Exacerbation of mitochondrial fission in human CD34+ cells halts erythropoiesis and hemoglobin biosynthesis

Erythropoiesis is the most powerful cellular differentiation and proliferation system, with a production of 1011 cells per day. In this fine-tuned process, the hematopoietic stem cells (HSCs) generate erythroid progenitors, which proliferate and mature into erythrocytes. During erythropoiesis, mitochondria are reprogrammed to drive the differentiation process before finally being eliminated by mitophagy. In erythropoiesis, mitochondrial dynamics (MtDy) is expected to be a regulatory key point that has not been described previously. We described that a specific MtDy pattern is occurring in human erythropoiesis from EPO-induced human CD34+ cells, characterized by a predominant mitochondrial fusion at early stages followed by predominant fission at late stages. The fusion protein MFN1 and the fission protein FIS1 are shown to play a key role in the accurate progression of erythropoiesis. Fragmentation of the mitochondrial web by the overexpression of FIS1 (gain of fission) resulted in both the inhibition of hemoglobin biosynthesis and the arrest of erythroid differentiation, keeping cells in immature differentiation stages. These cells showed specific mitochondrial features as compared with control cells, such as an increase in round and large mitochondria morphology, low mitochondrial membrane potential and a drop in the expression of the respiratory complexes II and IV. Interestingly, treatment with the mitochondrial permeability transition pore (mPTP) inhibitor cyclosporin A, rescued mitochondrial morphology, hemoglobin biosynthesis and erythropoiesis. Studies presented in this work revealed MtDy as a hot spot in the regulation of erythroid differentiation which might be signaling downstream for metabolic reprogramming through the aperture/close of the mPTP. Key Points-. Excessive fission disrupts erythroid progression, heme biosynthesis and mitochondrial function, keeping cells mostly in progenitors and proerythroblast stage. -. Mitochondrial Dynamics signaling for erythroid differentiation involves FIS1 and the mPTP