The mechanism of formation, structure and physiological relevance of covalent hemoglobin attachment to the erythrocyte membrane

Welbourn, Elizabeth M. and Wilson, Michael T. and Yusof, Ashril and Metodiev, Metodi V. and Cooper, Chris E. (2017) The mechanism of formation, structure and physiological relevance of covalent hemoglobin attachment to the erythrocyte membrane. Free Radical Biology and Medicine, 103. pp. 95-106. ISSN 0891-5849, DOI

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Covalent hemoglobin binding to membranes leads to band 3 (AE1) clustering and the removal of erythrocytes from the circulation; it is also implicated in blood storage lesions. Damaged hemoglobin, with the heme being in a redox and oxygen-binding inactive hemichrome form, has been implicated as the binding species. However, previous studies used strong non-physiological oxidants. In vivo hemoglobin is constantly being oxidised to methemoglobin (ferric), with around 1% of hemoglobin being in this form at any one time. In this study we tested the ability of the natural oxidised form of hemoglobin (methemoglobin) in the presence or absence of the physiological oxidant hydrogen peroxide to initiate membrane binding. The higher the oxidation state of hemoglobin (from Fe(III) to Fe(V)) the more binding was observed, with approximately 50% of this binding requiring reactive sulphydryl groups. The hemoglobin bound was in a high molecular weight complex containing spectrin, ankyrin and band 4.2, which are common to one of the cytoskeletal nodes. Unusually, we showed that hemoglobin bound in this way was redox active and capable of ligand binding. It can initiate lipid peroxidation showing the potential to cause cell damage. In vivo oxidative stress studies using extreme endurance exercise challenges showed an increase in hemoglobin membrane binding, especially in older cells with lower levels of antioxidant enzymes. These are then targeted for destruction. We propose a model where mild oxidative stress initiates the binding of redox active hemoglobin to the membrane. The maximum lifetime of the erythrocyte is thus governed by the redox activity of the cell; from the moment of its release into the circulation the timer is set.

Item Type: Article
Uncontrolled Keywords: Erythrocyte; Hemoglobin; Membrane; Hemichrome; Oxidative stress; Blood storage; β Cys-93; Exercise; Senescence; Badwater ultramarathon
Subjects: G Geography. Anthropology. Recreation > GV Recreation Leisure
Q Science > Q Science (General)
Q Science > QH Natural history > QH301 Biology
Divisions: Faculty of Sports and Exercise Science (formerly known as Centre for Sports & Exercise Sciences)
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 22 Oct 2019 05:51
Last Modified: 22 Oct 2019 05:51

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