Sphingosine-1-phosphate signaling modulates terminal erythroid differentiation through the regulation of mitophagy.

Erythropoiesis is a highly coordinated stepwise process involving the progressive clearance of mitochondria via mitophagy. Based on the expression of several macroautophagy and mitophagy specific genes, we identified a sequential change in the transcriptional pattern during terminal erythroid differentiation. Because erythroid cells are a major source of serum sphingosine-1-phosphate, we analyzed the role of sphingolipid signaling in erythropoiesis and demonstrate that sphingosine kinase activity promotes terminal erythroid differentiation by regulating the expression of key mitophagy genes Pink1 and Bnip3l/Nix. Sphingosine kinase 1 (Sphk1) inhibition also disrupted Pink1-p62 mediated mitochondria clearance in late erythroblasts. Notably, we show that supplementing sphingosine-1-phosphate in vitro can promote erythroid differentiation. Our study clarifies the role of sphingolipid signaling in regulating mitophagy during terminal erythroid differentiation and highlights the potential utility of modulating sphingolipid signaling to facilitate the large-scale production of transfusable red blood cells.