors regulates proliferation. 2323 57