Mitapivat increases ATP and decreases oxidative stress and erythrocyte mitochondria retention in a SCD mouse model

• Published in: Blood cells, molecules, & diseases Vol. 95; p. 102660
• Main Authors: Quezado, Zenaide M.N., Kamimura, Sayuri, Smith, Meghann, Wang, Xunde, Heaven, Michael R., Jana, Sirsendu, Vogel, Sebastian, Zerfas, Patricia, Combs, Christian A., Almeida, Luis E.F., Li, Quan, Quezado, Martha, Horkayne-Szakaly, Iren, Kosinski, Penelope A., Yu, Shaoxia, Kapadnis, Unnati, Kung, Charles, Dang, Lenny, Wakim, Paul, Eaton, William A., Alayash, Abdu I., Thein, Swee Lay
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2022
• Subjects: 2,3-Diphosphoglycerate - metabolism; Adenosine Triphosphate - metabolism; anemia; Anemia, Sickle Cell; Animals; Disease Models, Animal; Erythrocytes - metabolism; Hemoglobin, Sickle - metabolism; Hemoglobins - analysis; Humans; Mice; Mitochondria - metabolism; Oxidative Stress; Piperazines; Proteomics; Pyruvate kinase; Quinolines; Sickle cell; Oxidative stress; Pyruvate kinase; Sickle cell; anemia; Proteomics
• ISSN: 1079-9796; 1096-0961; 1096-0961
• DOI: 10.1016/j.bcmd.2022.102660

Polymerization of deoxygenated sickle hemoglobin (HbS) leads to erythrocyte sickling. Enhancing activity of the erythrocyte glycolytic pathway has anti-sickling potential as this reduces 2,3-diphosphoglycerate (2,3-DPG) and increases ATP, factors that decrease HbS polymerization and improve erythrocyte membrane integrity. These factors can be modulated by mitapivat, which activates erythrocyte pyruvate kinase (PKR) and improves sickling kinetics in SCD patients. We investigated mechanisms by which mitapivat may impact SCD by examining its effects in the Townes SCD mouse model. Control (HbAA) and sickle (HbSS) mice were treated with mitapivat or vehicle. Surprisingly, HbSS had higher PKR protein, higher ATP, and lower 2,3-DPG levels, compared to HbAA mice, in contrast with humans with SCD, in whom 2,3-DPG is elevated compared to healthy subjects. Despite our inability to investigate 2,3-DPG-mediated sickling and hemoglobin effects, mitapivat yielded potential benefits in HbSS mice. Mitapivat further increased ATP without significantly changing 2,3-DPG or hemoglobin levels, and decreased levels of leukocytosis, erythrocyte oxidative stress, and the percentage of erythrocytes that retained mitochondria in HbSS mice. These data suggest that, even though Townes HbSS mice have increased PKR activity, further activation of PKR with mitapivat yields potentially beneficial effects that are independent of changes in sickling or hemoglobin levels. •Mitapivat further increased ATP without changing 2,3-DPG or hemoglobin levels.•Mitapivat decreased extra-medullary hematopoiesis in SCD mice.•Mitapivat decreased leukocytosis and erythrocyte oxidative stress in SCD mice.•Mitapivat decreased percentage of erythrocytes retaining mitochondria in SCD mice.