Mitochondria regulate the cell fate decisions of megakaryocyte-erythroid progenitors

Recent studies highlight the critical role of mitochondria in hematopoiesis, especially in stem cell function and erythroid maturation. To explore mitochondrial contributions to cell lineage commitment of hematopoietic progenitors, we utilized Cars2-mutant mice, an ideal model for this purpose. CARS2, a mitochondrial isoform of cysteinyl-tRNA synthetase, has cysteine persulfide synthase (CPERS) activity. Our new mouse model, with reduced CPERS activity, showed that the Cars2 mutation led to mitochondrial inhibition and anemia by suppressing erythroid commitment in megakaryocyte-erythroid progenitors (MEPs). This suppression was reproduced using mitochondrial electron transport chain inhibitors. We identified two distinct MEP populations based on the mitochondrial content: mitochondria-rich MEPs favored erythroid differentiation, while the mitochondria-poor MEPs favored megakaryocyte differentiation. These findings reveal critical contributions of mitochondria to the MEP lineage selection, acting as a "mitochondrial navigation" for lineage commitment.