Intracellular Iron Controls HSC Metabolism By Affecting Mitochondrial Fitness

Iron is an important source of reactive oxygen species (ROS) within the cell and recent evidence highlighted its role in regulating HSC self-renewal and differentiation. However, whether and how iron influences HSC metabolism is still undetermined. Cellular metabolism is a key regulator of HSC maintenance and HSCs adapt their metabolic state to their function. Quiescent HSCs have low energy requirements and depend on anaerobic glycolysis, whereas active HSCs require high energy for proliferation and differentiation thus enhancing oxidative phosphorylation (OXPHOS), glycolysis and fatty acid oxidation (FAO). To explore which metabolic pathways are triggered by intracellular iron levels, we took advantage of the thalassemic Hbb th3/+mice ( th3), characterized by chronic iron overload (IO). We previously demonstrated an impaired function of th3 HSCs due to persistence into altered BM niche ( Aprile et al., 2020). Th3 HSCs showed higher levels of intracellular free reactive iron (1.7±0.2 calcein MFI fold to wt, p