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Hypoxia Functional hypoxia: induced by high activity. Environmental hypoxia: surrounding PO2 decreases. , Oxygen Regulator Glycolytic contribution ATP turnover Oxidative phosphorylation contribution to ATP production Anoxia Unlimiting O2 ^ Hypoxia Facultative Anaerobe Oxidative phosphorylation contribution to ATP production Metabolic depression is a key adaptation in intertidal marine invertebrates and it allows long-term hypoxia/anoxia tolerance Oxygen regulators undergo a Pasteur effect (top), but facultative anaerobes demonstrate a “reverse Pasteur effect” (bottom). Glucose utilization under AEROBIC and ANAEROBIC conditions. Glucose NAD+ G3PDH NADH + H+ NADH + H+ NAD+ Pyruvate Oxidation to CO2 and H2O Lactate NADH+ + H+ NAD+ Marine invertebrates have multiple anaerobic pathways Fermentations Energy yield Glucose Lactate: 2ATP/Glu Glucose Opine: 2ATP/Glu Glucose Succinate: 4ATP/Glu Glucose Propionate: 6ATP/Glu Aspartate Succinate: 1ATP/Asp Aspartate Propionate: 2ATP/Asp H+ yield 1ATP/H+ 1ATP/H+ 2ATP/H+ 3ATP/H+ There are also H+ consuming metabolic processes: Adenylate Deaminase reaction: AMP + H2O IMP + NH3 (forms NH4+) Cellular Energetics Under Hypoxia/Anoxia 4 reaction systems are linked (3 supply, 1 demand): Aerobic metabolism: Creatine kinase rxn: Glycolysis: ATPase: Glucose + ADP + Pi ATP PCr + ADP + H+ ATP + Cr Glucose + ADP + Pi ATP + Lactate + H+ ATP ADP + Pi Net effect of energy challenge: ↓PCr, ↑Cr, ↓Glucose, ↑Lactate, ↓pH, ↑ADP, ↑Pi Nuclear magnetic resonance can be used to assess cellular energetics noninvasively Phosphocreatine Pi Intracellular energetics in fish during hypoxia 31P-NMR analysis of muscle energetics in vivo in goldfish (A) (ethanol producers) and tilapia (B) (lactate producers). Note the decrease in PCr and increase in Pi during hypoxia. Also note the Pi peak has shifted to the left during hypoxia (decreased pH). The ATP levels remain fairly constant but G of ATP hydrolysis declines. Intracellular buffering of H+: Previously shown that buffering capacity was correlated with energy demand in fish (functional hypoxia) (Castellini and Somero, 1981). Is habitat related to the ability to regulate pH? 0.6 dH+ /dt (umol/ml/min) Buffering Capacity (umol/pH/ml) 60 50 40 30 20 0.5 30 mM acid 0.4 load 30 mM acid load 60 mM acid 0.3 load 0.2 60 mM acid load 0.1 High HighMid Mid Low Intertidal Position High HighMid Mid Low Intertidal Position Buffering capacity and the capacity for proton pumping is correlated with intertidal position in closely related intertidal whelks. Cellular pH regulation can be costly Portner et al. 2000. J. Exp. Biol. Extracellular pH decreases reduce the cost of membrane transport processes associated with pH regulation. Inhibitors: Ouabain (Na/K ATPase), DMA (amiloride, Na/H antiport), DIDS (anion exchange, such as Na+ dependent Cl/HCO3- exchange), Bafilomycin (V-ATPase H+ pump inhibitor). Gas exchange surfaces and hemoglobin binding affinity are dependent on environment and behavior Toadfish (sluggish, inshore) Scup (inshore still waters) Mackerel (fast, active, open water) Innes and Taylor, 1986 Stewart, 1991 Other environmental factors can alter hemoglobin P50 Brix et al. 1989 Euphausiid P50 is higher at lower T. Wood, 1991 Goldfish move to lower T when PO2 drops, which lowers metabolic rate and may help unload O2 at tissues. Fish respond by invoking anaerobic metabolism and increasing the ventilation rate Respiratory and metabolic response to hypoxia in the epaulette shark, which lives on reef platforms that become hypoxic at low tide. The pattern is typical of most vertebrates, lactate increases and VO2 decrease once a critical PO2 is reached. Ventilation rate is increased to compensate for the reduced oxygen (Routley et al. 2002). How is oxygen sensed by cells? Hypoxia-induced gene expression via HIF. HIF1 is constitutively expressed. A heme-based receptor detects O2 levels and leads to an oxygen-dependent modification of HIF1. This modification allows HIF1 to be ubiquinated, which targets it for destruction. When HIF1 is not modified, it can dimerize with ARNT to form a heterodimer transcription factor that can bind enhancer sites on DNA. Microarray analyses of Response to Hypoxia mRNA from tissue/cell cDNA (fluorescently label) Hybridize to an array Determine genes that are up-regulated (green), downregulated (red), or unchanged (yellow). Control Treatment Hypoxia-induced gene expression in the hypoxiatolerant goby Gillichthys mirabilis examined using cDNA microarrays. PO2 was approximately 10% of normoxia, which is below PO2 that induces a decrease in respiration. Gene expression was then measured in a control, and at times after hypoxia exposure (Gracey, Troll and Somero, 2001). ATP metabolism iron metabolism anti-growth/proliferation locomotion amino acid metabolism translation cryptic role Northern Blots A Special Case: The Diving Response in Marine Mammals From Hochachka and Somero (2002) Field studies of the Weddell seal showing increase in hematocrit during diving. Also, in the field, the lactate washout peak was often small or absent during short dives, and large during long dives. This led to the concept of the aerobic dive limit (ADL). Myoglobin Function 1H-spectra 31P-spectra Hydrophobic pocket Heme His F8 In vivo elephant seal NMR spectra during normal breathing (A), sleep apnea (B) and post-apnea normal breatning (C). The apnea duration was 110 min and the deoxy-Mb peak emerged after 3 min. The stability of the [Pi] (1), [PCr] (2), and [ATP] (3-5) suggest that Mb unloading supports oxidative phosphorylation during apnea (Ponganis et al. 2002). Top: [Mb] (bars) and maximum dive duration (circles) for species of cetaceans and pinnipeds. Bottom: Body mass relationship to maximum dive duration. (Noren and Williams, 2000). How do marine mammals exceed the aerobic dive limit without becoming anaerobic? Top: Dive depth vs. duration in marine mammals showing gliding time (red) and swimming time (black). Bottom: Recovery oxygen costs (repaying the oxygen debt) in the Weddell seal for a gliding dive is less than for a swimming dive. A gliding dive extends the aerobic dive time by 38%. Williams et al. (2000) Are marine mammals sensitive to pressure? Glycolytic flux in RBCs from marine and terrestrial mammals during a 2 h incubation under high hydrostatic pressure (Castellini et al. 2001).