Distinct and interacting roles of Mitofusins in hematopoiesis

Data for all figures and supplementary figures for a submitted manuscript. In this manuscript we described the role of mitofusins in hematopoiesis. We previously reported that the mitochondrial fusion mediator, mitofusin (Mfn)2, promotes maintenance of lymphoid-biased hematopoietic stem cells (HSCs). Here, we demonstrate that combined loss in the hematopoietic system of both Mfn homologues, Mfn1 and Mfn2, causes embryonic lethality, cytopenias, as well as long-term and short-term reconstitution failure after transplantation. A single Mfn1 allele rescued these defects. However, mice with a single Mfn2 allele showed impaired erythroid, B and T cell development. Mfn deletion caused abnormal regulation of mitochondrial mass in erythroid progenitors, a hyperenergetic state, and evidence of mitochondrial stress. Combined Mfn deletion in the lymphoid lineage was sufficient to impair lymphopoiesis, while ex vivo induction of mitochondrial stress in WT cells primarily impaired lymphoid progenitors, indicating mitochondrial stress as the primary driver of the lymphoid defects. Mfns therefore play only partially redundant and lineage-specific roles in hematopoiesis through maintenance of mass, prevention of hypermetabolism and mitigation of mitochondrial stress.