Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology
ReviewSurviving hypoxia without really dying☆
Introduction
With the exception of a few voluntary activities such as climbing at extreme altitude or breath-hold diving to extreme depths, severe O2 deprivation in humans is generally the result of some pathological condition arising along one or more steps of the respiratory cascade. Like humans, most other mammals possess little naturally-evolved tolerance to anoxia and their excitable cells and tissues are normally debilitated by any prolonged episode of O2 lack. One reason for this can be found in their metabolic response to hypoxia (Fig. 1A). As ATP generation by oxidative phosphorylation begins to fall off due to O2 limitation, the cellular ATP demands of most mammalian cells and tissues tend to remain constant, leading to an energetic deficit that can only be made up for by activation of anaerobic ATP supply pathways (the so-called ‘Pasteur effect’). Because anaerobic ATP production can only temporarily meet the sustained energy demands of the various cellular ATP consuming processes, finite stores of fermentable substrate together with the accumulation of deleterious end products (e.g. H+) set temporal constraints on anaerobiosis as a long-term solution to severe oxygen limitation in these animals. One obvious way to forestall the potentially lethal effects of a compromised metabolism would be to lower the energetic demands of one or more of the major ATP consuming functions, and to counter-balance such energetic economies with proportional and simultaneous reductions in ATP production. This is exactly the strategy employed by certain hypoxia-tolerant lower vertebrate species such as the carp Cyprinus carpio, the frog Rana temporaria and the turtle Chrysemys picta (Boutilier et al., 1997, Lutz and Nilsson, 1997). One hallmark of this naturally evolved tolerance to hypoxia is an unusually well-developed capacity for rapid and reversible entry into, and return from, metabolically depressed steady-states. Thus, unlike the typical mammalian response to O2 lack, ‘facultative’ vertebrate anaerobes use anaerobic metabolism not to maintain pre-existing rates of ATP production but to sustain reduced rates of energy turnover in hypoxia (Fig. 1B). The net effect of this balanced reduction of ATP supply and demand is that it spares fermentable fuel, reduces metabolic waste accumulation and extends survival time.
Section snippets
Preserving membrane ion integrity
Cell death caused by O2 lack begins when anaerobic ATP production fails to meet the energetic maintenance demands of ionic and osmotic equilibrium (Fig. 2). As high energy phosphates decline, this leads to a failure of ion-motive ATPases, followed by membrane depolarization and an uncontrolled influx of calcium through voltage gated Ca2+ channels. The rise in free cytosolic intracellular calcium concentration results in the activation of Ca2+-dependent phospholipases and proteases which further
Cellular responses to chronic hypoxia
Much of the preceding discussion has focused on the anoxic-defence mechanisms that enable ‘facultative anaerobes’ to survive periods of O2 deprivation that would prove fatal to most mammals. However, recent studies have shown that most animal cells exhibit a whole host of adaptive responses to sustainable levels of hypoxia (Fig. 5). The one most relevant to our earlier discussion of energy conservation is that of metabolic rate suppression. While ‘metabolic arrest’ is clearly not an option
Acknowledgements
Our work is supported by operating grants to R.G.B. from the Natural Environment Research Council. J. S.-P. was supported by Postgraduate Scholarships from NSERC (Canada) and Trinity College, Cambridge.
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Plenary lecture at the International Congress of Comparative Physiology and Biochemistry in August 1999, Calgary, Alta, Canada.