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At least 19 recordsLinked to original sources
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↗
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↗
PubMedDate not supplied

The impact of diabetes on CNS. Role of bioenergetic defects.

To address the problem of the pathogenesis in diabetic neuropathy, rats were made diabetic by streptozotocin administration, and discrete brain regions, such as cortex, cerebellum, brainstem, thalamus, and hypothalamus, were sampled for assay of activities of electron transport chain complexes I-IV at 1 and 3 mo after induction of diabetes. Significant decrease was seen in activities of dinitrophenylhydrazine DNPH-coenzyme Q reductase (complex I), coenzyme Q cytochrome-c reductase (complex III), and cytochrome-c oxidase (complex IV) from discrete brain regions with more pronounced changes in complex I. The decline in the complex I, III, and IV activity was more severe in the 3-mo group. Succinate dehydrogenase (SDH) coenzyme Q reductase (complex II), which is an enzyme shared by tricarboxylic acid (TCA) cycle and electron transport chain, showed a significant increase under the same set of conditions. These results suggest that the bioenergetic impairment has an important role in the pathophysiology of diabetes.

Animals↗
PubMed1995

Postnatal development of the complexes of the electron transport chain in synaptic mitochondria from rat brain.

The postnatal development of the complexes of the electron transport chain in mitochondria isolated from rat brain synaptosomes was investigated. Synaptosomal brain mitochondria were isolated from rats aged 10-60 days, and the activities of mitochondrial complex I, complex II-III, complex IV and complex V were measured. There was a significant increase in the activity of II-III from day 10 to day 15 and complex IV from day 10 to day 21, thereafter the activities of complexes I-III and IV did not change significantly. The activity of complex I did not change significantly during the period 10-60 days post partum. In synaptic mitochondria, complex V activity was higher than in non-synaptic mitochondria, whereas the activity of complex I was lower than in non-synaptic mitochondria. These data show that the complexes of the respiratory chain within synaptic mitochondria have activities different from those of non-synaptic mitochondria and may have major implications for the relative susceptibility of mitochondria in different brain cell types to neurotoxins such as MPP+, hypoxic/ischaemic damage and oxidative stress.

Acetylcholinesterase↗
PubMed1983

Mitochondrial complexes I, II, III, IV, and V in myocardial ischemia and autolysis.

Ischemic myocardium was produced by occluding the left circumflex coronary artery in anesthetized dogs. Autolyzed myocardium was produced by incubating transmural samples of canine left ventricle at 37 degrees C. Tissue pH was recorded continuously in each model using a microcombination pH electrode impaled into the midmyocardium. The activities of the five mitochondrial inner membrane enzyme complexes of electron transport and coupled oxidative phosphorylation were assayed as a function of time of ischemia or autolysis. While the activities of complex II (succinate-CoQ reductase) and IV (cytochrome c oxidase) were completely stable, that of complex I (NADH-CoQ reductase) decreased markedly, but largely only after 20 min of ischemia or autolysis. At 20 min and beyond, the decrease in the activity of complex I paralleled closely the decrease in whole mitochondrial oxygen uptake with NAD-linked substrates in both models. The activity of complex III (CoQH2-c reductase) decreased at a more gradual rate during ischemia or autolysis, and its rate of decrease paralleled that of succinate-supported oxygen uptake. The activity of complex V (oligomycin-sensitive ATPase) decreased most rapidly (by 40% in only 5 min of autolysis) but nearly leveled off beyond 20 min in the two models. A strikingly similar pattern of differential enzyme lability was observed in isolated control mitochondria incubated at lowered pH values. The results demonstrate 1) differential enzyme lability within the mitochondrial inner membrane, 2) a connection between severity of acidosis and the degree of enzyme activity loss, and 3) the usefulness of simple tissue autolysis as an analogue of in situ myocardial ischemia.

Adenosine Triphosphatases↗
PubMed1993

Changes in skeletal muscle, heart and liver mitochondrial electron transport activities in rats and dogs of various ages.

We determined skeletal muscle, heart and liver mitochondrial electron transport activities in rats and dogs of various ages. In the skeletal muscle mitochondria, decrease in the activity of complex I was observed in rats aged 28 weeks, and further reduction of the activity was observed in rats aged 55 weeks. A significant decrease in complex IV activity was observed in rats aged 55 weeks. No significant reduction in complex II and III activities were observed in rats aged up to 100 weeks. Significant decreases in complex I and IV activities were observed in heart muscles of rats aged 100 weeks, while no significant changes in the activity of complex I in liver mitochondria were observed in rats aged up to 100 weeks. Similar results were obtained in dogs, i.e., the activity of complex I was the most susceptible to aging among the activities of complexes; and skeletal muscle mitochondria were the most susceptible to aging among the tissues. From our results, involvement of mitochondria in the development of age-related decline in cellular function is especially emphasized in post mitotic cells, and age-associated mitochondrial functional changes are stressed in mitochondrial complexes which contain mitochondrial DNA-encoded subunits.

Aging↗
PubMed2002

Mitochondrial DNA and respiratory chain function in spinal cords of ALS patients.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective motor neuron death. In order to address the question of a putative role of mitochondrial dysfunction in the pathogenesis of ALS, we studied the mitochondrial DNA (mtDNA) and mitochondrial respiratory chain enzyme activities in spinal cords of ALS patients and in control subjects without neuropathologic abnormalities. Using a "double PCR and digestion" technique to estimate the levels of randomly distributed point mutations in two small regions of the mtDNA, we found significantly higher levels of mutant mtDNA in the spinal cord of ALS patients compared to controls. No large-scale rearrangements were found, but the amount of mtDNA, measured by Southern blot, was significantly lower in the ALS samples. This reduction correlated well with a decrease of citrate synthase (CS) activity, a mitochondrial marker, as were the activities of respiratory chain complexes I + III, II + III, and IV, suggesting a loss of mitochondria in ALS spinal cords.

Adult↗
PubMed2001

Effect of hypoenergetic feeding and refeeding on muscle and mononuclear cell activities of mitochondrial complexes I--IV in enterally fed rats.

BACKGROUND: Previous studies suggested that cell energetics are altered by malnutrition. OBJECTIVE: We hypothesized that nutritional manipulations influence mitochondrial enzyme activities of the electron transport chain in both skeletal muscle and blood mononuclear cells. DESIGN: After a gastrostomy tube was inserted, 44 rats were randomly assigned to 1 of 4 experimental groups: control fed (CF; 364 kJ/d for 7 d), hypoenergetic fed (HF; 92 kJ/d for 7 d), hypoenergetic protein refed (HPR; 92 kJ/d for 7 d and then 129 kJ/d for 1 d), and hypoenergetic glucose refed (HGR; 92 kJ/d for 7 d and then 129 kJ/d for 1 d). The protein and glucose contents of the liquid formulas were different for the HPR and HGR groups. After mitochondria were isolated from the soleus muscle, the activities of complexes I--IV were measured spectrophotometrically. Because of the lack of available tissue, only the activity of complex I was measured in the mononuclear cell extract. RESULTS: The recovery of complex activities in the CF and HF groups was not significantly different in the mitochondrial fraction of the soleus muscle. Compared with that in the CF group, the activities of complexes I--III in the mitochondrial fraction of the soleus muscle and the activity of complex I in mononuclear cells were significantly lower in the HF group. The activities of complexes I--III in the mitochondrial fraction of the soleus muscle and the activity of complex I in mononuclear cells were significantly higher in the HPR than in the HF group. The activity of complex IV was generally not affected by nutritional manipulations. CONCLUSION: Malnutrition decreases activities of mitochondrial complexes, which are restored by protein but not glucose refeeding.

Adenosine Triphosphate↗
PubMed2001

Glutathione depletion, lipid peroxidation and mitochondrial dysfunction are induced by chronic stress in rat brain.

Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neurodegenerative disorders. We have previously demonstrated that chronic stress induced an increase in nitric oxide (NO) production via an expression of inducible NO synthase (iNOS) in brain. Since it has been demonstrated that NO regulates mitochondrial function, we sought to study the susceptibility of the mitochondrial respiratory chain complexes to chronic restrain stress exposure in brain cortex. In adult male rats, stress (immobilization for six hours during 21 days) inhibits the activities of the first complexes of the mitochondrial respiratory chain (inhibition of 69% in complex I-III and of 67% in complex II-III), without affecting complex IV activity, ATP production and oxygen consumption. The mitochondrial marker citrate synthase is not significantly affected by stress after 21 days, indicating that at this time the mitochondrial structure is still intact. Moreover, the administration of the preferred inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine (400 mg/kg i.p. daily from days 7 to 21 of stress) protects against the inhibition of the activity of complexes of the mitochondrial respiratory chain as well as prevents NO(x)(-) accumulation, lipid peroxidation and glutathione depletion induced by stress. These results suggest that a sustained overproduction of NO via iNOS is responsible, at least in part, of the inhibition of mitochondrial respiratory chain caused by stress and that this pathway also accounts for the oxidative stress found in this situation.

Adenosine Triphosphate↗
PubMed1991

Functional respiratory chain studies in subjects with chronic progressive external ophthalmoplegia and large heteroplasmic mitochondrial DNA deletions.

The functional consequences of large heteroplasmic mtDNA deletions were investigated in a group of 6 patients with chronic progressive external ophthalmoplegia (CPEO) syndromes. State III respiration rates corrected for age were low with site I and II substrates in all cases and cytochrome oxidase activity was depressed. The severity of impairment varied and is consistent with inclusion of a variable percentage of non-functioning mitochondria (with deleted mtDNA) in the pellet. Western blot studies with a holocomplex antibody battery revealed no abnormalities in subunit content of complexes III and IV. A deficiency of several complex I subunits in 3 cases suggests that abnormal nuclear-mitochondrial regulation of complex I assembly may follow large mtDNA deletions.

Adult↗
PubMed1989

Deficiencies in complex I subunits of the respiratory chain in Parkinson's disease.

Immunoblotting studies on mitochondria prepared from the striata of patients who died of Parkinson's disease were performed using specific antisera against Complexes I, III and IV. In 4 out of 5 patients with Parkinson's disease, the 30-, 25- and 24-kDa subunits of Complex I were moderately to markedly decreased. No clear difference was noted in immunoblotting studies on subunits of Complexes III and IV between the control and Parkinson's disease. Deficiencies in Complex I subunits seem to be one of the most important clues to elucidate pathogenesis of Parkinson's disease.

Corpus Striatum↗
PubMed1996

Mitochondrial dysfunction in spontaneous inbred turkey cardiomyopathy.

Mitochondrial enzyme activities were examined in cardiac tissues of turkeys with spontaneous inbred cardiomyopathy. Marked declines in specific enzyme activities were noted for respiratory complexes III and V ranging from 65-90% of the control values. No significant differences in complexes I, IV and citrate synthase nor in mitochondrial DNA copy number were detected. These results suggest that specific mitochondrial enzyme defects occur in cardiac tissues during spontaneous inbred turkey cardiomyopathy.

Animals↗
PubMed1995

Enzymatic activities of mitochondrial respiratory complexes from children muscular biopsies. Age-related evolutions.

Measurements were performed to determine maximum enzymatic activities of citrate synthetase and respiratory complexes I, III, and IV of mitochondria obtained from muscular biopsies in control children. The significant number of determinations carried out (43 different biopsies in controls aged 3.8 to 19.1 years) permits the formulation of a table of statistically validated reference values for these activities. These values are independent of sex of the controls, and of the studied muscles. Citrate synthetase activity, which remains stable in this age range, thus constitutes a good internal indicator of mitochondrial activity. Complexes I and III manifest activity which does not vary with age. On the other hand, cytochrome oxidase activity shows a highly significant decrease in this age group. This decrease may be correlated with qualitative changes (subunits VIa and VIIa) in composition of this complex.

Adolescent↗
PubMed1988

Proton/electron stoichiometry of mitochondrial complex I estimated from the equilibrium thermodynamic force ratio.

The thermodynamic forces on electrons (delta Eh) and protons (delta p) across mitochondrial complexes I, III and IV were measured in isolated mitochondria respiring on succinate. The force ratio (delta Eh/delta p) across complex I close to equilibrium was found to be about 2. The equilibrium force ratio across complex I was measured during sulphite oxidation and was again close to 2. These results indicate that the proton/electron stoichiometry of complex I is 2, in conditions of high protonmotive force.

3-Hydroxybutyric Acid↗
PubMed1988

Myxothiazol resistance in human mitochondria.

We have investigated electron transfer activities of respiratory chain complexes in platelet mitochondria of a patient with intermittent ataxia and lactic acidosis who was previously reported to be deficient in the E1 (decarboxylase) component of the pyruvate dehydrogenase complex. Electron transfer from succinate to cytochrome c was normal, but the mitochondria exhibited moderately decreased (63% of control) quinol: cytochrome-c oxidoreductase activity, suggesting a defect in complex III. Consistent with some perturbation in complex III, electron flux through complex III was resistant to inhibition by myxothiazol compared to normal controls. In contrast, titration with antimycin revealed a less abnormal pattern of inhibition. The extreme specificity of myxothiazol binding at or near the quinol oxidase domain of mitochondrial cytochrome b, i.e., b-566, suggests a defect in this region of complex III which may perturb the kinetics or thermodynamics of quinol oxidation in the complex. These data suggest that the patient's illness results from a mutation in the quinol oxidase domain of mitochondrial cytochrome b (b-566).

Acidosis, Lactic↗
PubMed1992

Global ischaemia induces a biphasic response of the mitochondrial respiratory chain. Anoxic pre-perfusion protects against ischaemic damage.

Studies of Langendorff-perfused rat hearts have revealed a biphasic response of the mitochondrial respiratory chain to global ischaemia. The initial effect is a 30-40% increase in the rate of glutamate/malate oxidation after 10 min of ischaemia, owing to an increase in the capacity for NADH oxidation. This effect is followed by a progressive decrease in these oxidative activities as the ischaemia is prolonged, apparently owing to damage to Complex I at a site subsequent to the NADH dehydrogenase component. This damage is exacerbated by reperfusion, which causes a further decrease in Complex I activity and also decreases the activities of the other complexes, most notably of Complex III. Perfusion for up to 1 h with anoxic buffer produced only the increase in NADH oxidase activity, and neither anoxia alone, nor anoxia and reperfusion, caused loss of Complex I activity. Perfusing for 3-10 min with anoxic buffer before 1 h of global ischaemia had a significant protective effect against the ischaemia-induced damage to Complex I.

Animals↗
PubMed1984

Cytochrome c mediates electron transfer between ubiquinol-cytochrome c reductase and cytochrome c oxidase by free diffusion along the surface of the membrane.

Ubiquinol oxidase can be reconstituted from ubiquinol-cytochrome c reductase (Complex III) and cytochrome c oxidase (Complex IV) whose endogenous phosphatidylcholine and phosphatidylethanolamine have been replaced by dimyristoylglycerophosphocholine. Phase transition of the lipid has no effect on Complex III and Complex IV activities assayed separately, but ubiquinol oxidase activity rapidly decreases as the temperature is lowered through the phase transition. A spin-labelled yeast cytochrome c derivative has been synthesized. Binding of the cytochrome c to liposomes demonstrates that only cardiolipin is involved under the conditions used for the ubiquinol oxidase experiments. In liposomes consisting of cardiolipin and dimyristoylglycerophosphocholine, e.s.r. (electron-spin-resonance) measurements show that rotational diffusion of cytochrome c is slowed in the gel phase of the latter lipid. We propose that the cytochrome c pool is bound to cardiolipin molecules, whose lateral and rotational diffusion in the bilayer is adequate to account for electron-transport rates.

Cell Membrane↗