Respiratory Function of Hemoglobin: From Origin to Human Physiology and Pathophysiology

Hemoglobin packaged within erythrocytes stores, delivers, coordinates and actively regulates the exchange of multiple gases including oxygen (O2), carbon dioxide and nitric oxide among distant sites of uptake, production, utilization and elimination. Hemoglobin traces its origin to the earliest anaerobic prokaryote that ingested metals from the rock to produce hemoproteins that facilitate non-O2-based cellular respiration, only later acquiring O2-binding ability. In multi-cellular organisms, some hemoprotein-producing cells either extruded their product or detached to enter the circulation, becoming erythrocytes and co-evolving in complexity with the microvascular system. This article surveys the origin and natural selection of hemoglobin, its respiratory functions and close interactions with erythrocytes and the microvasculature, and how its evolutionary history informs gas transport physiology and clinical medicine in terms of understanding the pathophysiological disturbances in hemoglobin quantity, quality, function and dynamic regulation.