Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.9.3.1 (cytochrome oxidase)
 8,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondria play a pivotal role in the regulation of energy metabolism and apoptotic pathways. Properties and functions of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to a different extent to cellular stress and degeneration. We have investigated the effect of 3-nitropropionic acid (NPA), a mitochondrial toxin and mimicking symptoms of Huntington's disease (HD) when applied systemically, on mitochondrial function and viability of primary neurons isolated from mouse brain striatum and cortex. We observed a higher vulnerability of striatal compared with cortical neurons in response to NPA treatment. This effect might be correlated with the transcription pattern of cytochrome c oxidase (EC 1.9.3.1.; COX) subunit IV isoforms. In cortical neurons, NPA induced a down-regulation of the COX IV-2/COX IV-1 ratio, whereas an up-regulation was found in striatal neurons. Previously, we have shown that an increased COX IV-2/COX IV-1 ratio is responsible for a higher enzyme activity which is paralleled by elevated intracellular ATP levels at the expense of increased mitochondrial peroxide production. These effects could also be demonstrated in striatal neurons. On the contrary, a decreased COX IV-2/COX IV-1 ratio was observed in cortical neurons which was accompanied by a decrease in intracellular ATP content and no significant changes in mitochondrial peroxide production. We propose that COX isoform IV-2 mediates increased oxidative stress that is, at least in part, responsible for a higher vulnerability of striatal compared with cortical neurons against NPA. This mechanism, in turn, may serve as an explanation for brain region-specific differences in the neuronal susceptibility to toxic conditions.
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PMID:Brain region specificity of 3-nitropropionic acid-induced vulnerability of neurons involves cytochrome c oxidase. 2060 Apr 40

Hypoxia-inducible factor 1 (HIF-1) mediates adaptive responses to reduced oxygen availability by regulating gene expression. A critical cell-autonomous adaptive response to chronic hypoxia controlled by HIF-1 is reduced mitochondrial mass and/or metabolism. Exposure of HIF-1-deficient fibroblasts to chronic hypoxia results in cell death due to excessive levels of reactive oxygen species (ROS). HIF-1 reduces ROS production under hypoxic conditions by multiple mechanisms including: a subunit switch in cytochrome c oxidase from the COX4-1 to COX4-2 regulatory subunit that increases the efficiency of complex IV; induction of pyruvate dehydrogenase kinase 1, which shunts pyruvate away from the mitochondria; induction of BNIP3, which triggers mitochondrial selective autophagy; and induction of microRNA-210, which blocks assembly of Fe/S clusters that are required for oxidative phosphorylation. HIF-1 is also required for ischemic preconditioning and this effect may be due in part to its induction of CD73, the enzyme that produces adenosine. HIF-1-dependent regulation of mitochondrial metabolism may also contribute to the protective effects of ischemic preconditioning. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.
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PMID:Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioning. 2073 59

Patients with glioblastoma have one of the lowest overall survival rates among patients with cancer. Standard of care for patients with glioblastoma includes temozolomide and radiation therapy, yet 30% of patients do not respond to these treatments and nearly all glioblastoma tumors become resistant. Chlorpromazine is a United States Food and Drug Administration-approved phenothiazine widely used as a psychotropic in clinical practice. Recently, experimental evidence revealed the anti-proliferative activity of chlorpromazine against colon and brain tumors. Here, we used chemoresistant patient-derived glioma stem cells and chemoresistant human glioma cell lines to investigate the effects of chlorpromazine against chemoresistant glioma. Chlorpromazine selectively and significantly inhibited proliferation in chemoresistant glioma cells and glioma stem cells. Mechanistically, chlorpromazine inhibited cytochrome c oxidase (CcO, complex IV) activity from chemoresistant but not chemosensitive cells, without affecting other mitochondrial complexes. Notably, our previous studies revealed that the switch to chemoresistance in glioma cells is accompanied by a switch from the expression of CcO subunit 4 isoform 2 (COX4-2) to COX4-1. In this study, chlorpromazine induced cell cycle arrest selectively in glioma cells expressing COX4-1, and computer-simulated docking studies indicated that chlorpromazine binds more tightly to CcO expressing COX4-1 than to CcO expressing COX4-2. In orthotopic mouse brain tumor models, chlorpromazine treatment significantly increased the median overall survival of mice harboring chemoresistant tumors. These data indicate that chlorpromazine selectively inhibits the growth and proliferation of chemoresistant glioma cells expressing COX4-1. The feasibility of repositioning chlorpromazine for selectively treating chemoresistant glioma tumors should be further explored.
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PMID:Repositioning chlorpromazine for treating chemoresistant glioma through the inhibition of cytochrome c oxidase bearing the COX4-1 regulatory subunit. 2845 61