Abstract 16349: Mammalian Target of Rapamycin Regulates Cardiac Iron Homeostasis in vitro and in vivo through Modulation of Tristetraprolin Expression
Background: Iron deficiency affects over 2 billion people worldwide and can lead to anemia, cardiomyopathy and shortened lifespan, yet the mechanisms behind it remain elusive. Here we report that mTOR modulates cell viability in low-iron states, and regulates iron handling through tristetraprolin (TTP), an mRNA-binding protein.
Results: In a screen to identify novel players in iron deficiency response, we found mTOR activity to be repressed by iron chelator deferoxamine. This inhibition was protective, as the constitutively active mTOR dramatically increased cell death in the presence of iron chelators, while mTOR inhibition with rapamycin restored viability. Moreover, rapamycin decreased expression of iron-requiring proteins, suggesting a role for mTOR in regulation of cellular iron. To determine if mTOR regulates iron in vitro, we assessed iron uptake, content and expression of iron-regulatory genes after modulation of mTOR signaling. Constitutive activation of mTOR led to a reduction in heme and non-heme iron, induction of iron transporters, and increased cellular iron flux. The observed changes were reversible with rapamycin. In vivo, rapamycin suppressed expression of iron transporters and increased iron levels in the mouse heart. However, iron content was reduced in the liver, suggesting redistribution of iron from the sites of storage (liver) to the sites of utilization (heart). Systemic effects of rapamycin were not mediated by hepcidin, the master iron-regulatory hormone, and were not due to changes in the intestinal iron uptake. To study the mechanism of mTOR-mediated iron regulation, we examined TTP, the mammalian homolog of yeast Cth2 that destabilizes mRNAs of iron-requiring proteins and promotes cell survival in iron deficiency. Both, rapamycin and iron chelation induced expression of TTP, while mTOR activation and iron overload reduced TTP levels. Knockdown of TTP altered expression of iron transporters and increased cellular iron. Importantly, iron response to rapamycin was greatly attenuated with TTP knockdown, suggesting a role for TTP in the mTOR-dependent iron regulation.
Conclusions: We identified mTOR as a novel regulator of iron homeostasis and iron deficiency response via induction of TTP, an mRNA-binding protein.
- © 2011 by American Heart Association, Inc.