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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." - Wikipedia
    isplayed in a colony of ants." - Wikipedia  +
  • # A Mg<sup>2+</sup>-dependent
    # 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. # 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. # 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. # 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.
    e to an effect on the membrane structure.   +
  • # A specific succinate requirement for en
    # A specific succinate requirement for energy-linked reduction of mitochondrial pyridine nucleotide is demonstrated in pigeon heart and guinea pig kidney mitochondria. # The succinate used in this reduction can be generated in the oxidation of malate plus glutamate or of α-ketoglutarate. # The role of succinate is identified by the specific inhibitory responses of the reaction to malonate, phosphate, and fumarate. # 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.
    de may be considered to be compartmented.   +
  • # Aus Saeugetierlebern lassen sich Suspen
    # 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. # 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. # 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. # 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.
    rn infolge von Sauerstoffmangel erleiden.   +
  • # Estimations of the carbohydrate metabol
    # 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. # 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. # Xylose is not metabolised by tumour tissue. # Evidence is brought forward which suggests that the glycolytic activity of tumours exerts a checking effect on their respiration. # 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. 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.
    available for uncontrolled ptoliferation.   +
  • # Mechanically fragmented beef heart
    # 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. # The highly purified, soluble coupling factor catalyzed a dinitrophenol-stimulated hydrolysis of ATP. # 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. # The significance of these results in relation to current concepts of the mechanism of oxidative phosphorylation has been discussed.
    ve phosphorylation has been discussed.   +
  • # Submitochondrial particles have been se
    # 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. # Preparations of Fc2 purified from the sodium thiocyanate extract stimulated the 32Pi-ATP exchange reaction and oxidative phosphorylation in silicotungstate-treated submitochondrial particles. # 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.
    -ase to the inner mitochondrial membrane.   +
  • # Succinic dehydrogenase has been iso
    # 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. # 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. # 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. # The QO2, has been measured as 20,000 and the turnover number as 3000 under the standard assay conditions. # 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.
    enzyme from this type of inhibition.   +
  • # The pathway of electron transfer f
    # 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. # 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. # 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. # 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. # 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.
    nd of some consequence in state 4.   +
  • # The purification o f a soluble ATP
    # 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. # 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. # Attempts to demonstrate an exchange between either Pi32 or C14-ADP and ATP in the presence of the enzyme were unsuccessful. # The properties of the purified enzyme are discussed in relation to particulate mitochondrial ATPase and to myosin ATPase.
    hondrial ATPase and to myosin ATPase.   +
  • # The ability to phosphorylate ADP during
    # 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. # 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. # 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. # 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. # Phosphorylation efficiency can be significantly improved by purification of the vesicles on sucrose density gradients.
    he vesicles on sucrose density gradients.   +
  • # The reduction of added DPN by succinate
    # The reduction of added DPN by succinate catalyzed by submitochondrial particles from beef heart has been studied. # The reduction was endergonic and required specifically the addition of ATP. # 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. # The rate of reduction was influenced by phosphate and ADP and their effects became pronounced if added together. # The effect of DPNH was marked only if added in a concentration equal to or exceeding that of DPN. # Respiratory inhibitors acting in the flavin region of the respiratory chain blocked the reaction.
    e respiratory chain blocked the reaction.   +
  • # The α-ketoglutaric oxidase system of he
    # 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. # 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. # 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. # As the tonicity is increased by saline, sucrose or phosphate, the activity of the α-ketoglutaric oxidase system decreases. # 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. # Phosphate, in high concentration, decreases the P:O ratio; the optimal concentration is 0.03 M. # 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''.
    latter are deficient in cytochrome ''c''.   +
  • # [[Mitochondrial marker enzymes|Marker e
    # [[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. # The specific activity of marker enzymes for the matrix, inner membrane and inter-membrane space remained constant during liver regeneration. # 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. # The repression of kynurenine hydroxylase activity was shown to be unrelated to any independent variation in tryptophan catabolism, based on tryptophan pyrrolase assays. # These results are considered to indicate that enzymes of the inner and outer mitochondrial membranes are synthesized asynchronously during morphogenesis. # 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. # 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. # 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. # 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.
    ibly some form of primary outer membrane.   +
  • '''>> [[MiP2013 Abstracts|MiP2013 Abstracts in the MiPMap]] - >> [[Laner 2013 Mitochondr Physiol Network MiP2013]]'''  +
  • '''12<sup>th</sup> Conference
    '''12<sup>th</sup> Conference on Mitochondrial Physiology and MitoEAGLE WG and MC Meeting, 2017, Hradec Kralove, Czech Republic.''' Co-organized with COST Action MitoEAGLE: [[COST_Action_MitoEAGLE#Grant_periods |Management Committee Meeting and Working Group Meetings]].
    ttee 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.  +
  • '''15<sup>th</sup> MiP Conference: MitoEAGLE Summit (MC Meeting and MitoEAGLE WG), 2020, Obergurgl, Austria.'''  +
  • '''16th International Course on High-Resolution Respirometry.''' Innsbruck, Tyrol, Austria; 1998 December 10. :>> O2k-Workshop: [[Oroboros Events| Current dates]] :>> Product: [[Oroboros O2k]], [[Oroboros O2k-Catalogue | O2k-Catalogue]]  +
  • '''19<sup>th</sup> European Bioenergetics Conference 2016, Riva del Garda, IT'''  +
  • '''1<sup>st</sup> MC Meeting, [[COST Action MitoEAGLE]], Brussels, BE'''  +
  • '''2016 Jul 07-13, Kuehtai, AT.''' The pr
    '''2016 Jul 07-13, Kuehtai, AT.''' The project [[K-Regio MitoFit |MitoFit]] aims at developing novel laboratory standards and diagnostic monitoring of a mitochondrial fitness score. With an international team of outstanding mitochondrial experts, the '''MitoFit Science Camp''' will provide a unique opportunity to receive first-hand introductions to state-of-the-art diagnostic monitoring of mitochondrial respiratory function combined with hands-on training on HRR (IOC112). Diverse areas are covered such as protective medicine, exercise physiology, mitochondrial pharmacology, aging, and comparative mitochondrial physiology (cell types, tissues, species). The common focus is on methodology, experimental details and quality control. The MitoFit Science Camp is a student- and research-oriented even, and may be considered as a sequence of workshops rather than a conference or school, addressing key topics of the COST Action [[MitoEAGLE]] project. This will provide a key opportunity to prepare the [[COST Action MitoEAGLE |1<sup>st</sup> Management Committee Meeting]].
    t;/sup> Management Committee Meeting]].  +
  • '''2017 Jul 23-30, Obergurgl, AT.'''  +
  • '''2017 Jul 27-30, Obergurgl, AT.'''  +
  • '''2<sup>nd</sup> Padua-Mit-Innsbruck “Mitochondrial Conference”. Pauda, Italy; 2017 September.  +
  • '''2nd symposium Mitochondria in Health and Disease'''. New York, US; 2017.  +
  • '''5<sup>th</sup> MiP''school'' on Mitochondrial Physiology, 2012 Jul 09-13, Cambridge, UK.'''  +
  • '''64<sup>th</sup> Harden Conference on: Mitochondrial Physiology, 2007, Ambleside , United Kingdom.'''  +
  • '''79<sup>th</sup> Harden Conference: Oxygen Evolution and Reduction - Common Principles, [ Harden Conference 2016], Innsbruck, AT'''  +
  • '''A Mitochondrial Festival in the Spirit of [[Gentle Science]]''' [[File:Bioblast-icon.jpg|right|200px|Photo by Philipp Gradl, Artist: Bernd Weinmayer]]  +
  • '''AIM/HYPOTHESIS''':Studies have suggeste
    '''AIM/HYPOTHESIS''':Studies have suggested a link between insulin resistance and mitochondrial dysfunction in skeletal muscles. Our primary aim was to investigate the effect of aerobic training on mitochondrial respiration and mitochondrial reactive oxygen species (ROS) release in skeletal muscle of obese participants with and without type 2 diabetes. '''METHODS''': Type 2 diabetic men (''n'' = 13) and control (''n'' = 14) participants matched for age, BMI and physical activity completed 10 weeks of aerobic training. Pre- and post-training muscle biopsies were obtained before a euglycaemic-hyperinsulinaemic clamp and used for measurement of respiratory function and ROS release in isolated mitochondria. '''RESULTS''': Training significantly increased insulin sensitivity, maximal oxygen consumption and muscle mitochondrial respiration with no difference between groups. When expressed in relation to a marker of mitochondrial density (intrinsic mitochondrial respiration), training resulted in increased mitochondrial ADP-stimulated respiration (with NADH-generating substrates) and decreased respiration without ADP. Intrinsic mitochondrial respiration was not different between groups despite lower insulin sensitivity in type 2 diabetic participants. Mitochondrial ROS release tended to be higher in participants with type 2 diabetes. '''CONCLUSIONS/INTERPRETATION''': Aerobic training improves muscle respiration and intrinsic mitochondrial respiration in untrained obese participants with and without type 2 diabetes. These adaptations demonstrate an increased metabolic fitness, but do not seem to be directly related to training-induced changes in insulin sensitivity.
    ng-induced changes in insulin sensitivity.  +
  • '''AIMS/HYPOTHESIS:''' We previously showe
    '''AIMS/HYPOTHESIS:''' We previously showed that type 2 diabetic patients are characterised by compromised intrinsic mitochondrial function. Here, we examined if exercise training could increase intrinsic mitochondrial function in diabetic patients compared with control individuals. '''METHODS:''' Fifteen male type 2 diabetic patients and 14 male control individuals matched for age, BMI and VO(2max) enrolled in a 12 week exercise intervention programme. ''Ex vivo'' mitochondrial function was assessed by high-resolution respirometry in permeabilised muscle fibres from vastus lateralis muscle. Before and after training, insulin-stimulated glucose disposal was examined during a hyperinsulinaemic-euglycaemic clamp. '''RESULTS:''' Diabetic patients had intrinsically lower ADP-stimulated state 3 respiration and lower carbonyl cyanide 4-(trifluoro-methoxy)phenylhydrazone (FCCP)-induced maximal oxidative respiration, both on glutamate and on glutamate and succinate, and in the presence of palmitoyl-carnitine (''p'' < 0.05). After training, diabetic patients and control individuals showed increased state 3 respiration on the previously mentioned substrates (''p'' < 0.05); however, an increase in FCCP-induced maximal oxidative respiration was observed only in diabetic patients (''p'' < 0.05). The increase in mitochondrial respiration was accompanied by a 30% increase in mitochondrial content upon training (''p'' < 0.01). After adjustment for mitochondrial density, state 3 and FCCP-induced maximal oxidative respiration were similar between groups after training. Improvements in mitochondrial respiration were paralleled by improvements in insulin-stimulated glucose disposal in diabetic patients, with a tendency for this in control individuals. '''CONCLUSIONS/INTERPRETATION:''' We confirmed lower intrinsic mitochondrial function in diabetic patients compared with control individuals. Diabetic patients increased their mitochondrial content to the same extent as control individuals and had similar intrinsic mitochondrial function, which occurred parallel with improved insulin sensitivity.
    arallel with improved insulin sensitivity.  +
  • '''APS Conference: Physiological Bioenergetics: Mitochondria from Bench to Bedside, Bioenergetics17'''. San Diego CA, USA; 2017 August.  +
  • '''Abstract''': Add a short abstract here,
    '''Abstract''': Add a short abstract here, including title, authors, affiliations, text (up to 250 words), and 2-6 references. You may edit your abstract any time. Information will be provided on a deadline for editing/submitting final abstracts (including a pdf file in final format). '''Title''': Not capitalized. '''Authors''': Presenting author with full name (first name spelled out), other authors with initials only. Numbers in parentheses after each author should indicate the affiliations. '''Addresses''': Numbers in parentheses are placed at the beginning of the address for indicating the affiliation. The e-mail address of the presenting author should be given at the end of all addresses. '''Main text''': Structured into paragraphs without headers. The standard structure of abstracts should be followed as appropriate (Introduction / Methods / Results / Conclusions / References). '''Figure''': You may submit one or two figures (jpg format), without caption if full explanation is given in the abstract. '''References''' in the text are given by numbers in brackets. Full references should be numbered and include all authors (family name and initials without punctuation), followed by the year of publication in parentheses, full title, journal name abbreviated with punctuation (italic), volume number followed by a colon, and first and last pages. See abstracts on the MiP website for style – MiP2005/Organisation/Abstracts. Tick on appropriate boxes blow in the list of 'Labels', and add additional keywords not covered in these labels. An extension is possible in the free text (not more than 2 pages). Further comments may be added in the discussion.
    r comments may be added in the discussion.  +
  • '''Abstract''': Add a short abstract here,
    '''Abstract''': Add a short abstract here, including title, authors, affiliations, text (up to 250 words), and 2-6 references. You may edit your abstract any time. Information will be provided on a deadline for editing/submitting final abstracts (including a pdf file in final format), and on acceptance of the abstract for presentation at MiP2011. '''Title''': Not capitalized. '''Authors''': Presenting author with full name (first name spelled out), other authors with initials only. Numbers in parentheses after each author should indicate the affiliations. '''Addresses''': Numbers in parentheses are placed at the beginning of the address for indicating the affiliation. The e-mail address of the presenting author should be given at the end of all addresses. '''Main text''': Structured into paragraphs without headers. The standard structure of abstracts should be followed as appropriate (Introduction / Methods / Results / Conclusions / References). '''Figure''': You may submit one or two figures (jpg format), without caption if full explanation is given in the abstract. '''References''' in the text are given by numbers in brackets. Full references should be numbered and include all authors (family name and initials without punctuation), followed by the year of publication in parentheses, full title, journal name abbreviated with punctuation (italic), volume number followed by a colon, and first and last pages. See abstracts on the MiP website for style – MiP2005/Organisation/Abstracts. Tick on appropriate boxes blow in the list of 'Labels', and add additional keywords not covered in these labels. An extension is possible in the free text (not more than 2 pages). Further comments may be added in the discussion.
    r comments may be added in the discussion.  +
  • '''Abstracts are listed here in the frame of the [[MiPMap]] for the 7<sup>th</sup> MiP''school'' on Mitochondrial Physiology, 2015 Mar 24-28, Cape Town, ZA.'''  +
  • '''Aim''' To examine if the body mass inde
    '''Aim''' To examine if the body mass index (BMI) in midlife is related to cognitive function 30 years later in a dementia-free sample. '''Methods''' BMI was reported in 1963 at age 50–60 years, and cognitive abilities were examined 30 years later in a longitudinal design with 5 measurement occasions at 2-year intervals (n = 417). The cognitive abilities examined included tests of long-term memory, short-term memory, speed, verbal and spatial ability. '''Results''' Multilevel modeling adjusting for demographic and lifestyle factors, and relevant diseases showed that a higher BMI in midlife predicted lower test performance 30 years later. Significant associations between BMI and level of performance were found in all cognitive abilities; however, a higher midlife BMI was not associated with steeper cognitive decline. '''Conclusion''' Our results indicate that midlife overweight is related to lower overall cognitive function in old age. The fact that BMI-related effects were noted in mean-level cognitive performance, whereas only one ability showed differences in slopes, suggests that the negative effect of overweight has an onset before the entry into very old age.
    onset before the entry into very old age.  +
  • '''Aim''': Skeletal muscle insulin resista
    '''Aim''': Skeletal muscle insulin resistance has been linked to mitochondrial dysfunction. We examined how improvements in muscular insulin sensitivity following rosiglitazone (ROSI) or pioglitazone (PIO) treatment would affect muscle mitochondrial function in patients with type 2 diabetes mellitus (T2DM). '''Methods''': Muscle biopsies were obtained from 21 patients with T2DM before and after 12 weeks on either ROSI (4 mg once daily) [n = 12; age, 59.2 +/- 2.2 years; body mass index (BMI), 29.6 +/- 0.7 kg/m(2)] or PIO (30 mg once daily) (n = 9; age, 56.3 +/- 2.4 years; BMI, 29.5 +/- 1.5 kg/m(2)). An age- and BMI-matched control group was also included (n = 8; age, 61.8 +/- 2.3 years; BMI, 28.4 +/- 0.6 kg/m(2)). Insulin sensitivity, citrate synthase- and beta-hydroxyacyl-CoA-dehydrogenase (HAD) activity, intramuscular triglyceride (IMTG) and protein content of complexes I-IV were measured, while mitochondrial respiration per milligram muscle was measured in saponin-treated skinned muscle fibres using high-resolution respirometry. '''Results''': Mitochondrial respiration per milligram muscle was lower in T2DM compared to controls at baseline and decreased during ROSI treatment but increased during PIO treatment. Citrate synthase activity and average protein content of complexes I-IV were unchanged in the ROSI group, but protein content of complexes II and III increased during PIO treatment. Insulin sensitivity improved in all patients, but IMTG levels were unchanged. '''Conclusions''': We show opposite effects of ROSI and PIO on mitochondrial respiration, and also show that insulin sensitivity can be improved independently of changes in mitochondrial respiration. We confirm that mitochondrial respiration is reduced in T2DM compared to age- and BMI-matched control subjects.
    to age- and BMI-matched control subjects.  +
  • '''Aim:''' To investigate mechanisms behin
    '''Aim:''' To investigate mechanisms behind heptanol (Hp)-induced infarct size reduction and in particular if protection by pre-treatment with Hp is triggered through mitochondrial mechanisms. '''Methods:''' Langendorff perfused rat hearts, isolated mitochondria and isolated myocytes were used. Infarct size, mitochondrial respiration, time to mitochondrial permeability transition pore (MPTP) opening and AKT and glycogen synthase kinase 3 beta (GSK-3β) phosphorylation were examined. '''Results:''' Pre-treatment with Hp reduced infarct size from 29.7 ± 3.4% to 12.6 ± 2.1%. Mitochondrial potassium channel blockers 5-hydroxy decanoic acid (5HD) blocking mitoK(ATP) and paxilline (PAX) blocking mitoK(Ca) abolished cardioprotective effect of Hp (Hp + 5HD 36.7 ± 2.9% and Hp + PAX 40.2 ± 2.8%). Hp significantly reduced respiratory control ratio in both subsarcolemmal and interfibrillar mitochondria in a dose-dependent manner (0.5-5.0 mm). The ADP oxygen ratio was also significantly reduced by Hp (2 mm). Laser scanning confocal microscopy of tetramethylrhodamine-loaded isolated rat myocytes using line scan mode showed that Hp increased time to MPTP opening. Western blot analysis showed that pre-treatment with Hp increased phosphorylation of AKT and GSK-3β before ischaemia and after 30 min of global ischaemia. '''Conclusion''': Pre-treatment with Hp protects the heart against ischaemia-reperfusion injury. This protection is most likely mediated via mitochondrial mechanisms which initiate a signalling cascade that converges on inhibition of opening of MPTP.
    onverges on inhibition of opening of MPTP.  +
  • '''Aims/Hypothesis''': Mitochondrial respi
    '''Aims/Hypothesis''': Mitochondrial respiration has been linked to insulin resistance. We studied mitochondrial respiratory capacity and substrate sensitivity in patients with type 2 diabetes (patients), and obese and lean control participants. '''Methods''': Mitochondrial respiration was measured in permeabilised muscle fibres by respirometry. Protocols for respirometry included titration of substrates for [[Complex I]] (glutamate), [[Complex II]] (succinate) and both (octanoyl-carnitine). Myosin heavy chain (MHC) composition, antioxidant capacity (manganese superoxide dismutase [MnSOD]), [[citrate synthase]] activity and maximal oxygen uptake (VO2) were also determined. Insulin sensitivity was determined with the isoglycaemic-hyperinsulinaemic clamp technique. '''Results''': Insulin sensitivity was different (''P'' < 0.05) between the groups (patients<obese controls<lean controls). MnSOD was lower in patients than in lean controls. MHC I content was lowest in patients (37 ± 11% [mean ± SE] vs 53 ± 6% and 56 ± 4%) vs obese controls and lean controls, respectively. VO2 was highest in lean controls (40 ± 3 ml min(-1) kg(-1) [mean ± SE]) compared with patients (25 ± 2) and obese controls (27 ± 2). Mitochondrial content (citrate synthase) was higher (''P'' < 0.05) in lean controls than in patients and obese controls. When normalised for mitochondrial content by citrate synthase, mitochondrial respiratory capacity was similar in all groups. However, the half maximal substrate concentration (''C''<sub>50</sub>) for Complex I was significantly lower (''P'' = 0.03) in patients (1.1 ± 0.2 mmol/l [mean ± SE]) than in obese (2.0 ± 0.3) and lean (1.8 ± 0.3) controls. Likewise, ''C''<sub>50</sub> for Complex II was lower (''P'' = 0.02) in patients (3.5 ± 0.2 mmol/l [mean ± SE]) than in obese controls (4.1 ± 0.2), but did not differ from that in lean controls (3.8 ± 0.4). Substrate sensitivity for octanoyl-carnitine did not differ between groups. '''Conclusions/interpretation''': Increased mitochondrial substrate sensitivity is seen in skeletal muscle from type 2 diabetic patients and is confined to non-lipid substrates. Respiratory capacity per mitochondrion is not decreased with insulin resistance.
    is not decreased with insulin resistance.  +
  • '''AussieMit 2016, Sydney, AU'''  +
  • '''BACKGROUND & AIMS:''' Liver ischemi
    '''BACKGROUND & AIMS:''' Liver ischemia/reperfusion (I/R) injury is a frequent cause of organ dysfunction. Loss of the oxygen sensor prolyl hydroxylase domain enzyme 1 (PHD1) causes tolerance of skeletal muscle to hypoxia. We assessed whether loss or short-term silencing of PHD1 could likewise induce hypoxia tolerance in hepatocytes and protect them against hepatic I/R damage. '''METHODS:''' Hepatic ischemia was induced in mice by clamping of the portal vessels of the left lateral liver lobe; 90 minutes later livers were reperfused for 8 hours for I/R experiments. Hepatocyte damage following ischemia or I/R was investigated in PHD1-deficient (PHD1(-/-)) and wild-type mice or following short hairpin RNA-mediated short-term inhibition of PHD1 ''in vivo''. '''RESULTS:''' PHD1(-/-) livers were largely protected against acute ischemia or I/R injury. Among mice subjected to hepatic I/R followed by surgical resection of all nonischemic liver lobes, more than half of wild-type mice succumbed, whereas all PHD1(-/-) mice survived. Also, short-term inhibition of PHD1 through RNA interference-mediated silencing provided protection against I/R. Knockdown of PHD1 also induced hypoxia tolerance of hepatocytes ''in vitro''. Mechanistically, loss of PHD1 decreased production of oxidative stress, which likely relates to a decrease in oxygen consumption as a result of a reprogramming of hepatocellular metabolism. '''CONCLUSIONS:''' Loss of PHD1 provided tolerance of hepatocytes to acute hypoxia and protected them against I/R-damage. Short-term inhibition of PHD1 is a novel therapeutic approach to reducing or preventing I/R-induced liver injury.
    ng or preventing I/R-induced liver injury.  +
  • '''BACKGROUND AND AIMS:'''We investigated
    '''BACKGROUND AND AIMS:'''We investigated whether in patients with liver cirrhosis reduced muscle strength is related to dysfunction of muscle mitochondria. '''METHODS:''' The mitochondrial respiratory capacity of the tibial anterior muscle was evaluated in seven patients and eight healthy control subjects by 31P nuclear magnetic resonance spectroscopy (31PMRS) to express ATP turnover in vivo and by respirometry of permeabilized fibres from the same muscle to express the in vitro capacity for oxygen consumption. '''RESULTS:''' Maximal voluntary contraction force for plantar extension was low in the patients (46% of the control value; P < 0.05), but neither the capacity for mitochondrial ATP synthesis, V(max-ATP) (0.38 ± 0.26 vs. 0.50 ± 0.07 mM s(-1) ; P = 0.13) nor the in vitro VO(2max) (0.52 ± 0.21 vs. 0.48 ± 0.21 μmol O2 (min g wet wt.)(-1) P = 0.25) were lowered correspondingly. Also, the activity of citrate synthesis and the respiratory chain complexes II and IV were similar in patients and controls. However during the contractions, the contribution to initial anaerobic ATP production from glycolysis relative to that from PCr was reduced in the patients (0.73 ± 0.22 vs. 0.99 ± 0.09; P < 0.01). '''CONCLUSIONS:''' The results demonstrate that the markedly lower capacity for force generation in patients with liver cirrhosis is unrelated to their capacity for muscle ATP turnover, but the attenuated initial acceleration of anaerobic glycolysis suggests that these patients could be affected by a central limitation to force generation.
    a central limitation to force generation.  +
  • '''BACKGROUND:''' Mild cold exposure and o
    '''BACKGROUND:''' Mild cold exposure and overfeeding are known to elevate energy expenditure in mammals, including humans. This process is called adaptive thermogenesis. In small animals, adaptive thermogenesis is mainly caused by mitochondrial uncoupling in brown adipose tissue and regulated via the sympathetic nervous system. In humans, skeletal muscle is a candidate tissue, known to account for a large part of the epinephrine-induced increase in energy expenditure. However, mitochondrial uncoupling in skeletal muscle has not extensively been studied in relation to adaptive thermogenesis in humans. Therefore we hypothesized that cold-induced adaptive thermogenesis in humans is accompanied by an increase in mitochondrial uncoupling in skeletal muscle. '''METHODOLOGY/PRINCIPAL FINDINGS:''' The metabolic response to mild cold exposure in 11 lean, male subjects was measured in a respiration chamber at baseline and mild cold exposure. Skeletal muscle mitochondrial uncoupling (state 4) was measured in muscle biopsies taken at the end of the respiration chamber stays. Mild cold exposure caused a significant increase in 24h energy expenditure of 2.8% (0.32 MJ/day, range of -0.21 to 1.66 MJ/day, ''p''<0.05). The individual increases in energy expenditure correlated to state 4 respiration (''p''<0.02, ''R''(2) = 0.50). '''CONCLUSIONS/SIGNIFICANCE:''' This study for the first time shows that in humans, skeletal muscle has the intrinsic capacity for cold induced adaptive thermogenesis via mitochondrial uncoupling under physiological conditions. This opens possibilities for mitochondrial uncoupling as an alternative therapeutic target in the treatment of obesity.
    peutic target in the treatment of obesity.  +
  • '''Background ''' Mitochondrial dysfuncti
    '''Background ''' Mitochondrial dysfunction is one of the most characteristic properties of the cancer cell. However, it is not known whether oxidative energy metabolism has already become altered in conditions of atrophic gastritis, a precancerous state of gastric disease. The purpose of our study was to comparatively characterize oxidative phosphorylation (OXPHOS) in the atrophic and nonatrophic gastric corpus mucosa. '''Methods''' Mucosal biopsies were taken from 12 patients with corpus dominant atrophic gastritis and from 12 patients with nonatrophic mucosa (controls). One part of the tissue samples was permeabilized with saponin for analysis of the function of the respiratory chain using high-resolution respirometry, and another part was used for histopathological examination. The serum level of pepsinogen I (S-PGI) was determined with a specific enzyme immunoassay (EIA). '''Results''' Compared to the control group, the maximal capacity of OXPHOS in the atrophy group was almost twofold lower, the respiratory chain complex I-dependent respiration, normalized to complex II-dependent respiration, was reduced, and respiratory control by ADP in the presence of succinate was increased in the atrophic corpus mucosa. In the whole cohort of the patients studied, serum S-PGI level correlated positively with complex I-dependent respiration or complex Idependent to complex II-dependent respiration ratio. '''Conclusions''' Corpus dominant atrophic gastritis is characterized by decreased respiratory capacity and relative deficiency of the respiratory complex I of mitochondria in the mucosa, the latter defect probably limiting mitochondrial ATP production and energetic support of the secretory function of the zymogenic mucosal cells.
    y function of the zymogenic mucosal cells.  +
  • '''Background''' Mitochondrial dysfunction
    '''Background''' Mitochondrial dysfunction and degradation takes a central role in current paradigms of neurodegeneration in Parkinson's disease (PD). Loss of DJ-1 function is a rare cause of familial PD. Although a critical role of DJ-1 in oxidative stress response and mitochondrial function has been recognized, the effects on mitochondrial dynamics and downstream consequences remain to be determined. '''Methodology/Principal Findings''' Using DJ-1 loss of function cellular models from knockout (KO) mice and human carriers of the E64D mutation in the DJ-1 gene we define a novel role of DJ-1 in the integrity of both cellular organelles, mitochondria and lysosomes. We show that loss of DJ-1 caused impaired mitochondrial respiration, increased intramitochondrial reactive oxygen species, reduced mitochondrial membrane potential and characteristic alterations of mitochondrial shape as shown by quantitative morphology. Importantly, ultrastructural imaging and subsequent detailed lysosomal activity analyses revealed reduced basal autophagic degradation and the accumulation of defective mitochondria in DJ-1 KO cells, that was linked with decreased levels of phospho-activated ERK2. '''Conclusions/Significance''' We show that loss of DJ-1 leads to impaired autophagy and accumulation of dysfunctional mitochondria that under physiological conditions would be compensated via lysosomal clearance. Our study provides evidence for a critical role of DJ-1 in mitochondrial homeostasis by connecting basal autophagy and mitochondrial integrity in Parkinson's disease.
    hondrial integrity in Parkinson's disease.  +
  • '''Background''': Atherosclerosis is one o
    '''Background''': Atherosclerosis is one of the major complications of diabetes, which may result from insulin resistance via mitochondrial dysfunction. Although a strong association between insulin resistance and cardiovascular disease has been suggested, it is not clear yet whether stress-inducing factors damage mitochondria and insulin signaling pathway in cardiovascular tissues. '''Methods''': We investigated whether stress-induced mitochondrial dysfunction might alter the insulin/Akt signaling pathway in A10 rat vascular smooth muscle cells (VSMC). '''Results''': The treatment of oxidized low density lipoprotein (oxLDL) decreased ATP contents, mitochondrial respiration activity, mRNA expressions of OXPHOS subunits and IRS-1/2 and insulin-mediated phosphorylations of Akt and AMP-activated protein kinase (AMPK). Similarly, dideoxycytidine (ddC), the mtDNA replication inhibitor, or rotenone, OXPHOS complex I inhibitor, inhibited the insulin-mediated pAkt while increased pAMPK regardless of insulin. Reciprocally, an inhibitor of Akt, triciribine (TCN), decreased cellular ATP contents. Overexpression of Akt dominant positive reversed the oxLDL- or ddC-mediated ATP decrease but AMPK activator did not. Akt activation also normalized the aberrant VSMC migration induced by ddC. '''Conclusions''': Defective insulin signaling and mitochondrial function may collectively contribute to developing cardiovascular disease. '''General significance''': Akt may be a possible therapeutic target for treating insulin resistance-associated atherosclerosis.
    lin resistance-associated atherosclerosis.  +
  • '''Background''': It has been hypothesized
    '''Background''': It has been hypothesized that reduced axonal transport contributes to the degeneration of neuronal processes in Parkinson's disease (PD). Mitochondria supply the adenosine triphosphate (ATP) needed to support axonal transport and contribute to many other cellular functions essential for the survival of neuronal cells. Furthermore, mitochondria in PD tissues are metabolically and functionally compromised. To address this hypothesis, we measured the velocity of mitochondrial movement in human transmitochondrial cybrid "cytoplasmic hybrid" neuronal cells bearing mitochondrial DNA from patients with sporadic PD and disease-free age-matched volunteer controls (CNT). The absorption of low level, near-infrared laser light by components of the mitochondrial electron transport chain (mtETC) enhances mitochondrial metabolism, stimulates oxidative phosphorylation and improves redox capacity. PD and CNT cybrid neuronal cells were exposed to near-infrared laser light to determine if the velocity of mitochondrial movement can be restored by low level light therapy (LLLT). Axonal transport of labeled mitochondria was documented by time lapse microscopy in dopaminergic PD and CNT cybrid neuronal cells before and after illumination with an 810 nm diode laser (50 mW/cm<sup>2</sup>) for 40 s. Oxygen utilization and assembly of mtETS complexes were also determined. '''Results''': The velocity of mitochondrial movement in PD cybrid neuronal cells (0.175 +/- 0.005 SEM) was significantly reduced (p < 0.02) compared to mitochondrial movement in disease free CNT cybrid neuronal cells (0.232 +/- 0.017 SEM). For two hours after LLLT, the average velocity of mitochondrial movement in PD cybrid neurites was significantly (p < 0.003) increased (to 0.224 +/- 0.02 SEM) and restored to levels comparable to CNT. Mitochondrial movement in CNT cybrid neurites was unaltered by LLLT (0.232 +/- 0.017 SEM). Assembly of complexes in the mtETC was reduced and oxygen utilization was altered in PD cybrid neuronal cells. PD cybrid neuronal cell lines with the most dysfunctional mtETC assembly and oxygen utilization profiles were least responsive to LLLT. '''Conclusion''': The results from this study support our proposal that axonal transport is reduced in sporadic PD and that a single, brief treatment with near-infrared light can restore axonal transport to control levels. These results are the first demonstration that LLLT can increase axonal transport in model human dopaminergic neuronal cells and they suggest that LLLT could be developed as a novel treatment to improve neuronal function in patients with PD.
    ove neuronal function in patients with PD.  +