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At least 19 recordsLinked to original sources
PubMed1996

The effects of nitric oxide on electron transport complexes.

The effect of nitric oxide on mitochondrial electron transfer complexes was studied by comparing the activities of nitric oxide-treated and untreated, deoxygenated samples of purified beef heart succinate-cytochrome c reductase, succinate-ubiquinone reductase, and ubiquinol-cytochrome c reductase. More than 90% of succinate-cytochrome c reductase activity is lost during nitric oxide treatment. The activity of the succinate-ubiquinone reductase component of succinate-cytochrome c reductase decreases 95%, while the ubiquinol-cytochrome c reductase component is unaffected by nitric oxide. This inactivation is due primarily to the destruction of iron-sulfur clusters from succinate-ubiquinone reductase. When purified beef heart succinate-ubiquinone reductase was treated with nitric oxide, virtually all activity was irreversibly lost. The electron paramagnetic resonance (EPR) spectra of the treated complex showed typical iron-nitric oxide complex signals, confirming that inactivation is due to destruction of the iron-sulfur clusters. Similar results were obtained with purified Escherichia coli succinate-ubiquinone reductase. Pure beef heart ubiquinol-cytochrome c reductase treated with nitric oxide loses 40% of its initial activity, but regains most of it (90-100 % after 24 h of incubation at 0 degrees C in the absence of nitric oxide. This suggests that ubiquinol-cytochrome c reductase is protected from nitric oxide when complexed with succinate-ubiquinone reductase or that when split from succinate-ubiquinone reductase, ubiquinol-cytochrome c reductase undergoes a conformational change which allows access of nitric oxide to the Rieske iron-sulfur center. Such access is not possible when ubiquinol-cytochrome c reductase is complexed with succinate-ubiquinone reductase. The loss of ubiquinol-cytochrome c reductase activity correlates with a decrease in the Rieske protein EPR signal intensity without formation of any new EPR signal. The Rieske iron-sulfur cluster signal is recovered after 24 h incubation in the absence of nitric oxide.

Animals↗
PubMed2003

Mass spectrometric characterization of mitochondrial electron transport complexes: subunits of the rat heart ubiquinol-cytochrome c reductase.

Complex III of the mitochondrial electron transport chain, ubiquinol-cytochrome c reductase, was isolated by blue native polyacrylamide gel electrophoresis. Ten of the 11 polypeptides present in this complex were detected directly by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) following electroelution of the active complex. Tryptic and chymotryptic digestion of the complex permit the identification of specific peptides from all of the protein subunits with 70% coverage of the 250 kDa complex. The mass of all 11 proteins was confirmed by second dimension Tricine sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and elution of the separated polypeptides. Additionally, the identity of the core I, core II, cytochrome c and the Rieske iron-sulfur protein were confirmed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) characterization of the peptides generated by in-gel trypsin digestion of the SDS-PAGE separated proteins. The methodology demonstrated for analyzing this membrane-bound electron transport complex should be applicable to other membrane complexes, particularly the other mitochondrial electron transport complexes. The MS analysis of the peptides obtained by in-gel digestion of the intact complex permits the simultaneous characterization of the native proteins and modifications that contribute to mitochondrial deficits that have been implicated as contributing to pathological conditions.

Amino Acid Sequence↗
PubMed2000

Age-related changes in activities of mitochondrial electron transport complexes in various tissues of the mouse.

The purpose of the present study was to examine the role of mitochondria in the aging process by determining whether the activities of various electron transport chain oxidoreductases are deleteriously affected during aging and whether the hypothesized age-related alterations in different tissues follow a common pattern. Activities of respiratory complexes I, II, III, and IV were measured in mitochondria isolated from brain, heart, skeletal muscle, liver, and kidney of young (3.5 months), adult (12-14 months), and old (28-30 months) C57BL/6 mice. Activities of some individual complexes were decreased in old animals, but no common pattern can be discerned among various tissues. In general, activities of the complexes were more adversely affected in tissues such as brain, heart, and skeletal muscle, whose parenchyma is composed of postmitotic cells, than those in the liver and kidney, which are composed of slowly dividing cells. The main feature of age-related potentially dysfunctional alterations in tissues was the development of a shift in activity ratios among different complexes, such that it would tend to hinder the ability of mitochondria to effectively transfer electrons down the respiratory chain and thus adversely affect oxidative phosphorylation and/or autooxidizability of the respiratory components.

Aging↗
PubMed2006

Electron transport complex I is required for CD8+ T cell function.

After Ag encounter, CD8+ T cells become activated and begin to proliferate. Early during infection, when Ag-specific effector CD8+ T cells are proliferating, producing cytokines, and lysing infected cells in vivo, their mitochondrial potential is increased. The purpose of the experiments presented here was to determine whether mitochondrial function was required for CD8+ T cell function. To block mitochondrial function, transgenic CD8+ T cells were incubated with increasing doses of rotenone, an inhibitor of electron transport complex I. Within minutes of T cell activation, rotenone incubation decreased the production of H(2)O(2), calcium flux, and ERK1/2 phosphorylation. Failure to undergo signal transduction resulted in a decrease in T cell division initiated by peptide-coated cells, CD3/CD28 Abs, and PMA/ionomycin stimulation. Decreased function following rotenone incubation was not restricted to naive cells, as effector and memory CD8+ T cells isolated directly ex vivo from lymphocytic choriomeningitis virus-infected mice displayed decreased production of IFN-gamma and TNF-alpha production after peptide stimulation. Furthermore, incubation with rotenone decreased degranulation of effector and memory cells, a critical step in the cytolysis of infected cells. These data suggest that electron transport complex I is required for CD8+ T cell signal transduction, proliferation, cytokine production, and degranulation.

Animals↗
PubMed2001

Aging decreases electron transport complex III activity in heart interfibrillar mitochondria by alteration of the cytochrome c binding site.

Aging alters cardiac physiology and structure and enhances damage during ischemia and reperfusion. Aging selectively decreases the rate of oxidative phosphorylation in the interfibrillar population of cardiac mitochondria (IFM) located among the myofibers, whereas subsarcolemmal mitochondria (SSM) located beneath the plasma membrane remain unaffected. Aging decreased the rate of oxidative phosphorylation using durohydroquinone, an electron donor to complex III, in IFM only. Complex III activity was decreased in IFM, but not SSM. Aging did not alter the content of catalytic centers of complex III (cytochromes b and c(1)and iron-sulfur protein). Complex III activity measured at physiologic ionic strength in IFM from aging hearts was decreased by 49% compared to IFM from adults, whereas activity measured at low ionic strength was unchanged, localizing the aging defect to the cytochrome c binding site of complex III. Subunits VIII and X of the cytochrome c binding site were present in complex III with the aging defect, indicating that loss of subunits did not occur. Study of aging damage to complex III will help clarify the contribution of altered electron transport in IFM to increased oxidant production during aging, formation of the aging cardiac phenotype, and the relationship of aging defects to increased damage following ischemia.

Aging↗
PubMed1999

Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium.

Oxidative stress in the myocardium may play an important role in the pathogenesis of congestive heart failure (HF). However, the cellular sources and mechanisms for the enhanced generation of reactive oxygen species (ROS) in the failing myocardium remain unknown. The amount of thiobarbituric acid reactive substances increased in the canine HF hearts subjected to rapid ventricular pacing for 4 weeks, and immunohistochemical staining of 4-hydroxy-2-nonenal ROS-induced lipid peroxides was detected in cardiac myocytes but not in interstitial cells of HF animals. The generation of superoxide anion was directly assessed in the submitochondrial fractions by use of electron spin resonance spectroscopy with spin trapping agent, 5, 5'-dimethyl-1-pyrroline-N-oxide, in the presence of NADH and succinate as a substrate for NADH-ubiquinone oxidoreductase (complex I) and succinate-ubiquinone oxidoreductase (complex II), respectively. Superoxide production was increased 2.8-fold (P<0.01) in HF, which was due to the functional block of electron transport at complex I. The enzymatic activity of complex I decreased in HF (274+/-13 versus 136+/-9 nmol. min(-1). mg(-1) protein, P<0.01), which may thus have caused the functional uncoupling of the respiratory chain and the deleterious ROS production in HF mitochondria. The present study provided direct evidence for the involvement of ROS in the mitochondrial origin of HF myocytes, which might be responsible for both contractile dysfunction and structural damage to the myocardium.

Animals↗
PubMed2003

Reduction of mitochondrial electron transport complex activity is restricted to the ischemic focus after transient focal cerebral ischemia in rats: a histochemical volumetric analysis.

Using histochemical methods offering high topographical resolution for evaluation of changes in the ischemic focus and the penumbra, the mitochondrial electron transport chain (ETC) complexes I, II, and IV were examined in rats subjected to 2 h of proximal occlusion of the middle cerebral artery (MCAO) followed by no reperfusion, 1 h reperfusion, 4 h reperfusion, or 4 h reperfusion plus treatment with the free radical scavenger alpha-PBN. Serial brain cryosections were histochemically stained to visualize activity of complexes I, II, and IV, and the volumes of tissue with reduced activity in the ipsilateral cortex and caudate putamen were measured by densitometric image analysis. Reductions in complex I, II, and IV activity were restricted to areas in the ischemic foci in cortex and caudate putamen, which microscopically displayed signs of early morphological damage. In cortex, the tissue volume with reduced activity did not change significantly during reperfusion but progressively increased in the caudate putamen, possibly reflecting a faster maturation of morphological damage in this region. Treatment with alpha-PBN did not affect the observed reductions in activities. We deduce that inhibition of mitochondrial ETC complex activity does not play a critical role for recruitment of the penumbra in the infarction process.

Animals↗
PubMed2001

Ischemic injury to mitochondrial electron transport in the aging heart: damage to the iron-sulfur protein subunit of electron transport complex III.

The aging heart sustains greater injury during ischemia and reperfusion compared to adult hearts. Aging decreases oxidative function in interfibrillar mitochondria (IFM) that reside among the myofibers, while subsarcolemmal mitochondria (SSM), located beneath the plasma membrane, remain unaltered. Aging decreases complex III activity selectively in IFM via alteration of the cytochrome c binding site. With 25 min of global ischemia, complex III activity decreases in SSM and further decreases in IFM in the aging heart. Ischemia leads to a marked decrease in the electron paramagnetic resonance signal of the iron-sulfur protein (ISP) in both SSM and IFM, despite a preserved content of ISP peptide. Thus, ischemia results in a functional decrease in the iron-sulfur center in ISP without subunit peptide loss. In the aging heart, at the onset of reperfusion, IFM contain two tandem defects in the path of electron flow through complex III, providing a likely mechanism for enhanced oxidant production and reperfusion damage.

Age Factors↗
PubMed2002

Reactive oxygen species affect mitochondrial electron transport complex I activity through oxidative cardiolipin damage.

The aim of this study was to investigate the influence of reactive oxygen species (ROS) on the activity of complex I and on the cardiolipin content in bovine heart submitochondrial particles (SMP). ROS were generated through the use of xanthine/xanthine oxidase (X/XO) system. Treatment of SMP with X/XO resulted in a large production of superoxide anion, detected by acetylated cytochrome c method, which was blocked by superoxide dismutase (SOD). Exposure of SMP to ROS generation resulted in a marked loss of complex I activity and to parallel loss of mitochondrial cardiolipin content. Both these effects were completely abolished by SOD+catalase. Exogenous added cardiolipin was able to almost completely restore the ROS-induced loss of complex I activity. No restoration was obtained with other major phospholipid components of the mitochondrial membrane such as phosphatidylcholine and phosphatidylethanolamine, nor with peroxidized cardiolipin. These results demonstrate that ROS affect the mitochondrial complex I activity via oxidative damage of cardiolipin which is required for the functioning of this multisubunit enzyme complex. These results may prove useful in probing molecular mechanisms of ROS-induced peroxidative damage to mitochondria, which have been proposed to contribute to those pathophysiological conditions characterized by an increase in the basal production of reactive oxygen species such as aging, ischemia/reperfusion and chronic degenerative diseases.

Aminoacridines↗
PubMed2004

Oxidatively damaged proteins of heart mitochondrial electron transport complexes.

Protein modifications, such as carbonylation, nitration and formation of lipid peroxidation adducts, e.g. 4-hydroxynonenal (HNE), are products of oxidative damage attributed to reactive oxygen species (ROS). The mitochondrial respiratory chain Complexes I and III have been shown to be a major source of ROS in vitro. Additionally, modifications of the respiratory chain Complexes (I-V) by nitration, carbonylation and HNE adduct decrease their enzymatic activity in vitro. However, modification of these respiratory chain complex proteins due to in vivo basal level ROS generation has not been investigated. In this study, we show a basal level of oxidative damage to specific proteins of adult bovine heart submitochondrial particle (SMP) complexes, and find that most of these proteins are localized in the mitochondrial matrix. We postulate that electron leakage from respiratory chain complexes and subsequent ROS formation may cause damage to specific complex subunits and contribute to long-term accumulation of mitochondrial dysfunction.

Adenine Nucleotide Translocator 1↗
PubMed1983

The cytochrome f-b electron-transport complex. A common link between photosynthesis and respiration in the cyanobacterium Anacystis nidulans.

Reduced-minus-oxidized difference spectra were recorded on particle preparations of the cyanobacterium Anacystis nidulans. Physiological oxidation of anaerobic membranes was effected either by O2 or by light. In both cases the spectral changes observed in the 550-570nm region were essentially the same. The results were confirmed by dual-wavelength spectrophotometry. It is concluded that a membrane-bound cytochrome f-b complex participates in both respiratory and photosynthetic elevtron transport.

Cell Membrane↗
PubMed1984

Stoichiometries of electron transport complexes in spinach chloroplasts.

The stoichiometric relationship among photosystem II complexes, photosystem I complexes, cytochrome b/f complexes, high-potential cytochrome b-559, and chlorophyll in spinach chloroplasts has been determined. Two features of this data stand out, in contrast to currently proposed stoichiometries in which the ratio of photosystem II to photosystem I is reported to be 2:1 and the chlorophyll to reaction center ratio to be as low as 260:1. Using a variety of techniques it was found that the stoichiometry of photosystem II:photosystem I:cytochrome b/f complex was 1:1:1, within 10%, and that the ratio of total chlorophyll to these components was 600:1, also within 10%. A ratio of two high-potential cytochrome b-559 molecules per 640 chlorophyll, or two molecules per photosystem II reaction center, was found. These ratios were remarkably constant regardless of the time of year or the source of the spinach. The concentration of photosystem II complexes was determined using a pH electrode to measure the flash-induced proton release resulting from water oxidation. The photosystem I reaction center concentration was measured by two different techniques that compared favorably. In the first method a pH electrode was used to measure the amount of flash-induced proton consumption associated with the 3-(3,4-dichlorophenyl)-1,1-dimethylurea-insensitive oxidation of N,N,N',N'- tetramethylphenylenediamine , resulting in the production of hydrogen peroxide. In the second method the amount of P700 oxidized by far-red light was determined using dual-wavelength spectroscopy. The concentration of the cytochrome b/f complex was determined assuming 1 mol of cytochrome f per complex. The concentration of cytochrome f was measured spectroscopically by its light-induced turnover and by chemical difference spectra. The concentration of high-potential cytochrome b-559 was determined by chemical difference spectra. In addition to these studies, the light-induced absorbance change exhibiting a peak at 323 nm that has been attributed to the reduction of the primary quinone acceptor of photosystem II has been investigated. This measurement frequently has been used to quantitate the photosystem II to chlorophyll ratio. However, in view of these results it is argued that this technique significantly overestimates the photosystem II concentration.

Chlorophyll↗
PubMed1995

Low platelet mitochondrial complex I and complex II/III activity in early untreated Parkinson's disease.

Following the discovery of inhibition of electron transport complex 1 by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces a parkinsonian syndrome in humans, monkeys, and mice, several laboratories have reported abnormalities of complex I and other electron transport complexes (ETCs) in various tissues from patients with Parkinson's disease (PD). Criticism of the significance of these findings in the etiology of PD has centered on whether drug treatments or the debilitation of the disease process itself produced the low ETC activities. We present results from a blinded study of platelet mitochondrial ETC activities in 18 early untreated PD patients and 18 age- and sex-matched controls and in 13 spousal controls. Lower complex I activity in platelet mitochondria of PD patients was seen in early untreated disease and thus cannot be due to debilitation or drug therapy. Home environmental factors seem an unlikely explanation for the reduced complex I activity in PD patients but have not been excluded. Complex II/III activity was also reduced by 20% in PD compared with age-/sex-matched controls. The low complex I and II/III activities in platelet mitochondria appear to be related to the etiology of PD.

Adult↗
PubMed2002

Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease that causes degeneration of motoneurons. Mutation of Cu,Zn superoxide dismutase (SOD1) is one cause for this disease. In mice, expression of mutant protein causes motoneuron degeneration and paralysis resembling the human disease. Morphological change, indicative of mitochondrial damage, occurs at early stages of the disease. To determine whether mitochondrial function changes during the course of disease progression, enzyme activities of mitochondrial electron transport chain in spinal cords from mice at different disease stages were measured using three different methods: spectrophotometric assay, in situ histochemical enzyme assay, and blue native gel electrophoresis combined with in-gel histochemical reaction. The enzyme activities were decreased in the spinal cord, particularly in the ventral horn, beginning at early disease stages. This decrease persisted throughout the course of disease progression. This decrease was not detected in the spinal cords of non-transgenic animals, of mice expressing the wild-type protein, and in cerebellum and dorsal horn of the spinal cords from mice expressing mutant protein. These results demonstrate a functional defect in mitochondria in the ventral horn region and support the view that mitochondrial damage plays a role in mutant SOD1-induced motoneuron degeneration pathway.

Amyotrophic Lateral Sclerosis↗
PubMed1999

Regulation of tumor necrosis factor-induced, mitochondria- and reactive oxygen species-dependent cell death by the electron flux through the electron transport chain complex I.

Tumor necrosis factor (TNF) induces a caspase-independent but mitochondria-dependent cell death process in the mouse fibrosarcoma cell line L929. Mitochondria actively participate in this TNF-induced necrotic cell death by the generation of mitochondrial reactive oxygen species (ROS). The aim of this study was to identify the mitochondrial components involved in TNF-induced production of ROS and their regulation by bioenergetic pathways. Therefore, we analyzed the bioenergetic characteristics in two metabolic L929 variants that exhibit different sensitivities to TNF. L929gln cells use glutamine as respiratory substrate and are far more susceptible to TNF-induced ROS generation and cell death as L929glc cells that use glucose as respiratory substrate. We show that the higher levels of reducing NAD(P)H equivalents, detected in the desensitized L929glc cells, do not cause diminished ROS generation. To the contrary, TNF increases the levels of NAD(P)H, probably altering complex I activity. A multiparameter analysis of electron flux through the mitochondrial electron transport chain, TNF-induced ROS levels, and cell death convincingly demonstrates a dependence of TNF signaling on complex I activity. Also, the sensitizing effect of glutamine metabolism correlates with an enhanced contribution of complex I to the overall electron flux. This participation of complex I activity in TNF-induced cell death is regulated by substrate availability rather than by a direct modification of complex I proteins. From the results presented in this paper we conclude that TNF-induced ROS generation and cell death are strongly regulated by bioenergetic pathways that define electron flux through complex I of the electron transport chain.

Animals↗