The Roles of Mitophagy and Autophagy in Ineffective Erythropoiesis in β-Thalassemia

Abstract

β-Thalassemia is one of the most common genetically inherited disorders worldwide, and it is characterized by defective β-globin chain synthesis leading to reduced or absent β-globin chains. The excess α-globin chains are the key factor leading to the death of differentiating erythroblasts in a process termed ineffective erythropoiesis, leading to anemia and associated complications in patients. The mechanism of ineffective erythropoiesis in β-thalassemia is complex and not fully understood. Autophagy is primarily known as a cell recycling mechanism in which old or dysfunctional proteins and organelles are digested to allow recycling of constituent elements. In late stage, erythropoiesis autophagy is involved in the removal of mitochondria as part of terminal differentiation. Several studies have shown that autophagy is increased in earlier erythropoiesis in β-thalassemia erythroblasts, as compared to normal erythroblasts. This review summarizes what is known about the role of autophagy in β-thalassemia erythropoiesis and shows that modulation of autophagy and its interplay with apoptosis may provide a new therapeutic route in the treatment of β-thalassemia. Literature was searched and relevant articles were collected from databases, including PubMed, Scopus, Prospero, Clinicaltrials.gov, Google Scholar, and the Google search engine. Search terms included: β-thalassemia, ineffective erythropoiesis, autophagy, novel treatment, and drugs during the initial search. Relevant titles and abstracts were screened to choose relevant articles. Further, selected full-text articles were retrieved, and then, relevant cross-references were scanned to collect further information for the present review.

Keywords: ER stress; apoptosis; autophagy; ineffective erythropoiesis; β-thalassemia.

Figure 1

Epidemiology of β-thalassemia. Global epidemiological data including the percentages of populations carrying Hb variants, the number of newborns who have β-thalassemias per year, the number of patients who have TDT, and the percentage of TDT patients who are reached for blood transfusion, and the number of patients who died as a consequence of not receiving blood transfusion worldwide and in the individual sub-regions, according to the World Health Organization (WHO) as reported by Modell B and Darlison M published in the Bull World Health Organ 2008, 86, (6), 480–487 [13]. ^a Hemoglobin variants including HbS, HbC, HbE, HbD, etc., β-thalassemia and α-thalassemia. Hb; hemoglobin, TD β-thalassemia; transfusion dependent β-thalassemia. Source of WHO region map; wikipedia.org (accessed in September 2022). The map is in the public domain.

Figure 2

Pathophysiology of β-thalassemia. Defect in β-globin genes leads to reduced or absent β-globin production and consequent excess unbound α-globin chain accumulation and precipitation in erythroblasts, resulting in ineffective eythropoiesis. Abnormal RBCs, including anisopoikilocytosis, and RBCs with damaged membranes cause RBC destruction in the spleen leading to anemia, reticuloendothelial (RE) hyperplasia, and increased bilirubin production. Iron overload is a key factor in inducing a systemic pathology leading to increased mortality and morbidity in β-thalassemia patients. Blood transfusion and iron chelators are the conventional treatments for β-thalassemia. Curently, therapeutic drugs such as ruxolitinib, sotatercept, luspatercept, and mitapivat that target ineffective erythropoiesis by increasing Hb production are in clinical trials. Hb; hemoglobin, RBCs; red blood cells, and RE system; reticuloendothelial system.

Figure 3

Mechanism of program cell death in bone marrow β-thalassemic erythroblasts. Normal erythropoiesis occurs in bone marrow in the location of an erythroblastic island that contains a macrophage as a feeder cell to product cytokines, which is essential for erythroid differentiation from hematopoietic stem cells (HSCs) to erythroid precursor cells including pronormoblasts (ProE), basophilic normoblasts (BasoE), polychromatophilic normoblasts (PolyE), and orthochromatic normoblasts (OrthoE) and consequently enucleation and mitochondria clearance by autophagy resulting in terminal erythroid differentiation and yielding mature red blood cells (RBCs). In β-thalassemia, excess unbound α-globin chains precipitate into erythroblasts leading to hemichrome accumulation and cellular stress. Autophagy could be a process of cellular adaptation in β-thalassemic erythroblasts to reduce the toxicity from excess unbound α-globin chains by protein degradation and inhibit apoptosis. However, the imbalance of α-globin/non-α-globin and increased heme in erythroblasts cause reactive oxygen species (ROS) generation via the Fenton reaction that consequently induces an ER stress response, resulting in the release of calcium (Ca²⁺) into cytoplasm. Increased intracellular calcium (i[Ca²⁺]) effects to activate scramblase but inhibits translocase, leading to the loss of plasma membrane asymmetry, resulting in increased phosphatidylserine (PS) on the outer membrane leaflet. PS-bearing erythroblasts could be cleared by macrophages via PS-PS receptor interaction as the “eat me” signal of phagocytosis.