Abstract 18760: mTOR Regulates Cellular Iron Homeostasis and Modulates Cell Viability In Iron-Deficient Conditions.
Background: Mammalian Target of Rapamycin (mTOR) is a central sensor of nutrient availability and cellular stress and is implicated in carcinogenesis and acceleration of aging. Since iron is a required nutritional element, we assessed the role of mTOR in regulation of cellular iron homeostasis.
Methods and Results: To determine whether mTOR regulates iron homeostasis, we analyzed the expression of genes necessary for cellular iron uptake, storage, mitochondrial handling and export with mTOR modulation. Pharmacologic inhibition of mTOR with rapamycin decreased expression of several iron-regulatory genes in mouse embryonic fibroblasts (MEFs) and led to accumulation of heme and non-heme iron in H9C2 cardiac myoblasts. Constitutive activation of mTOR by genetic ablation of its inhibitor in TSC2−/− MEFs enhanced the expression of the above genes and decreased cellular iron content; both findings were reversible with rapamycin treatment. To study the mechanism of iron regulation by mTOR, we analyzed the effects of mTOR modulation on the expression of Tristetraprolin (TTP), a mammalian homolog of yeast Cth2 tandem zinc finger protein. Cth2 is induced in response to iron deficiency, and functions to destabilize mRNAs of non-essential iron-requiring proteins, securing the limited iron pool for vital processes. Consistent with findings in yeast, we observed a 9-fold increase in TTP mRNA levels in MEFs following iron chelation with Deferoxamine (DFO). Rapamycin treatment also increased, while TSC2 knockout decreased, the expression of TTP in MEFs, implicating a role for TTP in mTOR-mediated iron regulation. Finally, to determine whether mTOR inhibition is protective in iron-limiting conditions, we assessed cell viability in TSC2−/− MEFs treated with DFO. Iron chelation led to a significant increase in cell death, which was completely reversed by pre-incubation of cells with rapamycin. This suggests that mTOR inhibition attenuates the deleterious effects of iron chelation on cells.
Conclusions: Our findings suggest that mTOR regulates cellular iron homeostasis by altering gene expression profile and cellular iron content possibly through induction of a mammalian tandem zinc finger protein, TTP.
- © 2010 by American Heart Association, Inc.