CD73 and AMPD3 deficiency enhance metabolic performance via erythrocyte ATP that decreases hemoglobin oxygen affinity

Abstract

Erythrocytes are the key target in 5′-AMP induced hypometabolism. To understand how regulation of endogenous erythrocyte AMP levels modulates systemic metabolism, we generated mice deficient in both CD73 and AMPD3, the key catabolic enzymes for extracellular and intra-erythrocyte AMP, respectively. Under physiological conditions, these mice displayed enhanced capacity for physical activity accompanied by significantly higher food and oxygen consumption, compared to wild type mice. Erythrocytes from Ampd3−/− mice exhibited higher half-saturation pressure of oxygen (p50) and about 3-fold higher levels of ATP and ADP, while they maintained normal 2,3-bisphosphoglycerate (2,3-BPG), methemoglobin levels and intracellular pH. The affinity of mammalian hemoglobin for oxygen is thought to be regulated primarily by 2,3-BPG levels and pH (the Bohr effect). However, our results show that increased endogenous levels of ATP and ADP, but not AMP, directly increase the p50 value of hemoglobin. Additionally, the rise in erythrocyte p50 directly correlates with an enhanced capability of systemic metabolism.

A genomics approach reveals insights into the importance of gene losses for mammalian adaptations

“…19 , and Supplementary Table 5 ). AMPD3 encodes an erythrocyte-specific enzyme whose knockout in mice increases the erythrocyte ATP level by threefold 28 . Since ATP is an allosteric effector that stabilizes O 2 -unloaded hemoglobin in vertebrates, the loss of AMPD3 results in a reduced O 2 affinity of hemoglobin 28 .…”

“…AMPD3 encodes an erythrocyte-specific enzyme whose knockout in mice increases the erythrocyte ATP level by threefold 28 . Since ATP is an allosteric effector that stabilizes O 2 -unloaded hemoglobin in vertebrates, the loss of AMPD3 results in a reduced O 2 affinity of hemoglobin 28 . This is probably adaptive for long-diving sperm whales as a lower affinity facilitates O 2 release from hemoglobin to the O 2 -depleted tissue (Fig.…”

Hypoxia modulates the purine salvage pathway and decreases red blood cell and supernatant levels of hypoxanthine during refrigerated storage

“…Conversely, the human enzymopathy of AMPD3 deficiency does not produce any relevant phenotype except for inducing increased levels of RBC ATP and ADP, thereby promoting a hypometabolic state with decreased hemoglobin oxygen affinity. 65 , 66 …”

Comparison of human erythrocyte purine nucleotide metabolism and blood purine and pyrimidine degradation product concentrations before and after acute exercise in trained and sedentary subjects

“…A rise in ATP leads to increased Hb-A p50 values, resulting, in turn, in reduced erythrocyte affinity for oxygen. A linear correlation between increasing ATP concentration and increases in p50 values of Hb-A has been observed [ 23 ]. It is, therefore, possible that better tissue oxygenation occurs together with an increase in ATP concentration in RBCs and a decrease in Hb affinity for oxygen and the same increases physical capacity and exercise tolerance.…”

“…It is now accepted that the VO 2max during whole-body exercise in humans is not constrained by the capacity of mitochondrial oxygen consumption but by the magnitude of oxygen delivery to the working muscles [ 21 , 22 ]. A recent study has shown that erythrocyte ATP concentration and changes in its level may regulate the magnitude of oxygen delivery to tissues [ 23 ]. Therefore, the study evaluated a relationship between the VO 2max level and the ATP concentration.…”