Date of Graduation


Document Type

Dissertation (PhD)

Program Affiliation

Biochemistry and Molecular Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Cheng Chi Lee, Ph.D.

Committee Member

Diane Bick, Ph.D.

Committee Member

Mikhail Bogdanov, Ph.D.

Committee Member

Rodney Kellems, Ph.D.

Committee Member

Richard Kulmacz, Ph.D.


Erythrocytes are responsible for ensuring a sufficient supply of oxygen to meet activity demands. The mammalian erythrocytes primarily modulate their oxygen-carrying capacity by varying the levels of organic phosphates, such as 2,3-BPG. In other organisms, such as fish, ATP instead of 2,3-BPG is used to modulate their erythrocyte’s oxygen binding ability. Here, using a series of genetically modified mice, we investigated a previously unrecognized pathway of adenine nucleotide influx and efflux that modulates erythrocyte’s oxygen binding ability and controls systemic metabolism. Our studies show that the loss of AMPD3 and CD73, two important enzymes in regulating AMP levels intra- and extra-cellularly, respectively, allows for an increase in sustained metabolic activity. We show that this increase in work capacity is linked to an increase in erythrocyte’s intracellular ATP levels which modulates hemoglobin affinity for oxygen directly. Pharmacologically, we show that Ampd3-/-/Cd73-/- mice display an enhanced hypometabolic phenotype in response to AMP administration. Our studies reveal that the hypometabolism is associated with a severe reduction in oxygen binding affinity that results from erythrocyte’s uptake of AMP.


Metabolism, AMP-induced Hypometabolism, Erythrocytes, Adenine Nucleotides