SUMMARY In animals, longevity (maximal lifespan) is inversely related to mass-specific basal metabolic rates. However, contrary to expectation, in several mammalian taxa, exceptional longevity is associated with high basal metabolic rate,... more
SUMMARY In animals, longevity (maximal lifespan) is inversely related to mass-specific basal metabolic rates. However, contrary to expectation, in several mammalian taxa, exceptional longevity is associated with high basal metabolic rate, and also fast evolution of mtDNA-coded proteins. The association of these traits was suggested to result from adaptive selection of mutations in mtDNA-coded proteins, which accelerates basal respiration, thus inhibiting the generation of reactive oxygen species that constrain longevity. In birds, all the genera with high rate of cytochrome b evolution are songbirds (oscines). Within the songbirds group, both longevity residuals and lifetime expenditure of energy are positively correlated with the rate of cytochrome b evolution. Moreover, within the large songbirds family Fringillidae (true finches) mass-specific basal metabolic rates, longevity,longevity residuals and lifetime expenditure of energy are all positively correlated with the rate of evo...
Research Interests: Evolutionary Biology, Molecular Evolution, Biology, Medicine, Learning, and 14 moreBiological Sciences, Longevity, Mitochondrial DNA, Humans, Mutation, Reactive Oxygen Species, Animals, Songbirds, Cytochrome B, Basal metabolic rate (BMR), Radical, Base Sequence, Experimental Biology, and Medical and Health Sciences
Research Interests: Chemistry, Science, Medicine, Multidisciplinary, Animals, and 5 moreEthanol, Membrane, Rats, Membrane Fluidity, and Mitochondrion
31P nuclear magnetic resonance spectra of glycolyzing, anaerobic Escherichia coli cells and their perchloric acid extracts were obtained at 145.7 MHz. Time-dependent intracellular concentrations of nucleoside di- and triphosphates, Pi,... more
31P nuclear magnetic resonance spectra of glycolyzing, anaerobic Escherichia coli cells and their perchloric acid extracts were obtained at 145.7 MHz. Time-dependent intracellular concentrations of nucleoside di- and triphosphates, Pi, and sugar phosphates were measured during glycolysis with 2-min resolution, while intracellular and extra-cellular pH values were monitored simultaneously. Upon glucose addition, anaerobic E. coli cells rapidly produce acids and develop a transmembrane pH gradient (delta pH). Glycolysis rates were calculated from the changes in the external pH. It was found that glycolysis rates are strongly dependent on internal pH, sharply decreasing when the pH drops below approximately 7.2. The ATPase inhibitor, dicyclohexylcarbodiimide (DCCD), prevented NTP hydrolysis and inhibited delta pH formation. The uncoupler, carbonyl cyanide p-triflouromethoxyphenyl hydrazone (FCCP), drastically reduced both the delta pH and the NTP level. When the cells were previously t...
Research Interests: Biochemistry, Chemistry, Nuclear Magnetic Resonance, Magnetic Resonance Spectroscopy, Medicine, and 12 moreMultidisciplinary, Energy Metabolism, ATPase, Escherichia coli, Glycolysis, Time Dependent, Phosphates, Hydrolysis, Hydrogen-Ion Concentration, Nucleotides, ATP hydrolysis, and anaerobic glycolysis
Using the spin probe 5-doxylstearic acid, we studied the structural perturbations of rat liver mitochondrial membranes produced by exposure to ethanol in vitro and by chronic ethanol feeding. The addition of ethanol in vitro to... more
Using the spin probe 5-doxylstearic acid, we studied the structural perturbations of rat liver mitochondrial membranes produced by exposure to ethanol in vitro and by chronic ethanol feeding. The addition of ethanol in vitro to mitochondria from control animals appears to "fluidize" the membranes, as evidenced by a pronounced decrease in the order parameter. By contrast, in membranes from rats fed ethanol chronically, there was no effect on the order parameter. This resistance of the mitochondrial membranes from chronically intoxicated animals to the fluidizing effect of ethanol probably results from a change in the composition of the phospholipids, because the same differential response to ethanol was observed upon using vesicles of mitochondrial phospholipids extracted from control and chronically treated rats. In the presence of 0.025--0.1 M ethanol, a range that prevails in the blood of chronic alcoholics, the order parameter of mitochondrial membranes from rats fed et...
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Research Interests: Biochemistry, Chemistry, Phospholipids, Biological Chemistry, Medicine, and 15 moreBiological Sciences, Cytochrome C, Membrane Lipids, Electron Transport, CHEMICAL SCIENCES, Time Factors, Superoxide, Vesicle, Membrane Potential, Superoxides, Valinomycin, Mitochondrion, Ubiquinone, Medical and Health Sciences, and Antimycin A
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Research Interests: Chemistry, Arsenic, Medicine, Carbon Isotopes, Light, and 15 morePlants, Phosphorylation, Membrane, Time Factors, Phosphates, Proton, Sorbitol, Energy Transfer, Chloroplast, Fluorometry, Photophosphorylation, Biochemistry and cell biology, Adenosine Triphosphate, Adenosine Diphosphate, and Chloroplasts
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The mechanism of the uncoupling of oxidative phosphorylation in rat liver mitochondria by gramicidin and truncated gramicidin derivatives was investigated. The derivatives desformylgramicidin and des(formylvalyl)gramicidin are not... more
The mechanism of the uncoupling of oxidative phosphorylation in rat liver mitochondria by gramicidin and truncated gramicidin derivatives was investigated. The derivatives desformylgramicidin and des(formylvalyl)gramicidin are not expected to form head to head, dimeric, ion-conducting channels, and thus allow an evaluation of the relevance of the stimulation of transmembrane cation conductance (and the resulting collapse of the proton electrochemical gradient) to the uncoupling of oxidative phosphorylation. When assayed for the enhancement of the passive diffusion of KSCN, gramicidin was 100-fold more potent than desformylgramicidin and 50-fold more potent than des(formylvalyl)gramicidin. Yet, in a medium devoid of alkalai cations, all three compounds were nearly equally potent uncouplers at low concentrations. Moreover, this uncoupling was not associated with stimulation of cation transport or a reduction of the magnitude of the proton electrochemical potential. In the same medium, gramicidin stimulated 86Rb uptake 50-fold more than desformylgramicidin and 10 times more than des(formylvalyl)gramicidin. At higher concentrations, gramicidin induced further uncoupling, which was associated with reduction of membrane potential (and presumably with transport of alkali cations), while the truncated derivatives were considerably less effective than gramicidin in this range. Thus, with the truncated derivatives, a better separation between decoupling (i.e., uncoupling not associated with reduction of delta mu H) and uncoupling is observed. In the same medium, gramicidin, but not the truncated derivatives, strongly inhibits the formation of both the membrane potential and delta pH by the H+-ATPase. This finding suggests direct interaction of gramicidin with the H+-ATPase. The truncated derivatives stimulated the ATPase without collapsing the membrane potential.(ABSTRACT TRUNCATED AT 250 WORDS)
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Research Interests: Aging, Biology, Calcium, Cell Biology, Mitochondria, and 15 moreApoptosis, Medicine, Brain, Mice, Animals, Male, Cell Death, Cyclosporine, Mitochondrial dysfunction, Degeneration, Lymphocytes, Excitotoxicity, Biochemistry and cell biology, Medical biochemistry and metabolomics, and In Vitro Techniques
Research Interests: Flow Cytometry, Medical Microbiology, Fluorescence, Biology, Mitochondria, and 15 moreMedicine, Biological Sciences, Mice, Animals, Cell, Cell Death, Physical sciences, Membrane, Fluorescent probes, Lymphocytes, Membrane Potential, Mitochondrial Membrane Potential, Biochemistry and cell biology, Cell count, and fluorescent dyes
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The interaction of the cationic spin probe 4-(N,N-dimethyl-N-dodecyl)-ammonium-2,2,6,6-tetramethyl-piperidine-1-oxyl (Cat12) with intact mitochondria and submitochondrial particles was investigated as a function of salt concentration, pH... more
The interaction of the cationic spin probe 4-(N,N-dimethyl-N-dodecyl)-ammonium-2,2,6,6-tetramethyl-piperidine-1-oxyl (Cat12) with intact mitochondria and submitochondrial particles was investigated as a function of salt concentration, pH and energization by ATP. In the presence of 1 mM Fe(CN)-36, which inhibits the probe reduction by the mitochondria, the probe signal is stable and shows both bound and free forms. The partition of the probe into mitochondrial membranes is decreased by various salts depending on the cation valency, indicating that the membrane is negatively charged (-10 to -15 mV at pH 7.0). The surface potential increases with pH from -3 mV at pH 5.0 to -18 mV at pH 8.0. Energization of intact mitochondria by ATP reduces the magnitude of both bound and free signals by more than 50%; the signal of the bound form slowly disappears on further incubation. The ATP effect is inhibited and also reversed by either oligomycin or CCCP. Similar effects of ATP were observed in mitoplasts but not in submitochondrial particles. In submitochondrial particles ATP has no effect on the probe signal or binding. These results suggest that the formation of membrane potential in mitochondria induces uptake and internal binding of the probe which results in broadening of the EPR signal of the internally bound probe. It is concluded that Cat12 is not a suitable probe for measurement of surface potential in energized mitochondria.
Research Interests: Microbiology, Biophysics, Chemistry, Electrochemistry, Medical Microbiology, and 15 moreBiological Chemistry, Medicine, Biological Sciences, Animals, Male, Physical sciences, Organophosphorus Compounds, Membrane, CHEMICAL SCIENCES, Rats, Potential Energy Surface, Membrane Potential, Arsenicals, Biochemistry and cell biology, and Adenosine Triphosphate
Research Interests: Biochemistry, Biology, Phospholipids, Membrane Proteins, Mitochondria, and 15 moreApoptosis, Medicine, Biological Sciences, Permeability, Mice, Animals, Cytochrome C, Aminoglycosides, Adenylate Kinase, Mitochondrial Permeability Transition Pore, Melittin, Mitochondrial Membrane Potential, Oxygen Consumption, Biochemistry and cell biology, and Mitochondrion
Research Interests: Chemistry, Electrochemistry, Mitochondria, Medicine, Biological Sciences, and 15 moreGlutamate, Animals, Bacteria, Physical sciences, Cytochrome c oxidase, Electron Transport, Cattle, Proton, Recombinant Proteins, Hydrogen-Ion Concentration, Static Electricity, Tyrosine, Biochemistry and cell biology, binding sites, and proton pump
Research Interests: Biology, Virology, Mitochondria, Biological Chemistry, Medicine, and 13 moreBiological Sciences, Mice, Animals, Naphthoquinones, CHEMICAL SCIENCES, Spectrum, ATOVAQUONE, Antimalarials, Antiparasitic activity, Broad Spectrum, Erythrocytes, Mitochondrial Membrane Potential, and Medical and Health Sciences
The activity of the mitochondrial permeability transition pore, mPTP, a highly regulated multi-component mega-channel, is enhanced in aging and in aging-driven degenerative diseases. mPTP activity accelerates aging by releasing large... more
The activity of the mitochondrial permeability transition pore, mPTP, a highly regulated multi-component mega-channel, is enhanced in aging and in aging-driven degenerative diseases. mPTP activity accelerates aging by releasing large amounts of cell-damaging reactive oxygen species, Ca2+ and NAD+. The various pathways that control the channel activity, directly or indirectly, can therefore either inhibit or accelerate aging or retard or enhance the progression of aging-driven degenerative diseases and determine lifespan and healthspan. Autophagy, a catabolic process that removes and digests damaged proteins and organelles, protects the cell against aging and disease. However, the protective effect of autophagy depends on mTORC2/SKG1 inhibition of mPTP. Autophagy is inhibited in aging cells. Mitophagy, a specialized form of autophagy, which retards aging by removing mitochondrial fragments with activated mPTP, is also inhibited in aging cells, and this inhibition leads to increased m...
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It is widely reported that the mitochondrial membrane potential, ∆Ψm, is reduced in aging animals. It was recently suggested that the lower ∆Ψm in aged animals modulates mitochondrial bioenergetics and that this effect is a major cause of... more
It is widely reported that the mitochondrial membrane potential, ∆Ψm, is reduced in aging animals. It was recently suggested that the lower ∆Ψm in aged animals modulates mitochondrial bioenergetics and that this effect is a major cause of aging since artificially increased ∆Ψm in C. elegans increased lifespan. Here, I critically review studies that reported reduction in ∆Ψm in aged animals, including worms, and conclude that many of these observations are best interpreted as evidence that the fraction of depolarized mitochondria is increased in aged cells because of the enhanced activation of the mitochondrial permeability transition pore, mPTP. Activation of the voltage-gated mPTP depolarizes the mitochondria, inhibits oxidative phosphorylation, releases large amounts of calcium and mROS, and depletes cellular NAD+, thus accelerating degenerative diseases and aging. Since the inhibition of mPTP was shown to restore ∆Ψm and to retard aging, the reported lifespan extension by artific...
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The maximal lifespan of primates exceed the lifespan of most other mammals of equal body mass. In prosimian primates (lemurs and bushbabies) this exceptional longevity is associated with lower mass-specific basal metabolic rates, as... more
The maximal lifespan of primates exceed the lifespan of most other mammals of equal body mass. In prosimian primates (lemurs and bushbabies) this exceptional longevity is associated with lower mass-specific basal metabolic rates, as expected from the Free Radical Theory of Aging. However, in anthropoid primates (monkeys and apes including humans) exceptional longevity is associated with exceptional high metabolic rates, in apparent contradiction of the Theory. It was therefore suggested that in anthropoid primates (and several other taxa of mammals and birds) the mitochondrial electron transport complexes, that generate most of the Reactive Oxygen Intermediates in the cell, evolved to modify the relationship between basal electron transport and superoxide generation to allow for the evolution of exceptional longevity and higher basal metabolic rates. Cytochrome b, the core protein of the bc1 complex (complex III), is coded by the mitochondrial DNA, and is a major source of superoxide. The amino-acid sequence of cytochrome b evolved much faster in anthropoid than in prosimian primates and most other mammals resulting is in a large change in the amino-acids composition of the protein, most likely due to relaxation of the strong purifying selection that dominate the evolution of this protein. As a result of these changes cytochrome b in anthropoid primates is significantly less hydrophobic and contains more polar residues than other primates and most other mammals. In new world monkeys cytochrome b polarity and hydrophobicity are negatively correlated with exceptional longevity and positively correlated with the rate of the protein evolution. Most of these changes are clustered around the ubiquinone reduction site(Qi). In particular a key positively charged residue, arginine 313, that interacts with one of the propionate of heme bH, and thus affect its redox potential, is substituted in anthropoid primates with a neutral residue, glutamine, most likely resulting in a lower redox potential of heme bH. It is suggested that these changes contribute to the observed increased rates of basal metabolism and the reducion in the rates of superoxide production, thus allowing for increased lifespan.