9.3 Strategies and Mechanisms of Hypoxia and Anoxia Tolerance

Hypoxia and anoxia create many challenges that force cells to adjust their physiology. Once the cell has detected the oxygen limitation, there are multiple possible responses. If we consider hypoxia as a problem of oxygen demand exceeding oxygen supply, there are two main strategies an organism can use: decreasing their demand for oxygen, or increasing cellular access to oxygen (increasing supply). Organisms may employ both of these strategies, depending on the species. This chapter section will explore mechanisms that can support each of these strategies.

Mechanisms to Decrease Oxygen Demand

There are a variety of mechanisms that cells can put into place to reduce their demand for oxygen. Two examples include 1) downregulating cellular process that consume ATP, and 2) increasing ATP synthesis in the absence of oxygen via anaerobic pathways. Both of these mechanisms decreases the organism’s reliance on ATP produced via aerobic respiration.

Decreasing Cellular Activity that Consumes ATP

A myriad of cellular processes requires ATP. However, under hypoxia, it is difficult for the cell to synthesis enough ATP to keep all these processes going. For a cell to survive, certain cellular processes, such as the maintenance of the ion balance across cell membrane with Na⁺/K⁺ ATPase, cannot fully shut down. Nevertheless, there are a variety of cellular processes that require ATP (e.g., protein synthesis) which can be downregulated to conserve ATP within the cell. Therefore, to decrease its demand for oxygen a cell can downregulate certain processes that consume ATP. Since cellular activity is decreased, the need for oxygen to generate ATP is reduced, resulting in a net decrease in oxygen demand.

One species that clearly uses this strategy is the anoxia-tolerant painted turtle (Chrysemys picta; Figure 9.5). ^[1]A study conducted by Hochachka et al. concluded that during exposure to anoxic conditions, multiple pathways including protein synthesis, gluconeogenesis (synthesis of glucose), and protein breakdown were downregulated in the hepatocytes (liver cells) of this species. The downregulation of these pathways resulted in 94 % suppression of the total ATP demand. This response reduces the demand for oxygen in the cells and significantly contributes turtle’s ability to tolerate anoxia.

Anaerobic ATP Pathways

Even though anaerobic metabolism only produces 2 ATP per glucose (compared to 30-32 ATP per glucose with aerobic metabolism), the cell needs some way to synthesis ATP to support fundamental processes. Therefore, a cell can use anaerobic metabolic to synthesize sufficient ATP to support essential processes. Ultimately the cell relies less on aerobic metabolism, and its need for oxygen decreases.

As described in Chapter 9.1, cells can use glycolysis and fermentation to continue producing ATP in the absence of oxygen (Figure 9.6). The fermentation is important for generating NAD⁺ to support glycolysis. However, the build-up of fermentation products like lactic acid can have a toxic effect on cells; therefore, this a transient response to stress. The shift to anaerobic metabolism during hypoxia is aided by the accumulation of HIF-1, which upregulates the expression of genes responsible for several enzymes involved in glycolysis.

Utilizing anaerobic metabolism during hypoxia-induced stress has been observed in many animals, including the family Cottoidea, commonly known as the sculpin (Figure 9.7). ^[2]Several sculpin species rely on anaerobic pathways for ATP synthesis during periods of hypoxic stress. The brain is a vital organ; therefore, its cells are energetically demanding. When exposed to hypoxic stress, the neurons (brain cells) rely on glycolysis to prevent cellular death. Research has shown that the brain tissue of hypoxia-tolerant sculpins contains elevated levels of lactate dehydrogenase (LDH). LDH is an enzyme that catalyzes lactic acid fermentation. This increased enzyme activity is a significant factor that allows sculpins to tolerate hypoxic conditions.

Strategy: Increasing Oxygen Supply

Another way cells can combat hypoxic/anoxic stress is by increasing their oxygen supply. An increase in oxygen supply allows cells to minimize their oxygen deficit and therefore lessen the effects of hypoxia. How exactly can cells increase their oxygen supply? Behavioural avoidance is often the simplest and the first mechanism that most organisms employ to implement this strategy, along with changes to cellular physiology.

Behavioural Avoidance

One of the most common ways many cells increase their oxygen supply is by avoiding oxygen limiting environments. If an organism encounters an environment with unfavourable oxygen conditions, they may migrate to an environment with higher oxygen, or simply utilize characteristic of their current environment in a different way to increase oxygen uptake. One example of behavioural modification to increase oxygen uptake is seen in several fish species. Many fish species, including zebrafish (Danio rerio) (Figure 9.8A), utilize a behavioral response known as aquatic surface respiration (ASR) to increase their oxygen supply during hypoxic stress. ASR involves ventilating the gills at the water-air boundary, where the partial pressure of oxygen tends to be slightly higher. This behavioral response allows the fish to uptake more oxygen, increasing their oxygen supply. Additionally, some organisms will avoid stressful environments entirely. For instance, mangrove rivulus (Kryptolebias marmoratus), an amphibious fish, will often avoid hypoxic water conditions by exiting the water (Figure 9.8B). On land, this fish relies on cutaneous respiration and can survive up to two months! By avoiding hypoxic environments, these fish are increasing their oxygen supply, as a result mitigating hypoxic stress.

Increasing the Efficiency of Oxygen Delivery

Multicellular organisms can employ additional mechanisms to increase oxygen uptake and delivery of oxygen to tissues under hypoxia. For example, if you moved to a higher altitude (lower oxygen environments) location, you would probably start breathing at a faster rate to increase oxygen uptake into your lungs. If you stayed at high altitude a little longer, your body would start producing more red blood cells to maintain oxygen delivery to tissues through the circulatory system. Your body might also start increasing the number of blood vessels (specifically capillaries) around essential organs. These mechanisms would help you tolerate a lower oxygen environment, in addition to the metabolic mechanisms (e.g., lactic acid fermentation) described above.