Reduced O2 Availability Research Articles

Modulation of ATP production by oxygen in obstructive lung disease as assessed by 31P-MRS.

Inadequate O2 supply may impair intramuscular oxidative metabolism and O2 availability may modulate ATP production within exercising muscle. Therefore, we studied ATP flux from anaerobic glycolysis, the creatine kinase reaction, and oxidative phosphorylation using 31P-magnetic resonance spectroscopy kinetic data collected during exercise. We examined six chronic obstructive pulmonary disease (COPD) patients with severe hypoxemia (group 1), seven COPD patients with mild hypoxemia (group 2), and seven healthy control subjects. Exercise (90-s isometric contraction of the gastrocnemius-soleus muscle group, 40% of max) was performed on room air for all subjects; for COPD patients, it was repeated during supplemental O2 at identical power outputs, with 60-min rest between the two sets. In group 1 (air vs. O2), oxidative phosphorylation ATP production was lower (P < 0.05), anaerobic glycolysis ATP production was higher (P < 0.05), and anaerobic glycolysis plus creatine kinase ATP production tended to be higher (P = 0.06). In group 2, no differences were observed across conditions. Assuming that mitochondrial size, density, function, and redox state were not affected by acute changes in the inspired O2 fraction, reduced O2 availability is the remaining factor that could have limited oxidative ATP production during hypoxemia. In conclusion, in severely hypoxemic COPD patients, O2 availability apparently limits intramuscular oxidative metabolism because acute hypoxemia increases anaerobic and decreases aerobic ATP production.

Alcoholic Fermentation in Multicellular Organisms

1. Ethanol is an end product of anaerobic metabolism in a surprisingly large variety of multicellular organisms. These include Angiosperms, Platyhelminthes, Aschelminthes, Acanthocephala, Arthropoda, and Vertebrata. 2. Ethanol formation proceeds in two steps (via pyruvate decarboxylase and alcohol dehydrogenase). 3. Pyruvate decarboxylase of plants is located in the cytosol, whereas that of animals is intramitochondrial and probably part of the pyruvate dehydrogenase complex. 4. Alcohol dehydrogenases of facultative anaerobes are NAD-rather than NADP-dependent, with the enzyme in the parasitic worm Moliniformis dubius as the only known exception. 5. Regulation at the pyruvate branch point in plants seems to involve three different mechanisms: (i) increases of pyruvate decarboxylase and alcohol dehydrogenase activity due to increased gene expression, (ii) control of pyruvate decarboxylase by the intracellular pH and the cytoplasmic NADH/NAD⁺ ratio, and (iii) inhibition of lactate dehydrogenase by ATP at low pH values. There is no evidence for increased expression of the pyruvate decarboxylase and alcohol dehydrogenase genes of animals during anoxia. Here, pyruvate decarboxylase is controlled by the intracellular pH and the mitochondrial phosphorylation potential, whereas the ethanol/lactate production ratio is dependent on the magnitude of the glycolytic flux. 6. The ethanol route has significant advantages (minimal acidosis, avoidance of osmotic problems, and endproduct inhibition of the glycolytic chain) but also has disadvantages (relatively low energy yield, loss of carbobydrate carbon). This may explain why only a few animals produce ethanol during anoxia, in contrast to plants, which generally respond to reduced O₂ availability by alcoholic fermentation.

Altitude-aggravated illness: Examples from pregnancy and prenatal life

Nearly 40 million persons worldwide live permanently at elevation above 8,000 ft (2,439 m) and perhaps as great a number visit high-altitude regions annually. Health effects include the well-recognized altitude-specific syndromes of acute mountain sickness and high-altitude pulmonary edema. Emphasis is placed in this article on altitude-aggravated illness or those preexisting conditions that may be adversely affected by reduced O2 availability at high altitude. Examples from studies of pregnant women and their infants at high altitude are reviewed to demonstrate the effect of high altitude on maternal and fetal well-being. Increased maternal ventilation and ventilatory response to hypoxia during pregnancy at 10,200 ft (3,110 m) and 14,200 ft (4,329 m) raised arterial O2 saturation, helped to preserve arterial O2 content at levels present when nonpregnant, and correlated positively with the offspring's birth weight. Fetal growth retardation and an increased incidence of the complications of pre-eclampsia and neonatal hyperbilirubinemia at high altitude suggested that altitude may aggravate complications of pregnancy and prenatal life. Other conditions that may be aggravated at high altitude are reviewed. Virtually all studies on altitude-aggravated illness have been conducted on permanent residents. Future studies should seek to determine whether high altitude aggravates pre-existing conditions among the large and growing number of high-altitude visitors.

Metabolic arrest

In hypoxia sensitive cells and tissues, the rates of glucose and O2 consumption are inversely related (Pasteur Effect). Under O2 limiting conditions the demands for glucose (glycogen) in such cells may drastically rise as a means for maintaining ATP turnover close to normoxic rates; nevertheless ion and electrical potentials cannot be sustained due to energy insufficiency and high membrane permeability; metabolic and membrane functions, in effect, are decoupled. 'Good' animal anaerobes resolve these problems with a number of biochemical and physiological mechanisms; of these metabolic arrest and stabilized membrane functions are the most effective strategies for extending hypoxia tolerance. Metabolic arrest is achievable by means of a reversed or negative Pasteur Effect (reduced or unchanging glycolytic flux at reduced O2 availability) while coupling of metabolic and membrane function is achievable in spite of the lower energy turnover rates by maintaining membranes of low permeability (probably via reduced densities of ion-specific channels). Although the strategy of combining metabolic arrest with channel arrest has been recognized as a possible intervention, to date success has been minimal, mainly because cold depression of metabolism is the usual arrest mechanism used and this hypothermia in itself perturbs controlled cell function in most endotherms. The only endothermic systems currently known which appear able to use the dual strategy for extending hypoxia tolerance are hypoperfused hypometabolic tissues and organs of diving marine mammals.

Defense Strategies Against Hypoxia and Hypothermia

Because aerobic metabolic rates decrease in hypoxia-sensitive cells under oxygen-limiting conditions, the demand for glucose or glycogen for anaerobic glycolysis may rise drastically as a means of making up for the energetic shortfall. However, ion and electrical potentials typically cannot be sustained because of energy insufficiency and high membrane permeabilities; therefore metabolic and membrane functions in effect become decoupled. In hypoxia-tolerant animals, these problems are resolved through a number of biochemical and physiological mechanisms; of these metabolic arrest and stabilized membrane functions are the most effective strategies for extending tolerance to hypoxia. Metabolic arrest is achieved by means of a reversed or negative Pasteur effect (reduced or unchanging glycolytic flux at reduced O2 availability); and coupling of metabolic and membrane function is achievable, in spite of the lower energy turnover rates, by maintaining membranes of low permeability (probably via reduced densities of ion-specific channels). The possibility of combining metabolic arrest with channel arrest has been recognized as an intervention strategy. To date, the success of this strategy has been minimal, mainly because depression of metabolism through cold is the usual arrest mechanism used, and hypothermia in itself perturbs controlled cell function in most endotherms.

The reaction of cytochrome o in Escherichia coli K12 with oxygen. Evidence for a spectrally and kinetically distinct cytochrome o in cells from oxygen-limited cultures.

Intact cells harvested from O2-limited batch cultures of Escherichi coli K12 contained high levels of the CO-binding cytochromes d, o and a1. In photodissociation difference spectra (i.e. photolysed minus reduced + CO), a peak at 436 nm and a trough at 415 nm have been assigned to an 0-type cytochrome, and not cytochrome d, by photolysis with white light and an He-Ne laser. The reaction of reduced cytochrome o436 with O2 at sub-zero temperatures involved O2 binding to give intermediate(s) with spectral characteristics similar to those of the reduced oxidase-CO complex. The reaction with O2 at successively higher temperatures (range -98 to -59 degrees C) was accompanied by the formation of a trough (with reference to the CO-liganded state) at 436 nm which eventually shifted to 432 nm, indicative of the oxidized form. The apparent energy of activation at low temperatures was 44.6 kJ mol-1 (10.7 kcal mol-1). There was a linear relationship between the rate of formation of the oxygen compound and the O2 concentration up to about 0.5 mM. The second-order constant for this reaction was 10.9 M-1 s-1 at 100 degrees C, at least 10-fold greater than for the reaction of cytochrome o432 with O2 in cells from vigorously aerated cultures. The reaction of both types of cytochrome o with O2 was not readily reversible in the light or in the dark and was further distinguished from the reaction with CO by the markedly lower velocity of the CO reaction. Comparisons are drawn between the reactions with O2 of cytochrome(s) o in E. coli from O2-sufficient and O2-limited cultures and of mitochondrial cytochrome a3. It is proposed that, like the synthesis of cytochrome d, the formation of cytochrome o436 represents an adaptation of the organism to reduced O2 availability.