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PubMed2001

Mitochondrial coupling factor 6 is present on the surface of human vascular endothelial cells and is released by shear stress.

BACKGROUND: We showed that mitochondrial coupling factor 6 (CF6), an endogenous inhibitor of prostacyclin synthesis, is present in the systemic circulation as a pressor substance in rats. We investigated the possibility of vascular endothelial cells as a source of circulating CF6. METHODS AND RESULTS: We used 2 cultured endothelial cell lines, human umbilical vein endothelial cells (HUVECs) and ECV 304 cells (transformed HUVECs), for this study. Immunofluorescence microscopy of both ECV 304 and HUVECs confirmed the surface-associated immunoreactivity of anti-CF6 antibody on the plasma membrane. The concentration of CF6 in the medium increased gradually with time in both ECV 304 and HUVECs in static conditions. Exposure of ECV 304 and HUVECs to a fluid shear stress enhanced the release of CF6: In ECV 304, the concentration of CF6 in the medium (ng. well(-1). 6 hours(-1)) was 2.1+/-0.8 at baseline, 4.3+/-0.8 after shear at 15 dynes/cm(2), and 57.7+/-8.4 after shear at 25 dynes/cm(2). CF6 contents in the cell homogenate and mitochondria were both significantly increased after exposure of ECV 304 to 6-hour shear at 15 dynes/cm(2), whereas they were unchanged after shear stress at 25 dynes/cm(2). The ratio of CF6 to GAPDH mRNA was enhanced significantly, by 1.8+/-0.2-fold, after 6-hour shear stress at 25 dynes/cm(2). Flow cytometry analysis revealed that the surface-associated CF6 was significantly increased in a 3-hour static condition after the previous exposure of the cells to shear stress for 3 hours. CONCLUSIONS: Vascular endothelial cells are a source of CF6, and shear stress regulates the release of the surface-associated CF6.

Cell Line↗
PubMed1984

Immunologically reactive multiple species of mitochondrial coupling factor B.

Earlier work had indicated that mitochondrial coupling factor B (FB) could be obtained with differing molecular weights, a highly active 13,000 form, a 29,200 form with low activity, and a partially purified 46,000 form with activity higher than the 29,200 form. We have analyzed FB preparations of different purity and after different types of treatment on polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate (SDS-PAGE), followed by silver staining or immunostaining either with rabbit anti-FB serum or monoclonal FB antibody. Highly purified preparations which appear as single bands in SDS-PAGE develop additional higher molecular weight bands (silver staining), including a 48,000 and a 68,000 band, after lyophilization or repeated freezing and thawing or if subjected to SDS-PAGE in the absence of thiol compounds. FB prepared without addition of dithiothreitol and glycerol for stabilization also shows high molecular weight forms, although the active fractions are obtained consistently in the final gel filtration step of purification at a position corresponding to Mr = 13,000. When FB preparations are analyzed by immunoblots of SDS-PAGE using a monoclonal antibody to FB, fresh preparations of purified FB show a single band, while multiple bands are seen in samples which have been frozen and thawed repeatedly. Preparations made in the absence of dithiothreitol and glycerol also show cross-reactive forms of high molecular weight. Similar immunoblots using rabbit antiserum with mitochondria, its extracts, and partially purified FB preparations, all show the presence of several higher molecular weight forms. It is concluded that FB is probably a monomer in mitochondria, and it appears to undergo oligomerization after extraction and during purification.

Adenosine Triphosphatases↗
PubMed2006

Effect of vasoconstrictor coupling factor 6 on gene expression profile in human vascular endothelial cells: enhanced release of asymmetric dimethylarginine.

BACKGROUND: Coupling factor 6 (CF6), a component of ATP synthase, inhibits phospholipase A2 and induces vasoconstriction. However, because arachidonic acid acts in the widespread fields of vascular biology, CF6 might exert profound effects in addition to vasoconstriction. We investigated the effect of CF6 on the gene expression profile in human umbilical vein endothelial cells. METHODS AND RESULTS: The increased gene expression after 24-h exposure to CF6 at 10 mol/l, assessed by cDNA microarray (n = 3), included neuregulin-1 (1.84 +/- 0.07 fold compared with control, P < 0.05) and relaxin-1 (1.74 +/- 0.20, P < 0.05), both relating to congestive heart failure, urokinase type plasminogen activator receptor (1.77 +/- 0.24, P = 0.06) and estrogen receptor beta (1.74 +/- 0.36, P = 0.08), both relating to vascular inflammation and cell infiltration, and protein arginine methyltransferase (PRMT-1; 1.73 +/- 0.20, P < 0.05). Out of these genes, the enzyme relating to the synthesis (PRMT-1) of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), was further examined concomitantly with the degradation enzyme, dimethylarginine dimethylaminohydrolase 2 (DDAH-2). The ratio of PRMT-1 to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA, measured by real-time quantitative reverse transcription-polymerase chain reaction, was increased by 9 +/- 2% (n = 10, P < 0.01) at 48 h after CF6 at 10 mol/l, whereas the ratio of DDAH-2 to GAPDH was decreased by 12 +/- 2% (n = 8, P < 0.01). DDAH-2 protein and activity were decreased by 28 +/- 5% (n = 5, P < 0.01) and 19 +/- 2% (n = 6, P < 0.01) by CF6, respectively. ADMA release was enhanced by 20 +/- 8% and NOS activity was decreased by 13 +/- 1% (both n = 8, P < 0.05) by CF6. CONCLUSIONS: CF6 changes the gene expression profile to be proatherogenic and functions as a novel stimulator for ADMA release by enhancing its synthesis and suppressing its degradation.

Amidohydrolases↗
PubMed2004

Plasma mitochondrial coupling factor 6 in patients with acute myocardial infarction.

Previous studies have shown that mitochondrial coupling factor 6 (CF6) is an endogenous peptide that inhibits prostacyclin (PGI2) synthesis in vascular endothelial cells. In this study, we measured the plasma CF6 level of patients with acute myocardial infarction (AMI) to observe dynamic changes of CF6. All patients showed elevated plasma CF6 levels upon admission for treatment of AMI. Their CF6 levels peaked approximately 72 h after the onset of AMI and remained high for 7 days. At 7 days, their CF6 levels decreased to the level seen upon admission, but not to within a normal range. Hyperlipidemic patients had significantly greater CF6 levels at 24 h after onset of AMI than patients with a normal lipid profile. On admission, the plasma CF6 level in patients with a cardiac function of Killip class > or =II was higher than that in patients with a Killip class I cardiac function. At 3 days after the onset of AMI, the plasma CF6 levels of patients with a creatinine kinase (CK) peak value > or =1,500 units/l were significantly higher than those of patients with a CK peak value <1,500 units/l (p =0.05). At 7 days after the onset of AMI, the plasma CF6 levels of patients who received no reperfusion were significantly higher than those of patients who received a successful reperfusion. The plasma CF6 levels of AMI patients at admission, at 24 h, and at 3 days after onset of symptoms correlated positively with the cardiac function by Killip classification, respectively. At 24 h after onset of AMI, the plasma CF6 levels correlated positively with plasma total cholesterol levels and low-density lipoprotein levels. At 3 days, the plasma level of CF6 correlated positively with the plasma CK peak value and correlated negatively with left ventricular ejection fraction. These results suggest that the plasma CF6 level was elevated in patients with AMI.

Aged↗
PubMed1975

Energy transfer in mitochondrial synthesis of ATP; a survey.

The energy transduction in mitochondria, with its principal agent ATP, still represents a major challenge for biological research. In general, the energy transduction process is divided into three sections: (1) the redox processes; (2) a conservation of intermediary energy forms; (3) synthesis of ATP. All three processes are linked to the membrane and are, therefore, as difficult to resolve as are processes linked to other biomembranes. It is probable that the electron transport system is constructed in such a way as to provide energy for synthesis of ATP and related processes. Important for this function is the transversal distribution of these components across the membrane, facilitating generation of membrane potential by electron or proton transfer. The exact composition of the respiratory chain is not yet known, in particular with respect to iron-sulphur proteins. Progress is achieved by defining single species of the respiratory chain, subunit composition, amino acid sequences and genetic derivation from intra- or extra-mitochondrial translation. Energy generated by oxidation can be trapped before ATP is formed by a number of reactions, in particular reversed electron transport, energy-dependent transhydrogenation and uptake of anions or cations into the mitochondria. The latter reaction is of major importance for understanding the intermediate energy form, as it appears to use energy most directly and be driven mainly by membrane potential or proton gradient across the membrane. The formation of ATP is a major problem hindering elucidation of the mechanism of oxidative phosphorylation. The mechanism of this enzymic process is not yet understood although the enzymes have been isolated and the subunits have been defined. Most probably, a concerted reaction between ADP and phosphate, driven by some conformational transition of the complex, leads to the formation of ATP. Release of ATP from a hydrophobic to hydrophilic environment may consume most of the energy.

Adenosine Triphosphate↗
PubMed1991

Na(+)-coupled alternative to H(+)-coupled primary transport systems in bacteria.

Protons are the most common coupling ions in bacterial energy conversions. However, while many organisms, such as the alkaliphilic Bacilli, employ H(+)-bioenergetics for electron transport phosphorylation, they use Na+ as the coupling ion for transport and flagellar movement. The Na+ gradient required for these bioenergetic functions is established by the secondary Na+/H+ antiporter. In contrast, Vibrio alginolyticus and methanogenic bacteria have primary pumps for both H+ and Na+. They use the proton gradient for ATP synthesis while other, less energy-consuming membrane reactions are powered by the Na+ gradient. In a third mode, some anaerobic bacteria possess decarboxylases acting as primary Na+ pumps. For instance, in Klebsiella pneumoniae, the Na+ gradient established by oxaloacetate decarboxylase is used for the uptake of the growth substrate citrate, and Propionigenium modestum consumes the energy of the Na+ gradient formed by methylmalonyl-CoA decarboxylase directly for ATP synthesis.

Adenosine Triphosphate↗
PubMed1981

Isolation, characterization, and reconstitution of a solubilized fraction containing the hydrophobic sector of the mitochondrial proton pump.

The hydrophobic sector of the mitochondrial ATPase complex was purified by sequential extraction with cholate and octylglucoside, by further differential solubilization with guanidine and cholate in the presence of phosphatidylcholine, and by fractionation with ammonium sulfate. A polypeptide with a mass of 28,000 dalton was present in the purified hydrophobic section which was cleaved by trypsin, resulting in loss of reconstitution activity. In contrast, dicyclohexylcarbodiimide-binding proteolipid remained unimpaired after exposure to trypsin. The 32Pi-ATP exchange activity of the reconstituted ATPase complex was inhibited by p-hydroxymercuribenzoate, which reacted primarily with the 28,000-dalton protein, as monitored by acrylamide gel electrophoresis with 14C-labeled inhibitor. The function of a 22,000-dalton polypeptide and of some minor components in the region of the proteolipid remains unknown. An examination of the phospholipid requirements for reconstitution of an active complex revealed an unexpected discrepancy. With an excess of phosphatidylethanolamine, optimal reconstitution of 32Pi-ATP exchange and ATP synthesis in the presence of bacteriorhodopsin and light was achieved: at a high phosphatidylcholine:phosphatidylethanolamine ratio, the rate of ATP synthesis remained high, but the rate of 32Pi-ATP exchange dropped precipitously. A new procedure is described for the reconstitution of the ATPase complex with purified phospholipids which is stable for at least 15 days.

Adenosine Triphosphatases↗
PubMed1981

Effect of chemical modifiers of amino acid residues on proton conduction by the H+-ATPase of mitochondria.

The effect of chemical modifiers of amino acid residues on the proton conductivity of H+-ATPase in "inside out" submitochondrial particles has been studied. Treatment of submitochondrial particles prepared in the presence of EDTA (ESMP) with the arginine modifiers, phenylglyoxal or butanedione, or the tyrosine modifier, tetranitromethane, caused inhibition of the ATPase activity. Phenylglyoxal and tetranitromethane also caused inhibition of the anaerobic release of respiratory delta micro H+ in ESMP as well as in particles deprived of F1 (USMP). Butanedione treatment caused, on the contrary, acceleration of anaerobic proton release in both particles. The inhibition of proton release caused by phenylglyoxal and tetranitromethane exhibition in USMP a sigmoidal titration curve. The same inhibitory pattern was observed with oligomycin and with N,N'-dicyclohexylcarbodiimide. In ESMP, relaxation of delta micro H+ exhibited two first-order phases, both an expression of the H+ conductivity of the ATPase complex. The rapid phase results from transient enhancement of H+ conduction caused by respiratory delta micro H+ itself. Oligomycin, N,N'-dicyclohexylcarbodiimide, and tetranitromethane inhibited both phases of H+ release, and butanedione accelerated both. Phenylglyoxal inhibited principally the slow phase of H+ conduction. In USMP, H+ release followed simple first-order kinetics. Oligomycin depressed H+ release, enhanced respiratory delta micro H+, and restored the biphasicity of H+ release. Phenylglyoxal and tetranitromethane inhibited H+ release in USMP without modifying its first-order kinetics. Butanedione treatment caused biphasicity of H+ release from USMP, introducing a very rapid phase of H+ release. Addition of soluble F1 to USMP also restored biphasicity of H+ release. A mechanism of proton conduction by Fo is discussed based on involvement of tyrosine or other hydroxyl residues, in series with the DCCD-reactive acid residue. There are apparently two functionally different species of arginine or other basic residues: those modified by phenylglyoxal, which facilitate H+ conduction, and those modified by butanedione, which retard H+ diffusion.

Adenosine Triphosphatases↗
PubMed1980

Kinetic and thermodynamic properties of beef heart mitochondrial ATPase: effect of co-solvent systems.

The effects of glycerol and methanol upon beef heart mitochondrial ATPase (F1) were studied. Glycerol was found to be a potent reversible inhibitor of the F1-catalyzed hydrolysis of ATP and ITP. The inhibition of ATP hydrolysis was linear with respect to glycerol concentrations, while that of ITP was not. From the temperature dependence of Vmax for F1-catalyzed ATP and ITP hydrolysis in glycerol or methanol solutions, the energy of activation and the enthalpy of activation were calculated. The inhibitory effect of ADP on F1 hydrolytic activity was studied in three solvent systems (totally aqueous, 20% methanol, and 20% glycerol). Compared to the aqueous system, methanol decreased the potency of ADP as an inhibitor, and glycerol enhanced the potency.

Adenosine Triphosphatases↗
PubMed1995

Hexose metabolism in pancreatic islets: effect of D-glucose on the mitochondrial redox state.

The mitochondrial NADH/NAD+ ratio for free nucleotides in rat pancreatic islets was judged from the cell content in L-glutamate and L-alanine, 2-ketoglutarate and pyruvate, and NH4+. At a physiological concentration of D-glucose, such a ratio averaged 9.6 +/- 1.1%. A rise in hexose concentrations, above a threshold value in excess of 5.6 mM, caused a rapid, sustained and rapidly reversible decrease in the mitochondrial NADH/NAD+ ratio. It is speculated that in the process of glucose-stimulated insulin release, the latter change participates in the coupling between metabolic and secretory events by favouring both the activity of key mitochondrial dehydrogenases and the translocation of Ca2+ from the mitochondria into the cytosol.

Animals↗
PubMed1979

Inhibition of E coli ATPase activity by a troponin component, TN-I, and by mitochondrial ATPase inhibitor.

The enzymic activity of Mg2+- or Ca2+-stimulated ATPase from Escherichia coli was inhibited by one of the troponin components, TN-I, and by mitochondrial ATPase inhibitor (F1-inhibitor). The inhibitory ability of component TN-I against Mg2+-stimulated AtPase activity was lost after digestion of component TN-I with trypsin. The Mg2+-stimulated ATPase activity inhibited by component TN-I was completely restored by the addition of another troponin component TN-C.

Adenosine Triphosphatases↗
PubMed2006

Humanin expression in skeletal muscles of patients with chronic progressive external ophthalmoplegia.

We showed that humanin (HN), an endogenous peptide against Alzheimer disease-related insults, was expressed in muscles of patients with chronic progressive external ophthalmoplegia (CPEO), a major mitochondrial disease. Because HN was recently found to block proapoptotic Bax function and exert its versatile cytoprotective effects in association with an increase in ATP levels, HN expression may thus reflect a physiological response against degenerative changes in the muscles of patients with CPEO. We found HN expression in all four patients examined, each of whom had different mitochondrial DNA mutations including two different single DNA deletions, multiple deletions, and no major mutations detected. We also found that HN expression was not linked to focal cytochrome c deficiency, strongly associated with the subtype of CPEO with single deletions. These results suggest that HN expression is more closely related to degenerative changes in all types of CPEO. Notably, HN was also expressed in non-degenerative muscle fibers of patients with CPEO or Leigh syndrome, who had the 8993T>G mutation in the mitochondrial ATPase 6 gene known to be associated with impaired ATP synthesis. Collectively, our findings suggest that HN may be specifically expressed in response to defects in energy production in muscles with mitochondrial abnormalities.

Adolescent↗