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.本投稿论文所有主图及补充图的配套实验数据。本论文聚焦线粒体融合蛋白在造血过程中的功能研究。此前我们曾报道，线粒体融合介导蛋白线粒体融合蛋白2（mitofusin 2, Mfn2）可促进淋巴系偏向造血干细胞（lymphoid-biased hematopoietic stem cells, HSCs）的维持。本研究证实，在造血系统中同时缺失两种线粒体融合蛋白同源物Mfn1与Mfn2，可引发胚胎致死、血细胞减少症，以及移植后长期与短期造血重建失败。仅保留一个Mfn1等位基因即可挽救上述缺陷。但仅携带单个Mfn2等位基因的小鼠，其红细胞系、B细胞与T细胞的发育均受到损伤。敲除Mfn会导致红细胞系祖细胞的线粒体质量调控异常，使其处于高能耗状态，并出现线粒体应激相关特征。在淋巴系中特异性同时缺失Mfn即可损伤淋巴造血过程；而在体外对野生型（wild type, WT）细胞诱导线粒体应激时，主要损伤淋巴系祖细胞，这表明线粒体应激是淋巴系发育缺陷的核心诱因。综上，线粒体融合蛋白在造血过程中仅存在部分功能冗余，且具有谱系特异性，其通过维持线粒体质量、抑制过度代谢以及缓解线粒体应激发挥调控作用。