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The metabolic strategy of the anoxic goldfish Shoubridge, Eric Alan


The common goldfish is uncommonly resistant to total anoxia; at low temperature during the winter months, when resistance is greatest, it can survive several days in the complete absence of oxygen. Further, the anoxic goldfish produces true, metabolic CO₂ and does not accumulate lactate to the extent expected. In all these respects the goldfish is an exception to the general vertebrate paradigm. In this thesis I have examined the nature and control of the metabolic machinery underlying the remarkable resistance of the goldfish to anoxia. The major source of metabolic CO₂ in the anoxic goldfish is the pyruvate dehydrogenase reaction. The decarboxylation reactions in the Krebs cycle and pentose phosphate shunt make a very minor contribution to overall CO₂ production from glucose during anoxia. Thus ultimately, only a small proportion of individual glucose molecules are totally oxidized. The production of CO₂ and AcetylCoA in the PDH reaction puts the system out of redox balance, and two NAD⁺ must be regenerated for its continued operation: this is accomplished by reducing AcetylCoA to ethanol. A functional coupling exists between CO₂ and ethanol production. If anoxic goldfish are injected with an inhibitor of alcohol dehydrogenase, CO₂ excretion is depressed in direct proportion to the reduction in ethanol excretion. This demonstrates that the goldfish has no other quantitatively important sink for reducing equivalents. The physiological importance of this scheme is that it circumvents the problem of metabolic acidosis by generating neutral, easily disposable end products which do not interfere with the continued generation of energy. Minimizing the accumulation of acidic end products is crucial to prolonged survival in the anoxic goldfish because it has a poor bicarbonate buffering system, a direct result of having to breathe in an aquatic environment. There is another dimension to the metabolism of the anoxic goldfish. The goldfish possesses two spatially separate, but functionally integrated systems for the catabolism of glucose; the vertebrate glycolytic pathway, present in every tissue, and a pathway for alcoholic fermentation, entirely restricted to the skeletal muscles. While each system is internally consistent, the metabolic strategy hinges on their functional integration. The brain and the heart are the major glycolytic tissues; the liver and kidney sustain a metabolic depression. Metabolism in the heart and brain is coupled to that in the skeletal muscle through a common intermediate - lactate. Lactate is the major substrate for the alcoholic fermentation systems in the skeletal muscles and very little glucose is catabolized directly to CO₂ and ethanol. During anoxia, CO₂ is produced from lactate at rates 16-20 times greater than from glucose. The transport of lactate into the muscle cells is potentiated by the continuous generation of inwardly directed lactate and proton gradients, a process which appears to couple lactate transport and metabolism. Lactate outcompetes glucose as a substrate because it can be delivered at higher rates and because LDH outcompetes GAPDH for the cytosolic pool of free NAD⁺. The advantage of this two-tiered strategy is that it affords the goldfish a measure of flexibility in dealing with short and long term anoxia. The alcoholic fermentation system, which is wasteful of carbon, is not maximally activated until lactic acid levels become high in the general circulation.

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