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Sickle cell hemoglobin in the ferryl state promotes βCys-93 oxidation and mitochondrial dysfunction in Epithelial Lung Cells (E10)

Kassa, T and Jana, S and Strader, MB and Meng, F and Jia, Y and Wilson, MT and Alayash, AI (2015) 'Sickle cell hemoglobin in the ferryl state promotes βCys-93 oxidation and mitochondrial dysfunction in Epithelial Lung Cells (E10).' Journal of Biological Chemistry, 290 (46). 27939 - 27958. ISSN 0021-9258

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Abstract

Polymerization of intraerythrocytic deoxyhemoglobin S (HbS) is the primary molecular event that leads to hemolytic anemia in sickle cell disease (SCD). We reasoned that HbS may contribute to the complex pathophysiology of SCD in part due to its pseudoperoxidase activity. We compared oxidation reactions and the turnover of oxidation intermediates of purified human HbS and HbA. Hydrogen peroxide (H 2 O 2 ) drives a catalytic cycle that includes the following three distinct steps: 1) initial oxidation of ferrous (oxy) to ferryl Hb; 2) autoreduction of the ferryl intermediate to ferric (metHb); and 3) reaction of metHb with an additional H 2 O 2 molecule to regenerate the ferryl intermediate. Ferrous and ferric forms of both proteins underwent initial oxidation to the ferryl heme in the presence of H 2 O 2 at equal rates. However, the rate of autoreduction of ferryl to the ferric form was slower in the HbS solutions. Using quantitative mass spectrometry and the spin trap, 5, 5-dimethyl-1-pyrroline-N-oxide, we found more irreversibly oxidized βCys-93 in HbS than in HbA. Incubation of the ferric or ferryl HbS with cultured lung epithelial cells (E10) induced a drop in mitochondrial oxygen consumption rate and impairment of cellular bio-energetics that was related to the redox state of the iron. Ferryl HbS induced a substantial drop in the mitochondrial transmembrane potential and increases in cytosolic heme oxygenase (HO-1) expression and mitochondrial colocalization in E10 cells. Thus, highly oxidizing ferryl Hb and heme, the product of oxidation, may be central to the evolution of vasculopathy in SCD and may suggest therapeutic modalities that interrupt heme-mediated inflammation.

Item Type: Article
Subjects: Q Science > QH Natural history > QH301 Biology
Divisions: Faculty of Science and Health > Biological Sciences, School of
Depositing User: Jim Jamieson
Date Deposited: 12 Feb 2016 11:37
Last Modified: 14 Mar 2019 12:15
URI: http://repository.essex.ac.uk/id/eprint/15744

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