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This study examined the metabolic responses of the limpet Patella caerulea (L.) to anoxia and dehydration, attempting to tease apart the effect of these two stressful conditions, which are often not clearly distinguished in experiments. Specimens were exposed to: (a) oxygen-free sea water; (b) oxygen-saturated water (controls); (c) low-humidity air (55% RH); and (d) high-humidity air (100% RH). For each of the treatments, we took samples of five specimens after 6 and 18 h of exposure to the experimental conditions and determined the concentrations in the foot muscle of succinate, acetate, propionate, aspartate and alanine. Exposure to anoxia caused an increase in the levels of succinate (6 and 18 h) and acetate and propionate (18 h) with respect to control specimens. Anoxia also induced a decrease of aspartate and an increase of alanine after both 6 and 18 h. Exposure to both moist and dry air generally had negligible effects on the organic acid levels. Aspartate content increased after 18 h of exposure to moist air. Alanine levels also increased with respect to control values after exposure to air, with dry air having the more pronounced effect. In conclusion, the results of this study suggest that one should be cautious when inferring anaerobic conditions from the simple exposure of intertidal species to air, without strict control of the experimental conditions and actual respiration rates.
Comp Biochem Physiol A Mol Integr Physiol 2001 Aug
PMID:Metabolic responses of the limpet Patella caerulea (L.) to anoxia and dehydration. 1167 78

We evaluated the effects of freezing, dehydration and anoxia stresses on muscle PP-1 activity in the freeze-tolerant amphibian, Rana sylvatica. In addition, PP-1 catalytic subunit (PP-1c) was purified to homogeneity to assess the biochemical properties of the enzyme from a freeze-tolerant vertebrate. Freezing stimulated a rise in the amount of active PP-1 (70% above the control) at 20 min post-nucleation. With longer freezing (1-12 h), the amount of active enzyme returned to control levels, and the amount of total PP-1 fell, decreasing by up to 43%. This decline in total PP-1 kept the % active at a high value throughout the freeze. Anoxia exposure (12 h) reduced the active PP-1 by 60%, but had no effect on total PP-1 activity. Neither dehydration nor rehydration had any significant effect on the amounts of either total or active PP-1. PP-1 activity associated with the myofibril fraction increased, while activity associated with the glycogen pellet decreased in response to freezing and dehydration, but not anoxia. Purified frog PP-1c showed a variety of properties that are typical of the enzyme from other sources. In addition, the enzyme was strongly inhibited by AMP and weakly by ADP and ATP; the physiological relevance of inhibition by nucleotides remains to be determined. Overall, the results suggest an important role for PP-1 in signal transduction in the skeletal muscle of freeze-tolerant amphibians.
Comp Biochem Physiol B Biochem Mol Biol 2002 Jan
PMID:Protein phosphatase type-1 from skeletal muscle of the freeze-tolerant wood frog. 1174 55

The contribution of alterations in mitochondrial K(ATP) channel activity and the sarcoplasmic reticulum (SR) to anaerobic cardiac function in the anoxia tolerant armored catfish Liposarcus pardalis were assessed. K(ATP) channels contribute to hypoxic cardioprotection in mammals, but little is known of their action in more hypoxia tolerant animals. Anoxia resulted in a decrease in force in isometrically contracting ventricle strips to approximately 40% of the pre-anoxic level. This was maintained for at least 2 h. Upon reoxygenation, hearts recovered to the same level as control preparations. Treatment with 5-hydroxydecanoic acid (5HD), a specific mitochondrial K(ATP) blocker significantly increased force in preparations during anoxia and caused hypercontracture at reoxygenation. Ryanodine, a specific inhibitor of SR function, significantly increased force loss in ventricle preparations under anoxia. Results show that mitochondrial K(ATP) channel activity and SR function are important in anaerobic and post-anaerobic contractility in armored catfish heart.
Comp Biochem Physiol A Mol Integr Physiol 2003 Feb
PMID:Mitochondrial K(ATP) channels and sarcoplasmic reticulum influence cardiac force development under anoxia in the Amazonian armored catfish Liposarcus pardalis. 1254 74

Certain freshwater turtles and fish are extremely anoxia-tolerant, capable of surviving hours of anoxia at high temperatures and weeks to months at low temperatures. There is great interest in understanding the cellular mechanisms underlying anoxia-tolerance in these groups because they are anoxia-tolerant vertebrates and because of the far-reaching medical benefits that would be gained. It has become clear that a pre-condition of prolonged anoxic survival must involve the matching of ATP production with ATP utilization to maintain stable ATP levels during anoxia. In most vertebrates, anoxia leads to a severe decrease in ATP production without a concomitant reduction in utilization, which inevitably leads to the catastrophic events associated with cell death or necrosis. Anoxia-tolerant organisms do not increase ATP production when faced with anoxia, but rather decrease utilization to a level that can be met by anaerobic glycolysis alone. Protein synthesis and ion movement across the plasma membrane are the two main targets of regulatory processes that reduce ATP utilization and promote anoxic survival. However, the oxygen sensing and biochemical signaling mechanisms that achieve a coordinated reduction in ATP production and utilization remain unclear. One candidate-signaling compound whose extracellular concentration increases in concert with decreasing oxygen availability is adenosine. Adenosine is known to have profound effects on various aspects of tissue metabolism, including protein synthesis, ion pumping and permeability of ion channels. In this review, I will investigate the role of adenosine in the naturally anoxia-tolerant freshwater turtle and goldfish and give an overview of pathways by which adenosine concentrations are regulated.
Comp Biochem Physiol B Biochem Mol Biol 2004 Nov
PMID:Adenosine as a signal for ion channel arrest in anoxia-tolerant organisms. 1554 64

We investigated the effects of anoxia (8 h) and different periods of reoxygenation (20 and 40 min) on the oxidative balance in anterior and posterior gills of the crab Chasmagnathus granulata. Enzyme activity of catalase and GST was increased in the gills of the animals submitted to anoxia, and SOD activity was decreased. These enzymes returned approximately to control levels during the anoxia recovery time. These results demonstrated enzyme activities change with variations in environmental oxygen levels. The posterior gills showed a higher antioxidant enzyme activity than anterior gills. In the gills, there were no changes in the non-enzymatic antioxidant system (TRAP) during anoxia. On the other hand, during anoxia recovery, an increase of TRAP in both gills was observed. Anoxia does not change lipid peroxidation (TBARS) in the gills. During anoxia recuperation, an increase in levels of TBARS was observed. Thus the results demonstrate that C. granulata has a similar strategy of preparation for oxidative stress as observed in other intertidal species, enabling the crabs to survive in an environment with extreme variations in physical and chemical characteristics, such as salt marshes.
Comp Biochem Physiol B Biochem Mol Biol 2005 Jan
PMID:Effects of environmental anoxia and different periods of reoxygenation on oxidative balance in gills of the estuarine crab Chasmagnathus granulata. 1562 9

Changes in oxygen levels occur frequently in aquatic environments; therefore, water organisms, including fishes, evolve a wide spectrum of adaptations to both anoxia/hypoxia and hyperoxia. The review describes oxidative damage to cellular constituents by reactive oxygen species, alterations in glutathione status, and response of antioxidant enzymes to variable oxygen availability in fish. Anoxia- and hypoxia-tolerant species demonstrate an anticipatory increase of some antioxidant enzymes during low-oxygen state in order to enhance their antioxidant potential for dealing with possible oxidative stress upon return to normoxia. Under hyperoxic conditions, it seems that the glutathione system plays an important adaptive role. Most stressful conditions lead to a quick increase in lipid peroxidation products that, in turn, are detoxified rapidly by respective low- and high-molecular weight antioxidants. A scheme on possible ways of regulating antioxidant enzymes by different oxygen levels is proposed.
Comp Biochem Physiol B Biochem Mol Biol 2006 Jul
PMID:Effects of different environmental oxygen levels on free radical processes in fish. 1675 Sep 25

Freshwater turtles of the Trachemys and Chrysemys genera are champion facultative anaerobes able to survive for several months without oxygen during winter hibernation in cold water. They have been widely used as models to identify and understand the molecular mechanisms of natural anoxia tolerance and the molecular basis of the hypoxic/ischemic injuries that occur in oxygen-sensitive systems and underlie medical problems such as heart attack and stroke. Peter L. Lutz spent much of his career investigating turtle anaerobiosis with a particular focus on the mechanisms of brain ion homeostasis and neurotransmitter responses to anoxia exposure and the mechanisms that suppress brain ion channel function and neuronal excitability during anaerobiosis. Our interests intersected over the mechanisms of metabolic rate depression which is key to long term anoxia survival. Studies in my lab have shown that a key mechanism of metabolic arrest is reversible protein phosphorylation which provides coordinated suppression of the rates of multiple ATP-producing, ATP-utilizing and related cellular processes to allow organisms to enter a stable hypometabolic state. Anoxia tolerance is also supported by selective gene expression as revealed by recent studies using cDNA library and DNA array screening. New studies with both adult T. scripta elegans and hatchling C. picta marginata have identified prominent groups of genes that are up-regulated under anoxia in turtle organs, in several cases suggesting aspects of cell function and metabolic regulation that have not previously been associated with anaerobiosis. These groups of anoxia-responsive genes include mitochondrially-encoded subunits of electron transport chain proteins, iron storage proteins, antioxidant enzymes, serine protease inhibitors, transmembrane solute carriers, neurotransmitter receptors and transporters, and shock proteins.
Comp Biochem Physiol A Mol Integr Physiol 2007 Jun
PMID:Anoxia tolerance in turtles: metabolic regulation and gene expression. 1703 57

How cells die in the absence of oxygen (anoxia) is not understood. Here we report that cells deficient in Bax and Bak or caspase-9 do not undergo anoxia-induced cell death. However, the caspase-9 null cells do not survive reoxygenation due to the generation of mitochondrial reactive oxygen species. The individual loss of Bim, Bid, Puma, Noxa, Bad, caspase-2, or hypoxia-inducible factor 1beta, which are potential upstream regulators of Bax or Bak, did not prevent anoxia-induced cell death. Anoxia triggered the loss of the Mcl-1 protein upstream of Bax/Bak activation. Cells containing a mitochondrial DNA cytochrome b 4-base-pair deletion ([rho(-)] cells) and cells depleted of their entire mitochondrial DNA ([rho(0)] cells) are oxidative phosphorylation incompetent and displayed loss of the Mcl-1 protein under anoxia. [rho(0)] cells, in contrast to [rho(-)] cells, did not die under anoxia. However, [rho(0)] cells did undergo cell death in the presence of the Bad BH3 peptide, an inhibitor of Bcl-X(L)/Bcl-2 proteins. These results indicate that [rho(0)] cells survive under anoxia despite the loss of Mcl-1 protein due to residual prosurvival activity of the Bcl-X(L)/Bcl-2 proteins. Collectively, these results demonstrate that anoxia-induced cell death requires the loss of Mcl-1 protein and inhibition of the electron transport chain to negate Bcl-X(L)/Bcl-2 proteins.
Mol Cell Biol 2007 Feb
PMID:Loss of Mcl-1 protein and inhibition of electron transport chain together induce anoxic cell death. 1714 74

Nutlin-3 is a small-molecule inhibitor that acts to inhibit MDM2 binding to p53 and subsequent p53-dependent DNA damage signaling. Whether Nutlin-3 alters cell toxicity following DNA damage under oxic versus hypoxic conditions has not been studied. The potential radiosensitization (0-10 Gy) properties of Nutlin-3 (dose range, 2-10 micromol/L for up to 24 h) were investigated in vitro using three prostate cancer cell lines, 22RV1 [wild-type p53 (WTp53)], DU145 (mutated p53), and PC-3 (p53-null) under oxic (21% O(2)), hypoxic (0.2% O(2)), and anoxic (0% O(2)) conditions. As a single agent, Nutlin-3 (2-10 micromol/L) stabilized p53 and p21(WAF) levels and was toxic to WTp53-22RV1 cells (IC(50), 4.3 micromol/L) but had minimal toxicity toward p53-deficient cells (IC(50), >10 micromol/L). When combined with radiation under oxic conditions, Nutlin-3 decreased clonogenic survival in all three cell lines: 22RV1 [sensitizing enhancement ratio (SER), 1.24], DU145 (SER, 1.27), and PC-3 (SER, 1.12). Anoxia induced p53 protein expression in 22RV1 cells and this was augmented by Nutlin-3 treatment. Furthermore, Nutlin-3 was more effective as a radiosensitizer under hypoxic conditions particularly in WTp53-expressing cells: 22RV1 (SER, 1.78), DU145 (SER, 1.31), and PC-3 (SER, 1.28). The decrease in clonogenic survival with Nutlin-3 was not correlated to altered levels of radiation-induced apoptosis within the three cell lines. Our results indicate that Nutlin-3 can act as a radiosensitizer via p53-independent mechanisms under low O(2) levels. Nutlin-3 may be a useful adjunct to improve the therapeutic ratio using precision radiotherapy targeted to hypoxic cells and warrants further study in vivo.
Mol Cancer Ther 2008 Apr
PMID:Nutlin-3 radiosensitizes hypoxic prostate cancer cells independent of p53. 1841 12

Certain environmental stressors can impair cellular ATP production to the point of harming or even killing an animal. Some exceptional animals employ strategies that maintain the balance between ATP production and consumption, allowing them to tolerate prolonged exposure to stressors such as hypoxia and anoxia. Anoxia- and hypoxia-tolerant animals reduce ATP consumption by ion-motive ATPases while concomitant reductions in passive ion flux reduce the demand for ion pumping and maintain transmembrane ion gradients. Reductions in gene transcription and protein turnover decrease ATP demand in hibernating and hypoxia-tolerant animals. Proton leak uncouples mitochondrial substrate oxidation from ATP synthesis and accounts for a considerable proportion of cellular energy demand, but there is little evidence that the proton permeability of inner mitochondrial membranes decreases in animals that tolerate energy stress. Indeed in some cases proton leak increases, possibly reducing reactive oxygen species production. Because substrate oxidation is important to the control of cellular metabolism, the downregulation of ATP supply pathways contributes significantly to metabolic suppression under energy stress. Mechanisms that coordinate the downregulation of both ATP supply and demand pathways include AMP kinase and ATP-sensitive ion channels. Strategies employed by animals tolerant to one energy stress often convey "cross-tolerance" to completely different stresses.
Comp Biochem Physiol A Mol Integr Physiol 2009 Jun
PMID:Matching cellular metabolic supply and demand in energy-stressed animals. 1953 26


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