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  • "Hofstadter has emphasized that Gödel, Esc"Hofstadter has emphasized that Gödel, Escher, Bach is not about the relationships of mathematics, art, and music, but rather about how cognition emerges from hidden neurological mechanisms. At one point in the book, he presents an analogy about how the individual neurons of the brain coordinate to create a unified sense of a coherent mind by comparing it to the social organization displayed in a colony of ants." - Wikipediaisplayed in a colony of ants." - Wikipedia  +
  • "What is the O2 concentration in a normoxi"What is the O2 concentration in a normoxic cell culture incubator?" This and other frequently asked questions in hypoxia research will be answered in this review. Our intention is to give a simple introduction to the physics of gases that would be helpful for newcomers to the field of hypoxia research. We will provide background knowledge about questions often asked, but without straightforward answers. What is O2 concentration, and what is O2 partial pressure? What is normoxia, and what is hypoxia? How much O2 is experienced by a cell residing in a culture dish in vitro vs in a tissue in vivo? By the way, the O2 concentration in a normoxic incubator is 18.6%, rather than 20.9% or 20%, as commonly stated in research publications. And this is strictly only valid for incubators at sea level.ly only valid for incubators at sea level.  +
  • # A Mg<sup>2+</sup>-dependent</br># A Mg<sup>2+</sup>-dependent adenosine triphosphatase was solubilized and purified from bakers' yeast mitochondria. The enzyme resembled mitochondrial ATPase from beef heart with respect to substrate specificity, cold lability, and other physical properties.</br># An antiserum against the purified yeast enzyme inhibited the ATPase activity of the soluble enzyme as well as ATPase and oxidative phosphorylation in submitochondrial yeast particles. Mitochondrial ATPase from beef heart or from Neurospora crassa was not inhibited by the antiserum. </br># Submitochondrial beef heart particles devoid of endogenous ATPase could bind the purified yeast enzyme without changing its immunological specificity. The ATPase activity of the resultant "hybrid" particles, like that of beef heart particles, was strongly inhibited by low levels of rutamycin. In contrast, submitochondrial particles from yeast were much less sensitive to this inhibitor. </br># The yeast enzyme stimulated oxidative phosphorylation in beef heart particles which were deficient in, but not devoid of, endogenous ATPase. The stimulation was dependent on the presence of beef heart coupling factor 1 (F1) in these particles and was unaffected by the antiserum against the yeast enzyme. Antiserum against beef heart F1 strongly inhibited phosphorylation. These results suggest that yeast F1, in contrast to beef heart F1, does not significantly participate in phosphate transfer reactions when it functions as a coupling factor in beef heart particles. Rather, it is proposed that the stimulation by yeast F1 is due to an effect on the membrane structure.</br>yeast F1 is due to an effect on the membrane structure.   +
  • # A specific succinate requirement for en</br># A specific succinate requirement for energy-linked reduction of mitochondrial pyridine nucleotide is demonstrated in pigeon heart and guinea pig kidney mitochondria.</br># The succinate used in this reduction can be generated in the oxidation of malate plus glutamate or of α-ketoglutarate. </br># The role of succinate is identified by the specific inhibitory responses of the reaction to malonate, phosphate, and fumarate. </br># At least two kinds of mitochondrial pyridine nucleotide are shown to be reducible in State 4: (a) about one-third in the absence of added succinate in a malonate-insensitive reaction in the presence of a substrate such as malate plus glutamate and (b) about two-thirds in the presence of added succinate in a malonate-sensitive, energy-linked reaction. These two kinds of pyridine nucleotide may be considered to be compartmented.</br>tide may be considered to be compartmented.   +
  • # Aus Saeugetierlebern lassen sich Suspen</br># Aus Saeugetierlebern lassen sich Suspensionen kleiner, Brown'sche Bewegung zeigender Koernchen gewinnen, die Sauerstoff verbrauchen und Kohlensaeure bilden. Die Oxydationsgroesse war etwa 1/5 der Oxydationsgroesse der entsprechenden Menge intakten Lebergewebes, wenn der Masing'sche Mittelwert von 1200 ccm pro Kilo und Stunde der Vergleichsrechnung zugrunde gelegt wird. Die Koernchen sind wahrscheinlich identisch mit den praeformierten Lebergranula.</br># Aus Saeugetierlebern lassen sich mittels Filtration durch Berkefeld-Kerzen Fluessigkeiten gewinnen, die Sauerstoff verbrauchen und Kohlensaeure bilden. Die Oxydationsgroesse war etwa 4% von der Oxydationsgroesse der entsprechenden Menge intakten Lebergewebes. Filtratatmung und Zellatmung stehen, der Groessenordnung nach, in aehnlichem Verhaeltnis zueinander wie die Buchnersche Presssaftgaerung zur Hefezellengaerung.</br># Die akzessorische oder wasserloesliche Atmung aus frischem Lebergewebe, die Batelli und Stern beschrieben haben, ist wahrscheinlich zum groesseren Teil Koernchenatmung. Ein kleiner Teil ist auf Rechnung der Zwischenfluessigkeit zu setzen und kann in der ueblichen Terminologie als wasserloesliche Atmung bezeichnet werden.</br># Die Atmung intakter, aus dem Koerper entfernter Leberlaeppchen bleibt stundenlang konstant. Die Labilitaet der Atmung der intakten Zellen — der sogenannten Hauptatmung — wird bei der Versuchsanordnung von Batelli und Stern vorgetaeuscht durch Schaedigungen, die die Lebern infolge von Sauerstoffmangel erleiden.</br>bern infolge von Sauerstoffmangel erleiden.   +
  • # Estimations of the carbohydrate metabol</br># Estimations of the carbohydrate metabolism of several strains of mouse tumours are recorded. Great deviations from the standard values found for tumours of rat, fowl and a limited series of human tumours were observed in many cases. Wide variations are shown to occur between tumours of different strains, and also between members of the same strain. The most noticeable feature is the number of cases of high respiration, both in its absolute value and also in its relation to the aerobic and anaerobic glycolysis. This respiration is ineffective in checking the aerobic glycolysis, its activity in this direction being, in some cases, less than 10% of that found in the case of working muscle, and in many mammalian tumours. Some factors which might operate in causing these variations are changes in the respiratory quotient, differences of environment during growth, efficiency of blood supply, and the generally higher metabolic rate of the mouse as compared with larger animals.</br># A manometric method for the simultaneous measurement of the carbohydrate metabolism and the respiratory quotient is briefly described, based on the fact that the glycolysis effected by tumour tissue is a pure lactic fermentation. The respiratory quotients with one exception were found to be below unity. This would tend to make the actual aerobic glycolysis relatively higher than that usually recorded, since the assumption has hitherto been made that a respiratory quotient of unity would result from the experimental conditions. The results again illustrate the ineffectiveness of respiration in checking glycolysis.</br># Xylose is not metabolised by tumour tissue.</br># Evidence is brought forward which suggests that the glycolytic activity of tumours exerts a checking effect on their respiration.</br># The carbohydrate metabolism of tumours is to some extent influenced by the environment in which they grow. This is demonstrated by the study of two series of Jensen's rat sarcomata, simultaneously transplanted, one series subcutaneously and the other intraperitoneally. The respiration of the subcutaneous growths was, on the average, 50% higher than that of the intraperitoneal growths. The majority of these subcutaneous tumours do not exhibit a positive value for the excess fermentation, which was, until recently, regarded by Warburg as a criterion for the metabolism of tumour tissue. The correlation of these differences with the normal tissue tensions of CO2 and 02 iS difficult. Campbell found the oxygen tension in the abdominal cavity 50% higher than under the skin, the CO2 tensions being approximately the same. The higher respiration found in these two series of tu-mours corresponds to the lower 02 tension in the surrounding tissues, and vice versa. It is obvious that other factors which have not yet been analysed are operative. </br></br>The general result of these observations is to emphasise the difficulty of including the wide variations found in the carbohydrate metabolism of tumour tissue in one generalisation. The constant factor is the possession of a high aerobic glycolysis, which, though not specific for tumour tissue, is a source of energy available for uncontrolled ptoliferation.</br>y available for uncontrolled ptoliferation.   +
  • # Mechanically fragmented beef heart </br># Mechanically fragmented beef heart mitochondria have been resolved by differential centrifugation into a particulate and a soluble protein component, both of which were required for oxidative phosphorylation. The particulate fraction alone catalyzed the oxidation of succinate, β-hydroxybutyrate, isocitrate, and glutamate with little or no concomitant phosphorylation. Addition of the soluble factor to the particles resulted in a net uptake of inorganic phosphate with a P:O of 0.4 to 0.8. Similarly, both fractions were required for a P32-ATP exchange. </br># The highly purified, soluble coupling factor catalyzed a dinitrophenol-stimulated hydrolysis of ATP. </br># Comparative studies of the cold lability, heat stability, and other physical properties strongly favored the conclusion that the coupling and ATPase activity were catalyzed by the same protein. </br># The significance of these results in relation to current concepts of the mechanism of oxidative phosphorylation has been discussed.</br>tive phosphorylation has been discussed.   +
  • # Submitochondrial particles have been se</br># Submitochondrial particles have been sequentially treated with trypsin, urea, and sonic oscillation at an alkaline pH. These TUA particles required addition of a protein (Fc1) in order to render added ATPase (F1) sensitive to dicyclohexylcarbodiimide. Further resolution was obtained by exposure of TUA particles either to 2 M sodium thiocyanate or to 1.5% silicotungstate. These procedures removed a second soluble protein component (Fc2) which was also required for the sensitivity of ATPase to dicyclohexylcarbodiimide.</br># Preparations of Fc2 purified from the sodium thiocyanate extract stimulated the 32Pi-ATP exchange reaction and oxidative phosphorylation in silicotungstate-treated submitochondrial particles.</br># Treatment of TUA particles with silicotungstate reduced their ability to bind ATPase (F1). Addition of Fc2 restored the ability to bind ATPase. It is therefore proposed that Fc2 is a component which links the mitochondrial ATP-ase to the inner mitochondrial membrane.</br>TP-ase to the inner mitochondrial membrane.   +
  • # Succinic dehydrogenase has been iso</br># Succinic dehydrogenase has been isolated from beef heart mitochondria as a soluble protein in a state approaching homogeneity by physico-chemical criteria. The overall purification is about 100-fold compared with a mitochondrial acetone powder. </br># The enzyme is a ferroflavoprotein cont,aining 4 atoms of ferrous (non-hemin) iron and a mole of flavin per mole of protein (200,000 gm.). The dehydrogenase may be isolated from aged starting material with 2 atoms of iron per mole and half the specific activity. </br># Among the common electron acceptors, only the following function with the dehydrogenase, at the relative rates indicated in parentheses: phenazine methosulfate (100), ferricyanide (39), O2 (0.02). The first two of these acceptors react via the iron moieties, whereas O2 seems to react directly with the flavin. </br># The QO2, has been measured as 20,000 and the turnover number as 3000 under the standard assay conditions. </br># The properties of the isolated dehydrogenase agree with those previously described for mitochondrial and other particulate preparations of the enzyme, except for properties related to the absence of contaminating hemoproteins. At 38 °C the pH optimum is 7.7; the K, for succinate is 1.3 X 10-3 M at 38 °C and 5.2 X 10-4 M at 21 °C. Oxalacetate, malonate, and fumarate are competitive inhibitors. Antimycin A and BAL do not inhibit the dehydrogenase. The dehydrogenase is highly sensitive to sulfhydryl reagents, p-chloromercuribenzoate inhibiting it in a reversible manner and the substrate protecting the enzyme from this type of inhibition.</br> enzyme from this type of inhibition.   +
  • # The pathway of electron transfer f</br># The pathway of electron transfer from succinate to pyridine nucleotide shows a sensitivity to antimycin A, suggesting that carriers of the respiratory chain up to and including the antimycin-sensitive point are involved in succinate-linked reduction of pyridine nucleotide.</br># The sensitivity of succinate-linked reduction of pyridine nucleotide to Amytal suggests that a reverse of the flavoprotein-pyridine nucleotide interaction observed in the oxidation of pyridine nucleotide in phosphorylating mitochondria is also part of the electron transfer pathway. </br># Mechanisms indicating the interconnection of electrons from the antimycin-sensitive point to this flavoprotein via electron carriers such as cytochrome b and ubiquinone are considered. These mechanisms appear to apply to both aerobic and anaerobic (terminally inhibited) energy-linked reduction of pyridine nucleotide. </br># Three mechanisms for increased reduction of pyridine nucleotide in succinate-treated mitochondria that do not involve the above pathway fail to show responses of the experimentally observed sensitivity to Amytal or to antimycin A. </br># The properties of the energy-linked pool of pyridine nucleotide in metabolism are considered. Its participation is likely to be small in state 3 and of some consequence in state 4.</br> and of some consequence in state 4.   +
  • # The purification o f a soluble ATP</br># The purification o f a soluble ATPase from beef heart mitochondria is described. The activity is dependent on Mg++ and is stimulated by 2,4-dinitrophenol. The enzyme cleaves the terminal phosphate of ATP and is inhibited by ADP. The activity is therefore assayed in the presence of an ATP regenerating system. </br># The enzyme is cold labile. Although stable at room temperature, the enzyme rapidly loses activity at 4°. ATP, which protects the enzyme against inactivation by heat and dialysis, does not prevent the cold inactivation. </br># Attempts to demonstrate an exchange between either Pi32 or C14-ADP and ATP in the presence of the enzyme were unsuccessful. </br># The properties of the purified enzyme are discussed in relation to particulate mitochondrial ATPase and to myosin ATPase.</br>ochondrial ATPase and to myosin ATPase.   +
  • # The ability to phosphorylate ADP during</br># The ability to phosphorylate ADP during oxidation of NADH by ubiquinone-1 was restored to the NADH-ubiquinone reductase complex by combining the latter with phospholipids and a hydrophobic protein fraction derived from bovine heart mitochondria.</br># Phosphorylation was abolished by rotenone, uncoupling agents, or rutamycin. The efficiency of ATP formation was as high as 0.5 mole per mole of NADH oxidized under optimal conditions.</br># Reconstitution of phosphorylation had an absolute requirement for phosphatidylethanolamine and a partial requirement for phosphatidylcholine, a molar ratio of approximately 4:1 being optimal. A much more marked requirement for phosphatidylcholine was observed in the presence of low concentrations of cardiolipin (0.05 to 1.5% of the total phospholipid). In the presence of cardiolipin, an equal molar ratio of phosphatidylethanolamine to phosphatidylcholine gave the highest phosphorylation efficiency.</br># The NADH-ubiquinone reductase complex is oriented in the reconstituted vesicles such that approximately 50% of the molecules can react with added NADH. Reaction of all the molecules with NADH occurs in the presence of 0.5% deoxycholate.</br># Phosphorylation efficiency can be significantly improved by purification of the vesicles on sucrose density gradients.</br> the vesicles on sucrose density gradients.   +
  • # The reduction of added DPN by succinate</br># The reduction of added DPN by succinate catalyzed by submitochondrial particles from beef heart has been studied.</br># The reduction was endergonic and required specifically the addition of ATP.</br># The reaction had a limited specificity for electron acceptors; six DPN analogues tested were reduced at the same rate or nearly the same rate, as was DPN. TPN was only reduced at a very slow rate.</br># The rate of reduction was influenced by phosphate and ADP and their effects became pronounced if added together.</br># The effect of DPNH was marked only if added in a concentration equal to or exceeding that of DPN.</br># Respiratory inhibitors acting in the flavin region of the respiratory chain blocked the reaction.</br>the respiratory chain blocked the reaction.   +
  • # The α-ketoglutaric oxidase system of he</br># The α-ketoglutaric oxidase system of heartmuscle sarcosomes has a pH optimum at 7.4. The yield of oxidative phosphorylation (P:O ratio) is unchanged between pH 6.2 and 7.7.</br># Hypertonic sucrose (0.88 M) is an inhibitor of the succinic oxidase system in the Keilin & Hartree preparation. Its major effect appears to be on the accessibility of both the endogenous and added cytochrome ''c'' to the other components of the system.</br># Maximum activity of the α-ketoglutaric oxidase system of heart-muscle sarcosomes is obtained under the most highly hypotonic conditions studied, equivalent to about one-third isotonic. Under these conditions, sarcosomes are swollen, but shrink again when placed in isotonic medium. The effect of tonicity on the activity of the α-ketoglutaric oxidase system is also reversible. </br># As the tonicity is increased by saline, sucrose or phosphate, the activity of the α-ketoglutaric oxidase system decreases.</br># The P:O ratio is not affected over a wide range of sucrose concentrations which have a marked effect on the activity of the α-ketoglutaric oxidase system. This and other examples where the oxidase system is more sensitive than the P:O ratio to variations of the conditions indicates that the phosphorylative enzymes are normally in excess of the purely oxidative enzymes and increases the likelihood that measurements of the yield of oxidative phosphorylation on isolated tissue preparations represent the state of affairs in the cell. </br># Phosphate, in high concentration, decreases the P:O ratio; the optimal concentration is 0.03 M. </br># Hypertonic sucrose is unsuitable for the isolation of sarcosomes. There is, however, no significant difference between sarcosomes isolated with isotonic sucrose and isotonic saline, except that the latter are deficient in cytochrome ''c''.</br>t the latter are deficient in cytochrome ''c''.   +
  • # [[Mitochondrial marker enzymes|Marker enzymes]]</br># [[Mitochondrial marker enzymes|Marker enzymes]] for the mitochondrial matrix, inner membrane, inter-membrane space and outer membrane were measured in mitochondria isolated from control and regenerating rat liver. The specific activity of these enzymes was then followed for up to 30 days after operation. </br># The specific activity of marker enzymes for the matrix, inner membrane and inter-membrane space remained constant during liver regeneration.</br># However, the specific activities of monoamine oxidase and kynurenine hydroxylase, both outer-membrane markers, fell by 67% and 49% respectively from their control values at 4 days after operation, and returned to normal by about 3 weeks.</br># The repression of kynurenine hydroxylase activity was shown to be unrelated to any independent variation in tryptophan catabolism, based on tryptophan pyrrolase assays.</br># These results are considered to indicate that enzymes of the inner and outer mitochondrial membranes are synthesized asynchronously during morphogenesis.</br># The enzyme complement of purified outer membrane at 4 days after operation was about 50% of that of the appropriate control. Thus the composition of the outer membrane itself may vary dramatically, and supports the concept that constitutive enzymes may turn over independently of a membrane's existence.</br># The behaviour of the rotenone-insensitive, NADH cytochrome c reductase did not parallel the other outer-membrane enzymes for intact mitochondria, but did so when assayed in highly purified fractions of outer membrane. This suggests a labile binding to the outer membrane during the early stages of morphogenesis.</br># Electrophoresis of inner- and outer-membrane proteins revealed little difference between control and experimental mitochondria at 4 days, except for an increase in several, high-molecular-weight components of the outer membrane. These bands closely correspond to similar bands derived from smooth endoplasmic reticulum.</br># The results are discussed in relation to the biogenesis and turnover of mitochondria, and are considered to provide evidence for turnover as a unit, at least for the matrix, inner membrane, inter-membrane space and possibly some form of primary outer membrane.</br>ssibly some form of primary outer membrane.   +
  • '''''Significance:''''' Oxygen is indispen'''''Significance:''''' Oxygen is indispensable for aerobic life, but its utilization exposes cells and tissues to oxidative stress; thus, tight regulation of cellular, tissue, and systemic oxygen concentrations is crucial. Here, we review the current understanding of how the human organism (mal-)adapts to low (hypoxia) and high (hyperoxia) oxygen levels and how these adaptations may be harnessed as therapeutic or performance enhancing strategies at the systemic level. </br></br>'''''Recent Advances:''''' Hyperbaric oxygen therapy is already a cornerstone of modern medicine, and the application of mild hypoxia, that is, hypoxia conditioning (HC), to strengthen the resilience of organs or the whole body to severe hypoxic insults is an important preparation for high-altitude sojourns or to protect the cardiovascular system from hypoxic/ischemic damage. Many other applications of adaptations to hypo- and/or hyperoxia are only just emerging. HC-sometimes in combination with hyperoxic interventions-is gaining traction for the treatment of chronic diseases, including numerous neurological disorders, and for performance enhancement. </br></br>'''''Critical Issues:''''' The dose- and intensity-dependent effects of varying oxygen concentrations render hypoxia- and/or hyperoxia-based interventions potentially highly beneficial, yet hazardous, although the risks versus benefits are as yet ill-defined. </br></br>'''''Future Directions:''''' The field of low and high oxygen conditioning is expanding rapidly, and novel applications are increasingly recognized, for example, the modulation of aging processes, mood disorders, or metabolic diseases. To advance hypoxia/hyperoxia conditioning to clinical applications, more research on the effects of the intensity, duration, and frequency of altered oxygen concentrations, as well as on individual vulnerabilities to such interventions, is paramount.ities to such interventions, is paramount.  +
  • '''12<sup>th</sup> Conference '''12<sup>th</sup> Conference on Mitochondrial Physiology and MitoEAGLE WG and MC Meeting, 2017, Hradec Kralove, Czech Republic.'''</br></br>Co-organized with COST Action MitoEAGLE: [[COST_Action_MitoEAGLE#Grant_periods |Management Committee Meeting and Working Group Meetings]].[[COST_Action_MitoEAGLE#Grant_periods |Management Committee Meeting and Working Group Meetings]].  +
  • '''13<sup>th</sup> Conference on Mitochondrial Physiology and MitoEAGLE WG and MC Meeting, 2018, Jurmala, Latvia.'''  +
  • '''13th Workshop on High-Resolution Respirometry.''' Innsbruck, Tyrol, Austria; 1997 May 09-16. :>> O2k-Workshop: [[Oroboros Events| Current dates]] :>> Product: [[Oroboros O2k]], [[Oroboros O2k-Catalogue | O2k-Catalogue]]  +
  • '''14<sup>th</sup>Conference of the Asian Society of Mitochondrial Research and Medicine'''. Xi'an, Shaanxi, China; 2017 September.  +