Iron Overload-Related Oxidative Stress Leads to Hyperphosphorylation and Altered Anion Exchanger 1 (Band 3) Function in Erythrocytes from Subjects with β-Thalassemia Minor

• Published in: International journal of molecular sciences Vol. 26; no. 4; p. 1593
• Main Authors: Spinelli, Sara, Straface, Elisabetta, Gambardella, Lucrezia, Caruso, Daniele, Dossena, Silvia, Marino, Angela, Morabito, Rossana, Remigante, Alessia
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.02.2025; MDPI
• Subjects: Adult; Anemia; Anion Exchange Protein 1, Erythrocyte - metabolism; Antioxidants; beta-Thalassemia - blood; beta-Thalassemia - metabolism; beta-Thalassemia - pathology; Blood diseases; Carrier proteins; Cytoskeleton; Enzymes; Erythrocytes; Erythrocytes - metabolism; Erythrocytes - pathology; Female; Genetic aspects; Health aspects; Hemoglobin; Humans; Iron; Iron Overload - metabolism; Kinases; Lipid Peroxidation; Lipids; Male; Oxidative Stress; Phosphorylation; Physiological aspects; Proteins; Reactive Oxygen Species - metabolism; Rheology; Thalassemia; Young Adult; Italy; red blood cells; Na+-K+/ATPase; β-thalassemia minor (β-Thal+); anion exchanger 1 (AE1); oxidative stress
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms26041593

β-thalassemia, a hereditary hemoglobinopathy, is caused by reduced or absent synthesis of the β-globin chains of hemoglobin. Three clinical conditions are recognized: β-thalassemia major, β-thalassemia intermedia, and β-thalassemia minor (β-Thal ). This latter condition occurs when an individual inherits a mutated β-globin gene from one parent. In erythrocytes from β-Thal subjects, the excess α-globin chains produce unstable α-tetramers, which can induce substantial oxidative stress leading to plasma membrane and cytoskeleton damage, as well as deranged cellular function. In the present study, we hypothesized that increased oxidative stress might lead to structural rearrangements in erythrocytes from β-Thal volunteers and functional alterations of ion transport proteins, including band 3 protein. The data obtained showed significant modifications of the cellular shape in erythrocytes from β-Thal subjects. In particular, a significantly increased number of elliptocytes was observed. Interestingly, iron overload, detected in erythrocytes from β-Thal subjects, provoked a significant production of reactive oxygen species (ROS), overactivation of the endogenous antioxidant enzymes catalase and superoxide dismutase, and glutathione depletion, resulting in (a) increased lipid peroxidation, (b) protein sulfhydryl group (-SH) oxidation. Iron overload-related oxidative stress affected Na /K -ATPase activity, which in turn may have contributed to impaired β-Thal erythrocyte deformability. As a result, alterations in the distribution of cytoskeletal proteins, including α/β-spectrin, protein 4.1, and α-actin, in erythrocytes from β-Thal subjects have been detected. Significantly, oxidative stress was also associated with increased phosphorylation and altered band 3 ion transport activity, as well as increased oxidized hemoglobin, which led to abnormal clustering and redistribution of band 3 on the plasma membrane. Taken together, these findings contribute to elucidating potential oxidative stress-related perturbations of ion transporters and associated cytoskeletal proteins, which may affect erythrocyte and systemic homeostasis in β-Thal subjects.