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PubMed2005

The human mitochondrial proteome: oxidative stress, protein modifications and oxidative phosphorylation.

Mitochondria are one of the most complex of subcellular organelles and play key roles in many cellular functions including energy production, fatty acid metabolism, pyrimidine biosynthesis, calcium homeostasis, and cell signaling. In recent years, we and other groups have attempted to identify the complete set of proteins that are localized to human mitochondria as a way to better understand its cellular functions and how it communicates with other cell compartment in complex signaling pathways such as oxidative stress and apoptosis. Indeed, there is an increasing interest in understanding the molecular details of oxidative stress and the mitochondrial role in this process, as well as assessing how mitochondrial proteins become damaged or posttranslationally modified as a consequence of a major change in a cell's redox status. In this review, we report on the current status of the human mitochondrial proteome with an emphasis towards understanding how mitochondrial proteins, especially the proteins that make up the respiratory chain or oxidative phosphorylation (OXPHOS) enzymes, are modified in various models of age-related diseases such as cancer and Parkinson's disease (PD).

Cell Line, Tumor↗

PubMed1995

Bivascular liver perfusion in the anterograde and retrograde modes: zonation of the response to inhibitors of oxidative phosphorylation.

The action of cyanide (500 microM), 2,4-dinitrophenol (50 microM) and atractyloside (100 microM) on glycogen catabolism and oxygen uptake was investigated in the bivascularly perfused liver of fed rats. Cyanide, 2,4-dinitrophenol and attractyloside were infused at identical rates into the hepatic artery in either the anterograde or retrograde perfusion. The accessible aqueous cell spaces were determined by means of the multiple-indicator dilution technique. Glucose release, oxygen uptake and glycolysis were measured as metabolic parameters. Oxygen uptake changes per unit cell space caused by atractyloside (inhibition) and 2,4-dinitrophenol (stimulation) were equal in the retrograde perfusion (periportal cells) and the anterograde perfusion (space enriched in perivenous cells); the decreases caused by cyanide were higher in the retrograde perfusion. Glucose release from periportal cells was not increased upon inhibition of oxidative phosphorylation, a phenomenon which was independent of the mechanism of action of the inhibitor. There were nearly identical changes in glycolysis in the periportal and perivenous cells. It was concluded that: (1) oxygen concentration in the perfused rat liver, if maintained above 100 microM, had little influence on the zonation of the respiratory activity; (2) in spite of the lower activities of the key enzymes of glycolysis in the periportal hepatocytes, as assayed under standard conditions, these cells were as effective as the perivenous ones in generating ATP in the cytosol when oxidative phosphorylation was impaired; (3) the key enzymes of glycogenolysis and glycolysis in periportal and perivenous cells responded differently to changes in the energy charge.

2,4-Dinitrophenol↗

PubMed1981

Photoaffinity labeling of a mitochondrial hydrophobic protein by an anisotropic inhibitor of energy transduction in oxidative phosphorylation.

The monoazide derivative of ethidium, the parent compound of which is an anisotropic inhibitor of energy transduction in oxidative phosphorylation, was synthesized and shown to be useful as a photoaffinity probe. Results showed that monoazide ethidium specifically binds to a hydrophobic protein of mitochondria (with an apparent molecular weight of about 6200 in the presence of 0.1% sodium dodecyl sulfate). The molar binding ratios of monoazide ethidium to protein were about 5 and 17 with protein in the nonenergized and energized states, respectively. This protein differed from the dicyclohexylcarbodiimide-binding protein. We refer to this new hydrophobic protein, anisotropic inhibitor-binding protein, in this paper.

Affinity Labels↗

PubMed1982

Effect of uncoupling agents of oxidative phosphorylation on the spontaneous release of transmitter from insect motor nerve terminals.

1. The effect of uncoupling agents of oxidative phosphorylation, potassium warfarin and carbonylcyanide-p-trifluoromethoxy-phenylhydrazone (p-CCP), on the spontaneous release of transmitter was studied at the neuromuscular junction of cockroach muscles. 2. The agents produced a large increase in the frequency of occurrence of miniature excitatory postsynaptic potentials (MEPSPs). This increase also was observed in calcium-free saline. 3. The results may be explained on the hypothesis that the increase in the spontaneous release is due to the increase in free calcium concentration derived from an intracellular origin in the terminal. The mitochondria may play an important role in regulating the intracellular calcium concentration in the nerve terminals of insect muscles.

Animals↗

PubMed1997

Subunit rotation in Escherichia coli FoF1-ATP synthase during oxidative phosphorylation.

We report evidence for proton-driven subunit rotation in membrane-bound FoF1-ATP synthase during oxidative phosphorylation. A betaD380C/gammaC87 crosslinked hybrid F1 having epitope-tagged betaD380C subunits (betaflag) exclusively in the two noncrosslinked positions was bound to Fo in F1-depleted membranes. After reduction of the beta-gamma crosslink, a brief exposure to conditions for ATP synthesis followed by reoxidation resulted in a significant amount of betaflag appearing in the beta-gamma crosslinked product. Such a reorientation of gammaC87 relative to the three beta subunits can only occur through subunit rotation. Rotation was inhibited when proton transport through Fo was blocked or when ADP and Pi were omitted. These results establish FoF1 as the second example in nature where proton transport is coupled to subunit rotation.

Adenosine Diphosphate↗

PubMed1990

Myoplasmic phosphate metabolites in the integration of oxidative phosphorylation and contractile function in the myocardium.

The role of cytosolic concentrations of ADP, ATP, phosphocreatine, and Pi in the regulation of energy turnover in the myocardium has been investigated. For this purpose pool sizes of cytosolic adenine nucleotides or total creatine were significantly reduced, and creatine kinase activity completely inhibited. The findings show that the cytosolic ADP, the [ATP]/[ADP] ratio, and the phosphorylation potential are not uniformly related to the intensity of contractile function and the oxidative phosphorylation rate. Other mechanisms of coordination of these processes have to be taken into account.

Animals↗

PubMed1987

Enhancement of mitochondrial oxidative phosphorylation capability by hypoperfusion in isolated perfused rat heart.

To define alterations in myocardial mitochondrial function due to hypoperfusion, oxidative phosphorylation was simultaneously studied in 17 control (stable perfusion pressure) rat hearts and 17 hypoperfused isolated rat hearts. Hypoperfusion for 30 minutes was achieved by a reduction in coronary perfusion pressure from 77.8 +/- 1.2 mm Hg (mean +/- SEM) to 20.2 +/- 1.8 mm Hg in the experimental group (control perfusion pressure after 30 minutes 75.6 +/- 1.2). Hypoperfusion caused a reduction in left ventricular developed pressure to 20.5 +/- 1.5 mm Hg (versus control 74.8 +/- 3.3, p less than 0.0001), a reduction of coronary flow rate to 4.9 +/- 0.3 ml/min (versus control 19.4 +/- 1.2, p less than 0.0001), and a drop in myocardial oxygen consumption to 0.06 +/- 0.005 ml O2/min (versus control 0.17 +/- 0.01, p less than 0.0001). Myocardial lactate production was increased by hypoperfusion (3.0 +/- 0.6 mumol/min) compared with controls (0.7 +/- 0.5, p less than 0.02), but myocardial creatine kinase release was similar in the hypoperfused and control groups. Hypoperfusion was associated with an augmentation of state 3 mitochondrial respiration with glutamate and malate as respiratory substrates (448.8 +/- 14.0 ng atoms O/min/mg mitochondrial protein versus controls 290.7 +/- 13.4, p less than 0.001). When rates were normalized for mitochondrial malate dehydrogenase (MDHm), state 3 respiration was still increased in hypoperfused hearts (24.1 +/- 2.1 ng atoms O/min/IU MDHm) compared with controls (15.5 +/- 1.6, p less than 0.02). The rates of dinitrophenol-uncoupled electron transport were similar to the rates of state 3 respiration in both the hypoperfused and control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗

PubMed1992

Theoretical studies on the control of the oxidative phosphorylation system.

The dynamic model developed in our previous publications [1,2] was used to calculate the flux control coefficients of oxidation, phosphorylation and proton leak fluxes for isolated mitochondria and for three modes of work of intact cells (hepatocytes). The results obtained were compared with experimental data, especially those measured in the frame of the 'top-down approach' of the metabolic control theory. A good agreement for mitochondria and for intact cells was found. The control of the oxygen consumption flux is shared between the ATP utilization (main controlling factor), substrate dehydrogenation, proton leak and, in some conditions, the ATP/ADP carrier. The phosphorylation subsystem seemed to be controlled mainly by itself, while the proton leak was influenced by all three subsystems. It was also shown that the large relative change in the enzyme activity during inhibitor titration of mitochondria or cells could lead to the overestimation of some flux control coefficient values in experimental measurements. An influence of some hormones (glucagon, vasopressin, adrenaline and others) on the mitochondrial respiration was also simulated. Our results suggest that these hormones stimulate the substrate dehydrogenation as well as the phosphorylation system (ATP usage and, possibly, the ATP/ADP carrier).

Adenosine Triphosphate↗

PubMed2001

Parkinson's disease associated with impaired oxidative phosphorylation.

Parkinson's disease may be due to primary or secondary oxidative phosphorylation (OXPHOS) defects. In a 76-year-old man with Parkinson's disease since 1992, slightly but recurrently elevated creatine phosphokinase, recurrently elevated blood glucose, thickening of the left ventricular myocardium, bifascicular block and hypacusis were found. Cerebral MRI showed atrophy, periventricular demyelination, multiple, disseminated, supra- and infratentorial lacunas, and haemosiderin deposits in both posterior horns. Muscle biopsy showed typical features of an OXPHOS defect. Whether the association of Parkinson's disease and impaired OXPHOS was causative or coincidental remains unknown. Possibly, the mitochondrial defect acted as an additional risk factor for Parkinson's disease or the OXPHOS defect worsened the preexisting neurological impairments by a cumulative or synergistic mechanism. In conclusion, this case shows that Parkinson's disease may be associated with a mitochondrially or nuclearly encoded OXPHOS defect, manifesting as hypacusis, myopathy, axonal polyneuropathy, cardiomyopathy and recurrent subclinical ischaemic strokes and haemorrhages.

Aged↗

PubMedDate not supplied

Is there a calcium-caused defect of oxidative phosphorylation in cardiomyopathic hamster hearts?

Mitochondria from cardiomyopathic hamster hearts have elevated calcium levels, which may cause a defect of oxidative phosphorylation in a small fraction of them. Using a combination of dual labeling density-gradient centrifugation, it was not possible to isolate such an abnormal fraction. However, cardiomyopathic mitochondria are more susceptible to damage by calcium in vitro, suggesting that an abnormal fraction does exist nevertheless.

Animals↗

PubMed1992

Mitochondrial changes in phospholipid molecular species during the increased oxidative phosphorylation after hepatectomy.

The changes in liver mitochondrial and microsomal phospholipid molecular species were analyzed during the period of remarkably increased oxidative phosphorylation following partial hepatectomy in rabbits. At 24 hours after hepatectomy, phosphorylative activity increased significantly from 69.7 +/- 5.5 to 118.5 +/- 5.7 nmol of ATP synthesized/min/mg protein, compared to the sham operated group. The ratio of phosphatidylethanolamine to phosphatidylcholine (PE/PC) in mitochondria increased significantly in the hepatectomy group compared with the sham operated group. Remarkable changes in molecular species were observed in mitochondrial phosphatidylethanolamine. 1-Stearoyl-2-arachidonoyl species decreased in the hepatectomy group. On the other hand, microsomal phospholipids hardly changed compared with mitochondrial ones. The change in content of 1-stearoyl-2-arachidonyl phosphatidylethanolamine in mitochondria tended to return to normal levels concomitant with the normalization of phosphorylative activity. The changes in content of mitochondrial phospholipids, especially phosphatidylethanolamine, might also be related to enhancement of phosphorylative activity.

Animals↗

PubMed1987

An ATP/2e-stoichiometry of 1 1/2 is thermodynamically possible for site 3 of oxidative phosphorylation.

Free energy changes for ATP synthesis (delta GP) and 2e(-)-transfer across Site 3 (delta GR) were determined during oxidative phosphorylation by rat liver mitochondria. At static head, -delta GR/delta GP ranged narrowly between 1.55 and 1.59 with five different respiratory substrates. Thus, an ATP/2e- of 1 1/2 at Site 3 is thermodynamically possible with regards to overall reactants and products. Using nonequilibrium thermodynamics, phenomenological stoichiometries were close to 1 1/2 for all substrates suggesting that ATP/2e- at Site 3 is, in fact, 1 1/2. An ATP/2e- of 1 1/2 can only be possible if H+/O is 4 for cytochrome oxidase.

Adenosine Triphosphate↗

PubMed1994

SR-4233 (Tirapazamine) acts as an uncoupler of oxidative phosphorylation in human MCF-7 breast carcinoma cells.

SR-4233 (Tirapazamine) is a hypoxic cell selective cytotoxic agent currently in Phase I clinical trial. Although SR-4233 is selectively cytotoxic toward hypoxic cells some cytotoxicity toward normally oxygenated cells also occurs. SR-4233 (500 microM, 1 h) killed about 70% of normally oxygenated and 99% of hypoxic human MCF-7 breast carcinoma cells. Using a polarographic chamber and a Clark O2 electrode the O2 consumption of MCF-7 cells was measured in the presence or absence of SR-4233 (500 microM) or other inhibitors or uncouplers of oxidative phosphorylation. MCF-7 cells exhibited increased O2 consumption in the presence of SR-4233 alone and after treatment with oligomycin but not after treatment with retenone. The pattern of O2 consumption observed after treatment with SR-4233 was very similar to that seen when the cells were treated with the classical uncoupler FCCP. After 1 h of exposure to SR-4233 (500 microM) the cells were not responsive to treatment with oligomycin or FCCP for at least 3 h, but by 24 h post exposure to SR-4233 the cells had regained responsiveness to both FCCP and oligomycin. These results indicate that in normally oxygenated cells SR-4233 acts as an uncoupler of oxidative phosphorylation so that the cells continue to consume O2 but no ATP is produced. This condition can lead to ATP depletion especially in respiration intensive tissues and may provide an explanation for the muscle cramping observed in some patients treated with SR-4233.

Adenocarcinoma↗

PubMed2001

The ratio of oxidative phosphorylation complexes I-V in bovine heart mitochondria and the composition of respiratory chain supercomplexes.

The ratios of the oxidative phosphorylation complexes NADH:ubiquinone reductase (complex I), succinate:ubiquinone reductase (complex II), ubiquinol:cytochrome c reductase (complex III), cytochrome c oxidase (complex IV), and F1F0-ATP synthase (complex V) from bovine heart mitochondria were determined by applying three novel and independent approaches that gave consistent results: 1) a spectrophotometric-enzymatic assay making use of differential solubilization of complexes II and III and parallel assays of spectra and catalytic activities in the samples before and after ultracentrifugation were used for the determination of the ratios of complexes II, III, and IV; 2) an electrophoretic-densitometric approach using two-dimensional electrophoresis (blue native-polyacrylamide gel electrophoresis and SDS-polyacrylamide gel electrophoresis) and Coomassie blue-staining indices of subunits of complexes was used for determining the ratios of complexes I, III, IV, and V; and 3) two electrophoretic-densitometric approaches that are independent of the use of staining indices were used for determining the ratio of complexes I and III. For complexes I, II, III, IV, and V in bovine heart mitochondria, a ratio 1.1 +/- 0.2:1.3 +/- 0.1:3:6.7 +/- 0.8:3.5 +/- 0.2 was determined.

Animals↗

PubMed2002

Melatonin increases the activity of the oxidative phosphorylation enzymes and the production of ATP in rat brain and liver mitochondria.

We recently showed that melatonin counteracted mitochondrial oxidative stress and increased the activity of the mitochondrial oxidative phosphorylation (OXPHOS) enzymes both in vivo and in vitro. To further clarify these effects, we studied here the activity of OXPHOS enzymes and the synthesis of ATP in rat liver and brain mitochondria in vitro. In sub-mitochondrial particles, melatonin increases the activity of the complexes I and IV dose-dependently, the effect being significant between 1 and 10nM. Blue native-PAGE followed by histochemical analysis of the OXPHOS enzymes further showed the melatonin-induced increase of complex I activity. Titration studies show that melatonin counteracts the partial inhibition of complex IV induced by 5 microM potassium cyanide. However, melatonin (up to 5mM) was unable to recover the activity of complex IV when it was completely blocked by 100 microM cyanide. These data suggest that the indoleamine could stimulate the activity of the non-inhibited part of the complex IV. Melatonin also increases the production of ATP in control mitochondria and counteracts the cyanide-induced inhibition of ATP synthesis. These results provide new hormonal mechanism regulating mitochondrial homeostasis and may explain, at least in part, the anti-aging and neuroprotective properties of melatonin.

Adenosine Triphosphate↗

PubMed2002

Mitochondrial calcium ion and oxidative phosphorylation in regenerating rat liver.

BACKGROUND AND PURPOSE: Liver regeneration develops after partial hepatectomy. This study investigated the enhancement of oxidative phosphorylation in liver regeneration and its correlation to mitochondrial calcium ion in rats. METHODS: Respiratory functions of mitochondria isolated from regenerating rat liver 24, 48, 72, and 96 hours after 70% hepatectomy were studied including state 3 and state 4 oxygen consumption, respiratory control (RC) ratio, and ADP/O (molecules of adenosine diphosphate production per molecule of oxygen). Intramitochondrial matrix free calcium ion concentration ([Ca2+]m) was measured using the fluo-3 loading method. The changes in state 3 oxygen consumption and [Ca2+] were also evaluated in chloramphenicol-treated mitochondria, which were isolated from rats subjected to chloramphenicol injection for 48 hours. RESULTS: State 3 oxygen consumption was significantly enhanced 48 hours post-hepatectomy. The RC ratio also reached a peak value 48 hours after hepatectomy. No significant change was found in state 4 oxygen consumption and ADP/O during the first 96 hours after hepatectomy. The [Ca2+]m was significantly elevated as early as 24 hours post-hepatectomy, and reached its peak value 48 hours post-hepatectomy. The mitochondrial total calcium concentration was also elevated at 24 hours post-hepatectomy, but returned to near the control level 48 hours post-hepatectomy. In the chloramphenicol-treated group, state 3 oxygen consumption was depressed at 48 hours compared to the post-hepatectomy group, while the [Ca2+]m was significantly increased. CONCLUSIONS: The energy demand for liver regeneration is enhanced after partial hepatectomy. [Ca2+]m corresponds well to this energy demand, suggesting it may play an important role in the process of liver regeneration.

Animals↗

PubMed1991

[Oxidative phosphorylation in liver mitochondria in toxic form of experimental form of influenza].

The effect of free radical processes on the oxidation-phosphorylation activity in the liver of CBA-mice has been studied, using a model of toxic form viral infection. The EPR-spectroscopic and electrochemical methods applied in the study of animals infected with pathogenic form of the influenza virus made it possible to reveal a decrease in the activity of the respiratory chain in mitochondria. This seems likely to be due to accumulation of endogenic nitric oxide in the liver tissue.

Animals↗

PubMed1990

Oxidative phosphorylation system during steady-state hypoxia in the dog brain.

The relationship between biochemical and physiological responses and tissue O2 during hypoxia was investigated in vivo in the dog brain by 31P nuclear magnetic resonance (NMR) spectroscopy. Our findings demonstrate how ATP synthesis in the brain can be maintained during hypoxia because of compensatory changes in NADH, ADP, and Pi. Eleven beagle dogs were anesthetized and mechanically ventilated, and a steady-state graded hypoxia was induced by decreasing the fraction of inspired O2 (FIO2) stepwise at 20-min intervals. Biochemical metabolites were measured using 31P-NMR and fluorescence spectroscopy. When sagittal sinus O2 partial pressure (PVO2) had decreased to 15 Torr, NADH increased by 30%, Pi increased by 50%, and phosphocreatine (PCr) decreased by 20%. In contrast, ATP remained constant. There was a 10% increase in ADP in dogs that maintained a steady temperature, but ADP decreased by as much as 30% in dogs in which body temperature decreased with the falling PVO2. PCr/Pi was logarithmically related to the phosphorylation potential during steady-state hypoxia. Compensation for the O2 lack is attributed to increases in ADP, Pi, and NADH as a result of the reciprocal relationship of the Michaelis-Menten equation. If the Michaelis-Menten constants (Km) of ADP, Pi, and O2 are the same as determined in vitro in mitochondria, the minimum brain cytosolic O2 capable of maintaining a steady-state ATP is near its Km (0.1 Torr) at a PVO2 of 7.5 Torr. At this critical O2 level, PCr/Pi is 0.9, intracellular pH is 6.75, phosphorylation potential is 38.5 mM-1, and the calculated maximum velocity of ATP formation by oxidative phosphorylation is 55% of normal.

Adenosine Diphosphate↗