Breath Beneath the Waves
Investigating Hemoglobin's Role in Marine Mammals' Hypoxia Tolerance
Our Bass team, “Learning from Whales: Oxygen, Ecosystems, and Human Health,” is dedicated to exploring the adaptations of marine mammals to low oxygen environments, given their remarkable capabilities to dive deep in the sea. One specific facet of cellular adaptation that I concentrate on revolves around hemoglobin.
Hemoglobin, an oxygen-transport protein in red blood cells, plays a pivotal role in sustaining life through its intricate dance of carrying oxygen from the lungs to tissues, fueling aerobic respiration that produces energy and drives metabolism. It also dutifully transports carbon dioxide out of tissues, facilitating it getting expelled from the lung.
Figure 1. Oxyhemoglobin dissociation curve
At the heart of this physiological ballet lies the interplay of hemoglobin's oxygen affinity—a key determinant of its ability to bind and transport oxygen. The oxyhemoglobin dissociation curve, which describes the relationship between oxygen pressure in arteries and the amount of oxygen bound to hemoglobin, illustrates the critical dynamics of this process. A crucial metric, called P50, denotes the arterial oxygen tension at which hemoglobin is 50% saturated. A lower P50 signifies higher oxygen affinity, as hemoglobin and oxygen eagerly bind even under relatively low pressure.
Various factors influence hemoglobin's oxygen affinity, with research indicating that higher affinity correlates with a higher pH level, lower carbon dioxide levels, and lower body temperature (Grippi, 2020). The presence of carbon monoxide not only impedes oxygen loading in the lungs but also shifts the curve leftward, increasing oxygen affinity and restraining oxygen release in peripheral tissues.
The adaptation of oxyhemoglobin affinity to low-oxygen conditions, like hypoxia, has captivated scientific discourse. Studies propose that nature favors higher hemoglobin oxygen affinity at high altitudes to efficiently counter arterial hypoxemia (Winslow, 2007). For instance, the bar-headed goose, navigating the Himalayas, boasts a lower P50 (higher oxyhemoglobin affinity) as compared to the sea-level-dwelling Canada goose. Likewise, guinea pigs in the Andean mountains exhibit a lower P50 than sea-level-dwelling rats. Birds, too, showcase a robust positive relationship between hemoglobin oxygen affinity and native elevation (Storz, 2016).
Yet, the narrative becomes nuanced in human adaptations to high altitudes. In an early study, it was found that hemoglobin saturation in high-altitude natives was higher than that of individuals at sea level (Barcroft et al., 1923). Barcroft concluded that this helps blood to be more saturated in the lung and carry more oxygen. Conversely, other studies observed reduced oxygen saturation, interpreted as more efficient oxygen unloading at tissues (Hurtado, 1964). The tradeoff between lung loading and tissue unloading complicates the determination of whether increased or decreased hemoglobin oxygen affinity is advantageous in hypoxic conditions.
Motivated by the unique challenges faced by marine mammals in deep-sea environments with hypoxic conditions, we aim to discern potential differences in oxygen hemoglobin affinity between terrestrial and marine species. Our focus centers on the role of Bisphosphoglycerate Mutase (BPGM), a key protein orchestrating the regulation of hemoglobin's affinity for oxygen.
BPGM operates by converting 1,3-Bisphosphoglycerate (1,3-BPG), an intermediary in glycolysis, into 2,3-BPG. This resultant compound effectively binds with hemoglobin, inducing a conformational change that enhances the release of oxygen. To explore the nuances of BPGM expression, we conducted Western blot analyses on cells from diverse species: cow (BDF), human (NHDF), pilot whale (GMA), humpback whale (MN), bottlenose dolphin (TTR), and beaked whale (ZCA). The cell lysates used were exposed to either normoxic or hypoxic conditions.
Notably, our findings unveiled that marine species exhibited lower BPGM expression compared to their terrestrial counterparts, irrespective of oxygen levels. This intriguing result suggests a potential adaptation strategy for marine mammals—maintaining a lower baseline of BPGM expression, possibly leading to higher oxyhemoglobin affinity. This observed adaptation could be vital for the unique demands of diving and hypoxia tolerance in marine environments. By optimizing hemoglobin's ability to pull oxygen from the lungs and slow down oxygen consumption in tissues, these marine species may have developed a specialized mechanism to thrive in challenging conditions.
Figure 2. Western blot result for BPGM across various species
In the future, our bass subteam intends to conduct a more in-depth investigation into the levels of BPGM in marine species. Since our previous research has showed that marine mammals have an increased gene copy of BPGM, it is interesting to identify the specific processes that ultimately lead to the observed reduced expression, utilizing techniques such as q-PCR. Additionally, exploring other related adaptations that facilitate hemoglobin's ability to release oxygen as required is another intriguing area to focus on.
Adaptations to hypoxia are intricate, offering a window into understanding human physiology and diseases involving oxygen deprivation, such as cancer. Precisely controlling hemoglobin's oxygen affinity could play a significant role in enhancing hypoxia tolerance.
References
Barcroft, J., Binger, C. A., Bock, A. V., Doggart, J. H., Forbes, H. S., Harrop, G., Meakins, J. C., & Redfield, A. C. (1923). Observations upon the effect of high altitude on the physiological processes of the human body, carried out in the Peruvian Andes, chiefly at Carro de Pasco - Report to the Peru High-Altitude Committee. Philosophical Transactions of the Royal Society of London. Series B, Containing Papers of a Biological Character, 211(382-390), 351–480. https://doi.org/10.1098/rstb.1923.0008
Grippi, M. (2020, November 12). What factors affect hemoglobin’s oxygen affinity? Medmastery. https://www.medmastery.com/guides/blood-gas-analysis-clinical-guide/what-factors-affect-hemoglobins-oxygen-affinity
Hurtado, A. (1964). Animals in high altitude : resident man. Handbook of Physiology, Adaptation to the Environment, 843–860. https://cir.nii.ac.jp/crid/1574231874421885056
Storz, J. F. (2016). Hemoglobin–oxygen affinity in high-altitude vertebrates: is there evidence for an adaptive trend? The Journal of Experimental Biology, 219(20), 3190–3203. https://doi.org/10.1242/jeb.127134
Winslow, R. M. (2007). The role of hemoglobin oxygen affinity in oxygen transport at high altitude. Respiratory Physiology & Neurobiology, 158(2-3), 121–127. https://doi.org/10.1016/j.resp.2007.03.011