top of page

Metabolism of hypoxia tolerance

For complex organisms like animals, prolonged survival without oxygen is seemingly impossible. But certain fish species are remarkably tolerant of hypoxia. Here is what we in the Regan Lab are doing to understand how they attain this tolerance, and how this knowledge may be applied to conservation efforts.

Ultimately, life is the temporary avoidance of decay into disorder and equilibrium. Living things manage this by keeping their cells in ordered, or homeostatic, states relative to the surrounding universe. This requires the continual input of energy, and animals can supply this energy in two general ways: aerobically with oxygen, or anaerobically without oxygen. The aerobic way produces ~18 times more energy (in the form of ATP) per food molecule than the anaerobic way, and this high-efficiency energy supply has led to virtually all animals on Earth evolving an ultimate reliance on oxygen to generate the large quantities of ATP needed to sustain their survival.


But there are many environments on Earth that are low in oxygen (i.e., hypoxic), and amazingly, animals can be found living – even thriving – in most of them. These hypoxic environments include the subterranean, the high-altitude and the aquatic, and the fact that animals live here necessarily means that they are striking a balance between energy supply and demand despite the low levels of available oxygen.


There are three general strategies animals use to balance energy supply and demand in hypoxic environments. The first two—improved oxygen uptake and upregulated anaerobic ATP production pathways—aid in supplying ATP, while the third—metabolic depression—aids in reducing ATP demand. Animal species differ in not only their reliance on each strategy, but also their ability to make use of each strategy. For example, metabolic depression is an effective survival strategy for goldfish in severely hypoxic environments, but the related zebrafish is unable to depress its metabolic rate under the same conditions. In the end, cellular energy balance can be maintained by different combinations of these three strategies, and indeed it appears that different species use different combinations to achieve hypoxia tolerance. We call a species’ particular combination its "total hypoxic response (THR). In the Regan Lab, we are interested in how and why the THR varies among, and even within, species.


Our hypoxia research – basic

One question we are currently investigating is, What is the initial signal for hypoxic metabolic depression in fishes?


Metabolic depression is the most effective strategy for prolonging survival in severely hypoxic environments because it reduces the demand for oxygen when there is a very low supply of it. Some of the downregulated cellular ATP-supply and -use processes that contribute to hypoxic metabolic depression have been investigated in isolation; however, the upstream signal that induces their downregulation and the manner by which their modulation is linked via time and oxygen levels remain unknown.


Using the exceptionally hypoxia-tolerant goldfish as our model organism, we are investigating potential signals for hypoxic metabolic depression, how the cellular mechanisms of metabolic depression are linked sequentially, and what cellular mechanisms differ between species that are capable of, and incapable of, inducing metabolic depression.


Another question we are investigating in collaboration with Dr. Sandra Binning is, How does parasite infection affect the hypoxia tolerance of fishes?


Parasite infection is a common feature of fish life. The resulting immune response requires energy, which increases the fish’s resting (or standard) metabolic rate and, with it, the demand for oxygen. Theoretically, this should inherently reduce the fish’s hypoxia tolerance, but this hypothesis has never been tested. It’s important information because various human practices are rapidly altering the world’s freshwater environments in ways that are enhancing the prevalences of both hypoxia and parasitism. This could present compounding constraints for the fishes living in these environments, rendering them more susceptible to hypoxia right when hypoxia is becoming more prevalent.


Our hypoxia research – applied

The applied biology question we are addressing in collaboration with Dr. Nick Mandrak is, How might goldfish’s exceptional hypoxia tolerance contribute to its invasive success in the Great Lakes region?


Goldfish, originally native to eastern Asia, have become a successful invader of many aquatic environments around the world. The Great Lakes region is no exception, and the past 10 years have seen a rapid increase in goldfish numbers where they are now outcompeting the common carp as a dominant invasive species. The reasons for its success are not understood, but they may involve goldfish’s exceptional tolerance of hypoxia, a trait of increasing value as hypoxia becomes more and more prevalent throughout the world’s freshwater environments.


We are measuring the hypoxia tolerances of wild-caught invasive goldfish from the Great Lakes region and comparing them with the tolerances of another Great Lakes invader, the common carp. We are interpreting these tolerances in the context of the hypoxia actually experienced by these environments, both currently and projected. This will allow us to better understand how goldfish’s hypoxia tolerance may shape it current and future invasive success in these environments.


Key publications:

Regan MD, Gill IS, Richards JG. 2017. Calorespirometry reveals that goldfish prioritize aerobic metabolism over metabolic depression in all but near-anoxic environments. Journal of Experimental Biology 220.

Regan MD, Gill IS, Richards JG. 2017. Metabolic depression and the evolution of hypoxia tolerance in the threespine stickleback, Gasterosteus aculeatus. Biology Letters 13.

Mandic M, Regan MD. 2018. Can variation among hypoxic environments explain why different fish species use different hypoxic survival strategies? Journal of Experimental Biology 221.


Top image: Goldfish, a model system in the lab owing to its exceptional hypoxia tolerance and metabolic depression use. Photo from Wikimedia Commons.

Bottom image: Stickleback, including our model system the threespine stickleback, as drawn by Alexander Francis Lydon, 1879.

bottom of page