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Mechanisms of cell survival in hypoxia and hypothermia

R. G. Boutilier^*

Department of Zoology, Downing Street, Cambridge CB2 3EJ, UK

View larger version (26K): [in a new window]   Fig. 1. ATP turnover of cells as a function of time exposed to anoxia or hypothermia. The main figure shows the debilitating cascade of events leading to necrotic cell death. When cellular ATP demand exceeds ATP supply, this cascade is the same (in general if not in specific detail) whether the cells are ‘anoxia- or cold-sensitive’ or ‘anoxia- or cold-tolerant’. The inset shows that a regulated suppression of ATP turnover (i.e. a regulated hypometabolism in which ATP demand balances ATP supply) extends the time to the onset of the debilitating cascade in ‘anoxia- and cold-tolerant cells’. In contrast, an early mismatch between ATP supply and demand in ‘anoxia- and cold-sensitive cells’ leads to a forced hypometabolism which is, in effect, early metabolic failure. Mito, mitochondria; ER, endoplasmic reticulum.

View larger version (29K): [in a new window]   Fig. 2. Recordings of heat dissipation showing the metabolic depression response to anoxia in (A) turtle brain cortical slices incubated in oxygen-free medium (nitrogen) or in the presence of sodium cyanide (pharmacological anoxia) at 25°C (Doll et al., 1994), (B) turtle hepatocytes, where CN denotes addition of sodium cyanide to cell preparations incubated in oxygen-free medium (dotted line) or normoxic medium (solid line) at 25°C (from Buck et al., 1993a, with permission from the American Physiological Society), (C) frog sartorius muscle exposed to a progressively developing oxygen-free superfusate at 20°C (from West and Boutilier, 1998, with permission from Springer) and (D) frog heart ventricular ring (20mg) exposed to a progressively developing oxygen-free superfusate at 20°C (T. G. West and R. G. Boutilier, unpublished data). Turtle, Chrysemys picta belli; frog, Rana temporaria. 1mmHg=0.133kPa.

View larger version (1K): [in a new window]   Fig. 3. A generalised model of cell membrane ‘channel arrest’ and mitochondrial membrane ‘H+-ATPase activation’ in response to anoxia. In this model, anoxia-induced decreases in Na+ and K+ channel densities (and associated ion-channel activities) lead to a net reduction in Na+/K+-ATPase activity, thereby lowering the ATP demand for maintaining transmembrane ion concentration gradients. At the level of the mitochondria, oxidative phosphorylation during normoxia occurs when protons are transferred across the inner mitochondrial membrane (at complexes I, III and IV), thereby generating a proton-motive force that provides the driving force for proton influx through the F1Fo-ATPase (also known as ATP synthase). Proton influx apparently drives the ATP synthase to phosphorylate ADP to ATP. At standard metabolic rate (SMR) during normoxia, a significant fraction of the protons pumped out of the respiratory chain leak back into the mitochondrial matrix without synthesizing ATP (i.e. effectively uncoupling mitochondrial oxygen consumption from ATP synthesis). This futile cycle of mitochondrial proton pumping and proton leak across the inner mitochondrial membrane is estimated to make up approximately 20% of the SMR of mammals (Rolfe and Brown, 1997; Brand et al., 2000). In the absence of oxygen, proton transfer no longer occurs at complexes I, III and IV, but the inverse operation of the F1Fo-ATPase attempts to maintain the mitochondrial membrane potential by using ATP to translocate protons into the intermembrane space.

View larger version (10K): [in a new window]   Fig. 4. Model of the hypothermia response seen in rat brain glial cells. Hypothermia inhibits the Na+/K+-ATPase and also upsets the normal balance between Na+ influx and K+ efflux in favour of Na+ influx. This leads to a net accumulation of Na+ that is exacerbated by hypothermia-induced activation of the Na+/H+ exchanger, leading to cell swelling (redrawn in part from Plesnila et al., 2000, with permission of Cambridge University Press). Further details are given in the text.