Haemoglobin (Hb) accounts for >90% of the dry mass of the red blood cells (RBCs, erythrocytes), about 29 pg in each RBC, and about 98% of the cytoplasmic protein content. In an adult man the total amount of haemoglobin in the circulation is about 900 g. Kidneys function as oxygen and haematocrit sensor, producing erythropoietin (EPO) in response to hypoxia; EPO stimulates the production of erythrocytes in the bone marrow.
Haemoglobin is a tetrameric 65 kDa protein with almost spherical shape. It consists of two α-globin chains and two β-globin chains. Hb can bind four O2 molecules, with affinity that strongly depends on local oxygen partial pressure (PO2). Oxygen binding to haemoglobin can be described by the Adair equation, but in Hb-O2 saturation (SO2) range 20-80% the much simpler Hill equation provides an accurate dissociation curve:
P50 and n are dependent on the blood pH, temperature, and concentrations of CO2 and 2,3-biphosphoglycerate (2,3-BPG, or 2,3-DPG) (Dash & Bassingthwaighte, 2010). Erythrocytes can produce 2,3-DPG to reduce the affinity of haemoglobin to oxygen. RSR13 is a synthetic compound that also right-shifts the O2 dissociation curve. In human subjects, P50 is 3.5±0.1 kPa in arterial blood, and 3.7±0.2 kPa in venous blood (Siggaard-Andersen et al., 1990). In a larger group, arterial P50 was found to vary between 2.15 and 6.44, with median 3.44 kPa (Gøthgen et al., 1990). P50 and n may be different in trained and untrained people (Braumann et al., 1979).
The affinity of carbon monoxide (CO) to Hb is ∼210-250 times higher than that of O2, causing tissue hypoxia if ambient CO concentration is high or exposure is prolonged. CO binds also to other heme-proteins, including myoglobin, cytochrome P450, cytochrome c oxidase, and catalase, which may add to symptoms of CO intoxication (Wu & Wang, 2005; Levitt & Levitt, 2015). Normally, the majority of carbon monoxide in the body is produced by heme metabolism, catalysed by heme oxidase enzymes mainly in mononuclear phagocyte system in spleen and liver. Heme oxidase 1 (HO-1) is an inducible isoform, and HO-2 and HO-3 are constitutive isoforms of heme oxidase. The produced CO is exhaled though the lungs (Wu & Wang, 2005).
The α- and β-globins are not only found in the haemoglobin of red blood cells. The affinity of Hb monomers for O2 is higher than that of α2β2 tetramer, and they can thus participate in intracellular oxygen transport and storage. Hb monomers are expressed in many tissues, including macrophages (Liu et al., 1999) and neurons and glial cells (Biagioli et al., 2009; Richter et al., 2009.
In the brain α-globin may have an import role in regulating neuronal oxygenation and neuroprotection (Walser et al., 2021; Lu et al., 2022). Neuronal Hb-α expression is decreased in neurodegenerative disorders (Ferrer et al., 2011). In hypoxic mouse brain, EPO increases Hb-α expression and reduces hypoxia (Schelshorn et al., 2009).
In addition to Hb monomers, tissues also express neuroglobin (Nbg) and cytoglobin (Cygb), which are structurally similar to the α- and β-globins of Hb and to the myoglobin (Hundahl et al., 2013). Neuroglobin protects neurons from mitochondrial dysfunctions and neurodegenerative disorders, and it facilitates the survival of cancer cells (Fiocchetti et al., 2017). Cytoglobin may facilitate oxygen transport and storage, or protect cells against oxidative stress (Reeder et al., 2017). Nbg expression is not increased by EPO.
Adair GS, Bock AV, Field H Jr. The hemoglobin system: VI. The oxygen dissociation curve of hemoglobin. J Biol Chem. 1925; 63: 529-545. doi: 10.1016/S0021-9258(18)85018-9.
Gell DA. Structure and function of haemoglobins. Blood Cells Mol Dis. 2018; 70: 13-42. doi: 10.1016/j.bcmd.2017.10.006.
Pittman RN. Oxygen transport in the microcirculation and its regulation. Microcirculation 2013; 20(2): 117-137. doi: 10.1111/micc.12017.
Updated at: 2023-02-02
Created at: 2017-03-30
Written by: Vesa Oikonen