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)

Mitochondrial dysfunction is associated with cardiovascular damage; however, data on a possible association with kidney damage are scarce. Here, we aimed at investigating whether 1) kidney impairment is related to mitochondrial dysfunction; and 2) ANG II blockade, compared with Ca2+ channel blockade, can reverse potential mitochondrial changes in hypertension. Eight-week-old male spontaneously hypertensive rats (SHR) received water containing losartan (40 mg.kg-1.day-1, SHR+Los), amlodipine (3 mg.kg-1.day-1, SHR+Amlo), or no additions (SHR) for 6 mo. Wistar-Kyoto rats (WKY) were normotensive controls. Glomerular and tubulointerstitial damage, systolic blood pressure, and proteinuria were higher, and creatinine clearance was lower in SHR vs. SHR+Los and WKY. In SHR+Amlo, blood pressure was similar to WKY, kidney function was similar to SHR, and renal lesions were lower than in SHR, but higher than in SHR+Los. In kidney mitochondria from SHR and SHR+Amlo, membrane potential, nitric oxide synthase, manganese-superoxide dismutase and cytochrome oxidase activities, and uncoupling protein-2 content were lower than in SHR+Los and WKY. In SHR and SHR+Amlo, mitochondrial H2O2 production was higher than in SHR+Los and WKY. Renal glutathione content was lower in SHR+Amlo relative to SHR, SHR+Los, and WKY. In SHR and SHR+Amlo, glutathione was relatively more oxidized than in SHR+Los and WKY. Tubulointerstitial alpha-smooth muscle actin labeling was inversely related to manganese-superoxide dismutase activity and uncoupling protein-2 content. These findings suggest that oxidant stress is associated with renal mitochondrial dysfunction in SHR. The mitochondrial-antioxidant actions of losartan may be an additional or alternative way to explain some of the beneficial effects of AT1-receptor antagonists.
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PMID:Renal mitochondrial dysfunction in spontaneously hypertensive rats is attenuated by losartan but not by amlodipine. 1641 Apr 2

The physiological functions of nitric oxide (NO) are well established. The finding that the endothelium-derived relaxing factor (EDRF) is NO was totally unexpected. It was shown that NO is a reaction product of an enzymatically catalyzed, overall, 5-electron oxidation of guanidinium nitrogen from L-arginine followed by the release of the free radical species NO. NO is synthesized by a single protein complex supported by cofactors, coenzymes (such as tetrahydrobiopterin) and cytochrome P450. The latter can uncouple from substrate oxidation producing O2*- radicals. The research groups of Richter [Ghafourifar P, Richter C. Nitric oxide synthase activity in mitochondria. FEBS Lett 1997; 418: 291-296.] and Boveris [Giulivi C, Poderoso JJ, Boveris A. Production of nitric oxide by mitochondria. J Biol Chem 1998; 273: 11038-11043.] identified a mitochondrial NO synthase (NOS). There are, however, increasing reports demonstrating that mitochondrial NO is derived from cytosolic NOS belonging to the Ca2+-dependent enzymes. NO was thought to control cytochrome oxidase. This assumption is controversial due to the life-time of NO in biological systems (millisecond range). We found a nitrite reductase in mitochondria which is of major interest. Any increase of nitrite in the tissue which is the first oxidation product of NO, for instance following NO donors, will stimulate NO-recycling via mitochondrial nitrite reductase. In this paper, we describe the identity and the function of mitochondrial nitrite reductase and the consequences of NO-recycling in the metabolic compartment of mitochondria.
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PMID:The existence and significance of a mitochondrial nitrite reductase. 1643 99

This study investigated whether inducible heme oxygenase-1[corrected] (HO-1) [corrected] is targeted to mitochondria and its putative effects on oxidative metabolism in rat liver. Western blot and immune-electron microscopy in whole purified and fractionated organelles showed basal expression of HO-1 protein in both microsomes and mitochondria (inner membrane), accompanied by a parallel HO activity. Inducers of HO-1 increased HO-1 targeting to the inner mitochondrial membrane, which also contained biliverdin reductase, supporting that both enzymes are in the same compartmentalization. Induction of mitochondrial HO-1 was associated with a decrease of mitochondrial heme content and selective reduction of protein expression of cytochrome oxidase (COX) subunit I, which is coded by the mitochondrial genome and synthesized in the mitochondria depending on heme availability; these changes resulted in decreased COX spectrum and activity. Mitochondrial HO-1 induction was also associated with down-regulation of mitochondrial-targeted NO synthase expression and activity, resulting in a reduction of NO-dependent mitochondrial oxidant yield; inhibition of HO-1 activity reverted these effects. In conclusion, we demonstrated for the first time localization of HO-1 protein in mitochondria. It is surmised that mitochondrial HO-1 has important biological roles in regulating mitochondrial heme protein turnover and in protecting against conditions such as hypoxia, neurodegenerative diseases, or sepsis, in which substantially increased mitochondrial NO and oxidant production have been implicated.
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PMID:HO-1 is located in liver mitochondria and modulates mitochondrial heme content and metabolism. 1667 35

Sleep disorders are a form of stress associated with increased sympathetic activity, and they are a risk factor for the occurrence of cardiovascular disease. Given that nitric oxide (NO) may play an inhibitory role in the regulation of sympathetic tone, this study set out to determine the NO synthase (NOS) reactivity in the primary cardiovascular afferent neurons (i.e. nodose neurons) following total sleep deprivation (TSD). TSD was performed by the disc-on-water method. Following 5 days of TSD, all experimental animals were investigated for quantitative nicotinamine adenine dinucleotide phosphate-diaphorase (NADPH-d, a co-factor of NOS) histochemistry, neuronal NOS immunohistochemistry and neuronal NOS activity assay. In order to evaluate the endogenous metabolic activity of nodose neurons, cytochrome oxidase (COX) reactivity was further tested. All the above-mentioned reactivities were objectively assessed by computerized image analysis. The clinical significance of the reported changes was demonstrated by alterations of mean arterial blood pressure (MAP). The results indicated that in normal untreated rats, numerous NADPH-d/NOS- and COX-reactive neurons were found in the nodose ganglion (NG). Following TSD, however, both the labelling and staining intensity of NADPH-d/NOS as well as COX reactivity were drastically reduced in the NG compared with normal untreated ganglions. MAP was significantly higher in TSD rats (136+/-4 mmHg) than in normal untreated rats (123+/-2 mmHg). NO may serve as an important sympathoinhibition messenger released by the NG neurons, and decrease of NOS immunoexpression following TSD may account for the decrease in NOS content. In association with the reduction of NOS activity, a defect in NOS expression in the primary cardiovascular afferent neurons would enhance clinical hypertension, which might serve as a potential risk factor in the development of TSD-relevant cardiovascular disturbances.
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PMID:Total sleep deprivation inhibits the neuronal nitric oxide synthase and cytochrome oxidase reactivities in the nodose ganglion of adult rats. 1687 2

There is evidence that nitric oxide (NO), superoxide (O(2)(*-)), and their associated reactive nitrogen species (RNS) produced by vascular endothelial cells (ECs) in response to hemodynamic forces play a role in cell signaling. NO is known to impair mitochondrial respiration. We sought to determine whether exposure of human umbilical vein ECs (HUVECs) to steady laminar shear stress and the resultant NO production modulate electron transport chain (ETC) enzymatic activities. The activities of respiratory complexes I, II/III, and IV were dependent on the presence of serum and growth factor supplement in the medium. EC exposure to steady laminar shear stress (10 dyn/cm(2)) resulted in a gradual inhibition of each of the complexes starting as early as 5 min from the flow onset and lasting up to 16 h. Ramp flow resulted in inhibition of the complexes similar to that of step flow. When ECs were sheared in the presence of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 100 microM), the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO; 100 microM), or the peroxynitrite (ONOO(-)) scavenger uric acid (UA; 50 microM), the flow-inhibitory effect on mitochondrial complexes was attenuated. In particular, L-NAME and UA abolished the flow effect on complex IV. Increased tyrosine nitration was observed in the mitochondria of sheared ECs, and UA blocked the shear-induced nitrotyrosine staining. In summary, shear stress induces mitochondrial RNS formation that inhibits the electron flux of the ETC at multiple sites. This may be a critical mechanism by which shear stress modulates EC signaling and function.
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PMID:Shear-induced reactive nitrogen species inhibit mitochondrial respiratory complex activities in cultured vascular endothelial cells. 1702 Sep 31

Deprenyl is a selective monoamine oxidase (MAO) B inhibitor, widely used for treatment of Parkinson's disease. The present study shows that deprenyl treatment was able to improve mitochondrial function. Fourteen month old mice were injected i.p. with deprenyl (20 mg/kg) and killed 1.5 h after the administration. Different brain subcellular fractions were isolated from control and deprenyl-treated animals to evaluate the effect of deprenyl on nitric oxide synthase (NOS) activity. Oxygen consumption, hydrogen peroxide (H(2)O(2)) production, mitochondrial membrane potential and calcium-induced permeability transition (MPT) were studied in intact mitochondria. In addition, the effect of deprenyl on respiratory complexes and MAO activities were evaluated in submitochondrial particles (SMP). Monoamine oxidase activity was found to be decreased by 55% in mitochondria from deprenyl-treated animals and as a consequence, H(2)O(2) production was significantly decreased. Deprenyl inhibited NOS activity in cytosolic fractions and SMP by 40% and 55%, respectively. In similar conditions, SMP from deprenyl-treated animals showed increased cytochrome oxidase activity. A 51% increase in the oxygen uptake in state 3 (active respiration state) was found after deprenyl treatment, but no significant changes were observed in state 4 (resting respiration state). Deprenyl treatment protected against calcium-induced depolarization and was able to inhibit calcium-induced MPT. This work provides evidence that deprenyl treatment exerts an improvement of brain mitochondrial function, through a reduction of free radical production, prevention of calcium-induced MPT and maintaining a mitochondrial transmembrane potential.
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PMID:Improvement of mouse brain mitochondrial function after deprenyl treatment. 1708 86

The renal and cardiac benefits of renin-angiotensin system (RAS) inhibition in hypertension exceed those attributable to blood pressure reduction, and seem to involve mitochondrial function changes. To investigate whether mitochondrial changes associated with RAS inhibition are related to changes in nitric oxide (NO) metabolism, four groups of male Wistar rats were treated during 2 wk with a RAS inhibitor, enalapril (10 mg x kg(-1) x day(-1); Enal), or a NO synthase (NOS) inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME) (1 mg x kg(-1) x day(-1)), or both (Enal+L-NAME), or were untreated (control). Blood pressure and body weight were lower in Enal than in control. Electron transfer through complexes I to III and cytochrome oxidase activity were significantly lower, and uncoupling protein-2 content was significantly higher in kidney mitochondria isolated from Enal than in those from control. All of these changes were prevented by L-NAME cotreatment and were accompanied by a higher production/bioavailability of kidney NO. L-NAME abolished mitochondrial NOS activity but failed to inhibit extra-mitochondrial kidney NOS, underscoring the relevance of mitochondrial NO in those effects of enalapril that were suppressed by L-NAME cotreatment. In Enal, kidney mitochondria H(2)O(2) production rate and MnSOD activity were significantly lower than in control, and these effects were not prevented by L-NAME cotreatment. These findings may clarify the role of NO in the interactions between RAS and mitochondrial metabolism and can help to unravel the mechanisms involved in renal protection by RAS inhibitors.
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PMID:Mitochondrial function and nitric oxide metabolism are modified by enalapril treatment in rat kidney. 1718 9

Nitric oxide (NO) is an intercellular signaling molecule; among its many and varied roles are the control of blood flow and blood pressure via activation of the heme enzyme, soluble guanylate cyclase. A growing body of evidence suggests that an additional target for NO is the mitochondrial oxygen-consuming heme/copper enzyme, cytochrome c oxidase. This review describes the molecular mechanism of this interaction and the consequences for its likely physiological role. The oxygen reactive site in cytochrome oxidase contains both heme iron (a(3)) and copper (Cu(B)) centers. NO inhibits cytochrome oxidase in both an oxygen-competitive (at heme a(3)) and oxygen-independent (at Cu(B)) manner. Before inhibition of oxygen consumption, changes can be observed in enzyme and substrate (cytochrome c) redox state. Physiological consequences can be mediated either by direct "metabolic" effects on oxygen consumption or via indirect "signaling" effects via mitochondrial redox state changes and free radical production. The detailed kinetics suggest, but do not prove, that cytochrome oxidase can be a target for NO even under circumstances when guanylate cyclase, its primary high affinity target, is not fully activated. In vivo organ and whole body measures of NO synthase inhibition suggest a possible role for NO inhibition of cytochrome oxidase. However, a detailed mapping of NO and oxygen levels, combined with direct measures of cytochrome oxidase/NO binding, in physiology is still awaited.
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PMID:Nitric oxide regulation of mitochondrial oxygen consumption II: Molecular mechanism and tissue physiology. 1732 2

Peripheral sensory diabetic neuropathy is characterized by morphological, electrophysiological and neurochemical changes to a subpopulation of primary afferent neurons. Here, we utilized a transgenic mouse model of diabetes (OVE26) and age-matched controls to histologically examine the effect of chronic hyperglycemia on the activity or abundance of the enzymes acid phosphatase, cytochrome oxidase and NADPH-diaphorase in primary sensory neuron perikarya and the dorsal horn of the spinal cord. Quantitative densitometric characterization of enzyme reaction product revealed significant differences between diabetic, compared to control, animals for all three enzymes. Levels of acid phosphatase reaction product were found to be significantly reduced in both small diameter primary sensory somata and the dorsal horn. Cytochrome oxidase activity was found to be significantly lower in small primary sensory somata while NADPH-diaphorase labeling was found to be significantly higher in small primary sensory somata and significantly lower in the dorsal horn. In addition to these observed biochemical changes, ratiometric analysis of the number of small versus large diameter primary sensory perikarya in diabetic and control animals demonstrated a quantifiable decrease in the number of small diameter cells in the spinal ganglia of diabetic mice. These results suggest that the OVE26 model of diabetes mellitus produces an identifiable disturbance in specific metabolic pathways of select cells in the sensory nervous system and that this dysfunction may reflect the progression of a demonstrated cell loss.
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PMID:Hyperglycemia alters enzyme activity and cell number in spinal sensory ganglia. 1745 60

Nitric oxide (NO) inhibits the mitochondrial respiratory chain, resulting in inhibition of ATP production, increased oxidant production and increased susceptibility to cell death. NO reversibly binds to the oxygen binding site of cytochrome oxidase, reacting either with the oxidised copper to give inhibitory nitrite, or with the reduced haem, resulting in reversible inhibition in competition with oxygen. Because of this competition, NO may sensitise tissues to hypoxia. NO, or derivative N(2)O(3) or S-nitrosothiols, may inactivate complex I by S-nitrosation. Peroxynitrite (ONOO(-)) inhibits mitochondrial respiration at multiple sites, and also causes mitochondrial permeability transition. Inhibition of mitochondrial respiration by NO and its derivatives stimulates production of reactive oxygen and nitrogen species by mitochondria, which have signalling roles in the heart, but may also contribute to cell death. In the heart, NO is produced by endothelial NO synthase (eNOS) in endothelium and caveolae of cardiomyocytes, by neuronal NO synthase (nNOS) in sarcoplasmic reticulum and possibly mitochondria, and under pathological situations by inducible NO synthase (iNOS) in the sarcoplasm. Haemoglobin and myoglobin may have multiple roles in determining oxygen and NO gradients within the heart, which may remove NO at high oxygen, but possibly supply it at low oxygen. Stimulating or inhibiting NOS in the heart has been found to cause small changes in heart oxygen consumption in vivo; however, it is still unclear whether these changes are due to direct NO inhibition of mitochondrial respiration or indirect actions of NO. NO inhibition of mitochondrial respiration is likely to be more important in the heart during hypoxia and/or pathologies where iNOS is expressed.
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PMID:Nitric oxide and mitochondrial respiration in the heart. 1746 59


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