Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Expression of the human protooncogene bcl-2 protects neural cells from death induced by many forms of stress, including conditions that greatly elevate intracellular Ca2+. Considering that Bcl-2 is partially localized to mitochondrial membranes and that excessive mitochondrial Ca2+ uptake can impair electron transport and oxidative phosphorylation, the present study tested the hypothesis that mitochondria from Bcl-2-expressing cells have a higher capacity for energy-dependent Ca2+ uptake and a greater resistance to Ca(2+)-induced respiratory injury than mitochondria from cells that do not express this protein. The overexpression of bcl-2 enhanced the mitochondrial Ca2+ uptake capacity using either digitonin-permeabilized GT1-7 neural cells or isolated GT1-7 mitochondria by 1.7 and 3.9 fold, respectively, when glutamate and malate were used as respiratory substrates. This difference was less apparent when respiration was driven by the oxidation of succinate in the presence of the respiratory complex I inhibitor rotenone. Mitochondria from Bcl-2 expressors were also much more resistant to inhibition of NADH-dependent respiration caused by sequestration of large Ca2+ loads. The enhanced ability of mitochondria within Bcl-2-expressing cells to sequester large quantities of Ca2+ without undergoing profound respiratory impairment provides a plausible mechanism by which Bcl-2 inhibits certain forms of delayed cell death, including neuronal death associated with ischemia and excitotoxicity.
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PMID:Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria. 879 Apr 27

Cytochrome b5 reductase purified from liver plasma membrane reduces coenzyme Q (CoQ) in reconstituted liposomes in the absence of cytochrome b5. Both CoQ and its reductase are responsible for the reduction of the ascorbate free radical at the cell surface. Thus, NADH-CoQ reductase represents a partial reaction of NADH-AFR reductase in the plasma membrane. Cytochrome b5 reductase maintains CoQ and ascorbate in their reduced state to support antioxidations. Reduced CoQ prevents lipid peroxidation in liposomes and plasma membranes. Also, oxidized CoQ can prevent lipid peroxidations in the presence of cytochrome b5 reductase and NADH. Addition of CoQ to intact cells prevents serum withdrawal-induced lipid peroxidation and apoptosis. The prevention of apoptosis by CoQ is independent of the bcl-2 protein content in the cell. Antioxidants that act at the plasma membrane as CoQ and ascorbate would represent a first barrier to protect lipids from oxidative stress and subsequent apoptosis. Cytochrome b5 reductase is then an enzyme leading this function at the plasma membrane. These data support the idea that when the plasma membrane barrier fails, bcl-2 protein would be required to prevent cell death.
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PMID:Role of cytochrome b5 reductase on the antioxidant function of coenzyme Q in the plasma membrane. 926 1

Manganese superoxide dismutase (MnSOD) is the mitochondrial enzyme that disposes of superoxide generated by respiratory chain activity. Of all electrons passing down the mitochondrial respiratory chain, 1-2% are diverted to form superoxide; thus production of hydrogen peroxide occurs at a constant rate due to MnSOD activity. Mice lacking MnSOD develop cardiomyopathy and basal ganglia lesions, have no lipid peroxidation products, but show destruction of enzymes with 4Fe-4S centres. Patients with complex I (NADH-CoQ oxidoreductase) deficiency show variable hyperinduction of MnSOD that is at least partially dependent on the extent of disturbance of redox state. This in turn appears to result in production of excess hydroxyl radicals, which are damaging to proteins, lipids and DNA. An alternative method of protection from oxygen radicals is employed by complex I-deficient cell types that do not induce MnSOD in that they show induction of the bcl-2 protein.
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PMID:The role of manganese superoxide dismutase in health and disease. 972 39

Death of dopamine neurons in Parkinson disease (PD) may arise from consequences of the complex I (C-I) defect in the mitochondrial electron transport chain (ETC). Whether cells activate programmed death (apoptosis) pathways derives, in part, from relative activities of proteins such as bcl-2 and bcl-X(L), that have anti-apoptotic actions. We studied the responses of bcl-2 and bcl-X(L) genes in pharmacologic (acute incubation with methylpyridinium (MPP+)) and mitochondrial transgenic ("cybrid") models of Parkinson disease C-I defects. MPP+ incubation increased levels of bcl-2 and bcl-X(L) proteins in native SH-SY5Y cells but not in rho(0) cells devoid of ETC activity. MPP+ increased bcl-2 mRNA levels by 40% at 8 hr. Confocal microscopic imaging showed that the intracellular distribution of immunoreactive bcl-2 was not significantly associated with mitochondrial membranes at baseline but was associated with mitochondria after 12 hr of MPP+. Immunoreactive bcl-X(L) protein was significantly and equally associated with mitochondrial membranes both at baseline and after MPP+. PD cybrids showed increased basal levels of bcl-2 and bcl-X(L) proteins, similar to the maximum levels found after MPP+ treatment of control SY5Y cells. After MPP+ exposure, bcl-2 protein levels increased in control cybrids but did not increase further in PD cybrids. Both pharmacologically generated and transgenically induced C-I inhibition increases levels of anti-apoptotic bcl proteins, possibly from increased gene transcription. Augmentation of bcl-2 and bcl-X(L) expression may delay neurodegeneration in PD.
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PMID:Disrupted mitochondrial electron transport function increases expression of anti-apoptotic bcl-2 and bcl-X(L) proteins in SH-SY5Y neuroblastoma and in Parkinson disease cybrid cells through oxidative stress. 1097 66

Bcl-2 has been shown to exert its antiapoptotic activity predominantly at the level of mitochondria by preventing cytochrome c release. Whether Bcl-2 is involved in the regulation of mitochondrial function prior to an apoptotic stimulus remains elusive. Using functional and spectrophotometric measurements in an inducible PC12-Tet-on-bcl-2 cell line we demonstrate that induction of Bcl-2 overexpression rapidly reduced cytochrome b and c levels as well as complex I activity. To confirm that these changes were specific for Bcl-2 we generated a bcl-2 antisense construct under the control of the tetracycline responsive promotor. Transient transfection with this antisense plasmid prevented both the decrease of cytochrome b and c levels and the loss of complex I activity. The decrease of cytochrome b levels was paralleled by a decrease of cytochrome b mRNA levels while Northern blot analysis of cytochrome c mRNA expression did not reveal any overt changes in Bcl-2 cells. We propose that the antiapoptotic properties of Bcl-2 are related to the reduction of mitochondrial complex I activity and lowered mitochondrial cytochrome b and c levels.
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PMID:Overexpression of bcl-2 results in reduction of cytochrome c content and inhibition of complex I activity. 1116 29

We have studied the effect of N-(4-hydroxyphenyl)retinamide on either malignant human leukaemia cells or normal cells and investigated its mechanism of action. We demonstrate that 4HPR induces reactive oxygen species increase on mitochondria at a target between mitochondrial respiratory chain complex I and II. Such oxidative stress causes cardiolipin peroxidation which in turn allows cytochrome c release to cytosol, caspase-3 activation and therefore apoptotic consumption. Moreover, this apoptotic pathway seems to be bcl-2/bax independent and count only on malignant cells but not normal nor activated lymphocytes.
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PMID:Implication of mitochondria-derived ROS and cardiolipin peroxidation in N-(4-hydroxyphenyl)retinamide-induced apoptosis. 1208 92

In the search for retinoids active against Burkitt's lymphoma (BL), we found that the arotinoid mofarotene (Ro 40-8757) induced strong antiproliferative and apoptotic responses in most established BL cell lines as well as in primary BL cells. Ro 40-8757-induced apoptosis is associated with mitochondrial membrane depolarization, activation of caspase-3 and -9, and enhanced production of reactive oxygen species. These effects were related to a transient drop in intracellular ATP content, probably favored by a downregulation of NADH dehydrogenase subunit-1, a component of the mitochondrial respiratory chain (MRC) Complex I. Inhibition of MRC with thenoyltrifluoroacetone suppressed both the ATP recovery and apoptosis, confirming that the effects of Ro 40-8757 are mediated by changes in mitochondrial function. Compared to EBV-negative lines, EBV-carrying BLs were more resistant to Ro 40-8757-induced apoptosis. EBV infection and ectopic LMP-1 expression increased the resistance of BL cells to Ro 40-8757-induced apoptosis, probably through bcl-2 upregulation. Finally, we also show that 2-methoxyoestradiol, an inhibitor of the scavenger enzymes superoxide dismutases, enhanced Ro 40-8757-mediated apoptosis. These findings provide the rationale for evaluating the clinical efficacy of Ro 40-8757 in BL patients and suggest that the combination of Ro 40-8757 with inhibitors of scavenger enzymes may be a promising therapeutic approach for this aggressive lymphoma.
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PMID:Inhibition of oxidative phosphorylation underlies the antiproliferative and proapoptotic effects of mofarotene (Ro 40-8757) in Burkitt's lymphoma cells. 1258 70

In osteoarthritis (OA) a time or age dependent process leads to aberrant cartilage structure which is characterized by reduced number of chondrocytes, loss of existing cartilage extracellular matrix, the production of matrix with abnormal composition and pathologic matrix calcification. Because chondrocyte matrix synthesis and mineralization are modulated by the balance between ATP generation and consumption, the mechanism by which chondrocytes generate energy have been a topic of interest. The analysis of mitochondrial respiratory chain (MRC) activity in OA chondrocytes shows a significant decrease in complexes II and III compared to normal chondrocytes. On the other hand, mitochondrial mass is increased in OA, as demonstrated by a significant rise in CS activity. Furthermore, OA cells show a reduction in the mitochondrial membrane potential (deltapsim) as demonstrated by using the fluorescent probe JC-1. OA cartilage contains high number of apoptotic chondrocytes, and mitochondria play a key role in apoptosis. Interestingly, OA cartilages show markedly elevated Bcl-2 and caspasa-3 expression. This expression is also correlated with chondrocyte apoptosis and OA lesions. The pathogenesis of OA includes elaboration of increased amounts of NO as a consequence of up-regulation of chondrocyte-inducible NO synthase induced by IL-1, TNF-alpha and other factors. NO reduces chondrocyte survival and induces cell death with morphologic changes characteristic of chondrocyte apoptosis. NO reduces the activity of complex IV and decreases the deltapsim as measured as the ratio of red/green fluorescence. Furthermore, NO induces the mRNA expression of caspase-3 and -7, and it reduces the expression of mRNA bcl-2 and the bcl-2 protein synthesis. Some studies suggest that the chondrocyte mitochondria are specialized for calcium transport and are important in the calcification of the extracellular matrix. Mineral formation has been demonstrated in matrix vesicles (MV) and within mitochondria. Direct suppression of mitochondrial respiration promoted MV-mediated mineralization in chondrocytes. Regulation of MRC may be one of the signaling pathways by which NO modulates articular cartilage matrix biosynthesis and pathologic mineralization. After age 40, the incidence of OA in humans increases progressively with increasing age. Studies show a trend to statistic significance between the age and the reduction of complex I activity of human normal chondrocytes. However, the study of relation between age and deltapsim in normal chondrocytes do not demonstrate any significant correlation. It has been reported that as the number of population doublings increased, mitochondrial DNA was degraded and the number of mitochondria per chondrocyte decline. One approach for determining the role of mitochondria in OA is to determine the effects of the MRC inhibition and to compare them with the findings in OA. Inhibition of MRC with antimycin prevents the normal ability of TGFbeta to increase excretion of Pi, thereby worsening deposition of pathologic HA crystals. In chondrocytes, the inhibition of complex IV with NaN3 modified both the deltapsim and the survival of cells inducing apoptosis. Inhibition of complex I with rotenone increases the expression and synthesis of Bcl-2 and Cox-2, both effects are similar effects to produced by IL-1 in human chondrocytes.
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PMID:Mitochondrial dysfunction in osteoarthritis. 1612 Apr 27

Granzyme A (GzmA) is the most abundant serine protease in killer cell cytotoxic granules. GzmA activates a novel programed cell death pathway that begins in the mitochondrion, where cleavage of NDUFS3 in electron transport complex I disrupts mitochondrial metabolism and generates reactive oxygen species (ROS). ROS drives the endoplasmic reticulum-associated SET complex into the nucleus, where it activates single-stranded DNA damage. GzmA also targets other important nuclear proteins for degradation, including histones, the lamins that maintain the nuclear envelope, and several key DNA damage repair proteins (Ku70, PARP-1). Cells that are resistant to the caspases or GzmB by overexpressing bcl-2 family anti-apoptotic proteins or caspase or GzmB protease inhibitors are sensitive to GzmA. By activating multiple cell death pathways, killer cells provide better protection against a variety of intracellular pathogens and tumors. GzmA also has proinflammatory activity; it activates pro-interleukin-1beta and may also have other proinflammatory effects that remain to be elucidated.
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PMID:Granzyme A activates another way to die. 2053 57

Metformin displays antileukemic effects partly due to activation of AMPK and subsequent inhibition of mTOR signaling. Nevertheless, Metformin also inhibits mitochondrial electron transport at complex I in an AMPK-independent manner, Here we report that Metformin and rotenone inhibit mitochondrial electron transport and increase triglyceride levels in leukemia cell lines, suggesting impairment of fatty acid oxidation (FAO). We also report that, like other FAO inhibitors, both agents and the related biguanide, Phenformin, increase sensitivity to apoptosis induction by the bcl-2 inhibitor ABT-737 supporting the notion that electron transport antagonizes activation of the intrinsic apoptosis pathway in leukemia cells. Both biguanides and rotenone induce superoxide generation in leukemia cells, indicating that oxidative damage may sensitize toABT-737 induced apoptosis. In addition, we demonstrate that Metformin sensitizes leukemia cells to the oligomerization of Bak, suggesting that the observed synergy with ABT-737 is mediated, at least in part, by enhanced outer mitochondrial membrane permeabilization. Notably, Phenformin was at least 10-fold more potent than Metformin in abrogating electron transport and increasing sensitivity to ABT-737, suggesting that this agent may be better suited for targeting hematological malignancies. Taken together, our results suggest that inhibition of mitochondrial metabolism by Metformin or Phenformin is associated with increased leukemia cell susceptibility to induction of intrinsic apoptosis, and provide a rationale for clinical studies exploring the efficacy of combining biguanides with the orally bioavailable derivative of ABT-737, Venetoclax.
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PMID:Biguanides sensitize leukemia cells to ABT-737-induced apoptosis by inhibiting mitochondrial electron transport. 2728 92


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