flavin-adenine-dinucleotide and Hypoxia

Diminished availability of oxygen at the cellular level might account for organ dysfunction in sepsis. Although the classical forms of tissue hypoxia due to hypoxemia, anemia, or inadequate perfusion all might be important under some conditions, it seems increasingly likely that a fourth mechanism, namely cytopathic hypoxia, might play a role as well. The term cytopathic hypoxia is used to denote diminished production of adenosine triphosphate (ATP) despite normal (or even supranormal) PO2 values in the vicinity of mitochondria within cells. At least in theory, cytopathic hypoxia could be a consequence of several different (but mutually compatible) pathogenic mechanisms, including diminished delivery of a key substrate (e.g., pyruvate) into the mitochondrial tricarboxylic acid (TCA) cycle, inhibition of key mitochondrial enzymes involved in either the TCA cycle or the electron transport chain, activation of the enzyme, poly-(ADP)-ribosylpolymerase (PARP), or collapse of the protonic gradient across the inner mitochondrial membrane leading to uncoupling of oxidation (of NADH and FADH) from phosphorylation of ADP to form ATP. Tantalizing, but limited, data support the view that cytopathic hypoxia occurs in both animals and patients with sepsis or endotoxemia.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Anemia; Animals; Cell Hypoxia; Citric Acid Cycle; Electron Transport; Endotoxemia; Enzyme Activation; Enzyme Inhibitors; Flavin-Adenine Dinucleotide; Humans; Hypoxia; Mitochondria; NAD; Oxidation-Reduction; Oxygen; Oxygen Consumption; Phosphorylation; Poly(ADP-ribose) Polymerases; Pyruvates; Sepsis

This essay illustrates the ways in which beta-oxidation and the citric acid cycle interact. These included: 1) competition for CoASH, 2) competition for NAD+, and 3) competition for FADH2 oxidation. By means of the above, the cell is able to maintain a precise coordination between the activation of fatty acids in the cytosol, beta-oxidation in the mitochondria, and the complete oxidation of acetyl-CoA to CO2 via the citric acid cycle throughout a wide range of energy demands and oxygen availability.

Topics: Animals; Citric Acid Cycle; Coenzyme A; Cytosol; Fatty Acids; Fatty Acids, Nonesterified; Flavin-Adenine Dinucleotide; Genes; Hypoxia; Insecta; Lipid Metabolism; Mitochondria, Muscle; Muscles; Myocardium; NAD; Species Specificity; Vertebrates

Activity of the energy production systems in rabbit liver and kidney under conditions of unfavorable vibration exposure was studied by the polarography method using a galvanic-type closed oxygen sensor. The rate of oxidation of endogenous substrates by mitochondria was determined by the tissue and was 5.2±0.6 and 8.13±1.4 (ng-atom O)×min

Topics: 2,4-Dinitrophenol; Animals; Electron Transport; Flavin-Adenine Dinucleotide; Hypoxia; Kidney; Liver; Male; Mitochondria; NAD; Organ Specificity; Oxidative Phosphorylation; Rabbits; Succinic Acid; Vibration

Hyper- but not normoglycemic cats exposed to 8 min of anoxia show neurologic signs (fasciculations, myoclonic jerks, seizures) that develop after a symptom-free period. We examined brain mitochondrial function and metabolite concentrations at 0, 1, 3, and 5 h following exposure to anoxia, to correlate biochemical findings with the presence ("symptomatic") or absence ("presymptomatic") of neurologic signs. Brain mitochondria isolated postexposure only from symptomatic cats showed markedly decreased (-50%), state 3 (ADP-stimulated), and uncoupler-stimulated respiration rates with NAD- and FAD-linked substrates. Respiratory control and ADP/oxygen (ADP/O) ratios remained unchanged, indicating, respectively, that coupling and efficiency of ATP synthesis were preserved. Thus, inhibition of electron transport chain function, not phosphorylative activity, may be rate limiting for respiration. During anoxia, hyperglycemic cats showed higher brain lactate levels (26 versus 20 mumol/g), but similar ATP and phosphocreatine concentrations, compared with normoglycemic cats. After exposure, in all animals lactate and phosphocreatine were restored to control levels, whereas ATP remained at 85%. Cats that became symptomatic demonstrated four- to sixfold increases in lactate and 50% reductions in phosphocreatine. At 3 and 5 h postexposure, symptomatic animals showed significant reductions in ATP concentrations. We conclude that although initially asymptomatic, hyperglycemic cats exposed to anoxia undergo a neurologic deterioration over several hours following reoxygenation that is correlated with inhibition of mitochondrial respiration, increases in tissue lactate, and decreases in energy state.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Blood Glucose; Brain; Carbon Dioxide; Cats; Cytochrome b Group; Female; Flavin-Adenine Dinucleotide; Glutamates; Glutamic Acid; Hydrogen-Ion Concentration; Hypoxia; Lactates; Lactic Acid; Male; Mitochondria; NAD; Organ Size; Oxygen; Oxygen Consumption; Phosphocreatine; Succinates; Succinic Acid

Topics: Adenosine Triphosphate; Amobarbital; Animals; Anura; Biological Transport; Flavin-Adenine Dinucleotide; Gastric Juice; Gastric Mucosa; Hypoxia; Membrane Potentials; NAD; Oxidoreductases; Oxygen Consumption; Spectrophotometry