Deciphering the Heterogeneity of Mitochondrial Functions During Hematopoietic Lineage Differentiation

The heterogeneity of mitochondrial function is an important feature of hematopoietic cell lineage differentiation, but its stage wise contribution is not adequately studied. To establish a model to compare the lineage differentiation of hematopoietic stem cells (HSCs), hematopoietic progenitor cells (HPCs), and differentiated blood cells, the mitochondrial mass (MM), mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and mitophagy level were analyzed.

HSCs had lower mitochondrial metabolic activity than committed progenitor populations, indicated by lower MM, MMP, and ROS and higher mitophagy. HPC1s shared more stem cell characteristics than HPC2s and committed progenitor populations in terms of mitochondrial number and function. The mitochondrial metabolism of mature blood cells had greater heterogeneity than hematopoietic stem and progenitor cells, with granulocytes being similar to monocytes. Moreover, HSCs exhibited heterogeneity in the selection of mitophagy-related PINK1/PARK2, BNIP3/NIX, and FUNDC1 pathways. Myeloid differentiation had greater morphological and functional heterogeneity of hematopoietic cells than lymphoid differentiation. Additionally, leukemia stem cells had higher aerobic metabolism and better stem cell function through elevated mitophagy than normal hematopoietic cells. ROS and MMP levels in differentiated leukemia cells were higher, but the level of mitophagy was lower than in differentiated hematopoietic cells.

This study provides a complete set of methods and basic reference values for the systematic study of the mitochondrial metabolic function of different types of hematopoietic cells under physiological and pathological conditions. The findings contribute to the future research of tumor and aging based on mitochondrial metabolism.