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Intracellular iron overload rewires HSC metabolism by impairing mitochondrial fitness

ABSTRACT: 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.

INSTRUMENT(S): Liquid Chromatography MS - alternating - hilic, Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS11778 | MetaboLights | 2024-12-04

REPOSITORIES: MetaboLights

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Project description:Pre-leukemic mutations are thought to promote clonal expansion of hematopoietic stem cells (HSCs) by increasing self-renewal and competitiveness. However, mutations that increase HSC proliferation tend to reduce competitiveness and self-renewal potential, raising the question of how a mutant HSC can sustainably outcompete wild-type HSCs. Activating mutations in NRAS are prevalent in human myeloproliferative disease and leukemia. Here we show that a single allele of oncogenic NrasG12D increases HSC proliferation but also increases reconstituting and self-renewal potential upon serial transplantation in irradiated mice, all without immortalizing HSCs or causing leukemia in our experiments. NrasG12D also confers long-term self-renewal potential upon multipotent progenitors. To explore the mechanism by which NrasG12D promotes HSC proliferation and self-renewal we assessed HSC cell cycle kinetics using H2B-GFP label retention. We found that NrasG12D had a bimodal effect on HSCs, increasing the proliferation of some HSCs while increasing the quiescence and competitiveness of other HSCs. One signal can therefore increase HSC proliferation, competitiveness, and self-renewal through a bimodal effect that promotes proliferation in some HSCs and quiescence in others. 12 RNA samples from mouse bone marrows were analyzed. There are three biological replicates for each subtype.

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