Autophagy Defects and Mitochondrial Retention in Erythroid Diseases.

Erythropoiesis requires extensive cellular remodeling, culminating in enucleation and organelle clearance to generate mature red blood cells (RBCs). Over the past 15 years, accumulating evidence has established that macroautophagy-particularly ULK1-, NIX-, and PINK1-dependent mitophagy-plays a central role in erythroid maturation. Defective autophagy can lead to mitochondrial retention, increased reactive oxygen species (ROS) production, membrane alterations, and ineffective erythropoiesis. Such abnormalities have now been documented in several hematological disorders, including myelodysplastic syndromes, Fanconi anemia, Diamond-Blackfan anemia, sickle cell disease, and β-thalassemia. This review summarizes current knowledge of autophagy regulation during erythropoiesis, the molecular mechanisms governing mitochondrial clearance, and the pathological consequences of impaired autophagy in red blood cell disorders. Finally, we discuss emerging therapeutic strategies targeting autophagy pathways.