Intracellular iron overload rewires HSC metabolism by impairing mitochondrial fitness

Iron is an essential element for several cellular processes and recent evidence highlighted its role in regulating the function of hematopoietic stem cells (HSCs). When in excess it reduces quiescence and self-renewal, however, whether and how iron influences HSC metabolism is still unknown. Here, we show that intracellular iron overload (IO) impairs mitochondrial fitness and bioenergetics, inducing metabolic rewiring in HSCs. In three models of IO, HSCs accumulate mitochondria with elevated reactive oxygen species (ROS), low membrane potential and reduced oxidative phosphorylation (OXPHOS). IO HSCs proliferate despite low mitochondrial activity and OXPHOS and rely on glycolysis for energy production. Notably, restoration of mitochondrial function by targeting in vivo iron and mitochondrial ROS improved the quiescence and self-renewal of IO HSCs. Our results unravel the critical interplay between iron, ROS and mitochondria in HSCs, disclosing that iron acts as an extrinsic regulator of HSC metabolic programs.