Abstract 19291: Iron Deprivation Inhibits mTOR Activity by Regulating Amino Acid Homeostasis

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Background: Cells require iron to carry out myriad enzymatic functions necessary for growth and metabolism. Derangements in cellular iron regulation have been linked to multiple forms of both genetic heart disease and acquired hypertrophic cardiomyopathy. Recently, we described a novel mammalian target of rapamycin (mTOR) -dependent pathway regulating cellular iron levels that was independent of the iron regulatory response (IRP)-1/2 and HIF1α systems. However, the mechanism by which mTOR senses iron levels and coordinates the transcription of the iron deprivation inducible genes, such as Tristetraprolin (TTP), is unknown. mTOR is a serine/threonine kinase that is a master regulator of protein synthesis and glucose metabolism that is dependent on amino acid (AA) sufficiency. Therefore, we hypothesis that a consequence of iron deprivation is the reduction in cellular levels of AAs that leads to the inhibition of mTOR activity and ultimately initiates an adaptive response through gene transcription of TTP.

Results: Iron chelation using the iron chelator desferoxamine (DFO) resulted in inhibition of mTOR activity while simultaneously increasing TTP expression. This process was preserved in AKT 1/2, AMPK, and TSC2 KO, as well as Rheb1 overexpressing (OE) cells, suggesting iron chelation regulates mTOR activity independent of canonical growth factor pathways. Inhibition of mTOR activity by direct AA deprivation also increased transcription of TTP. To test if iron deprivation directly regulates AA levels, we measured total cellular AA content and observed a significant decrease in the levels of leucine in cells with iron chelation. Additionally, repletion with cell-permeable leucine or constitutively active Rag B/C OE, which render mTOR insensitive to alterations in AA, blocked the inhibition of mTOR and subsequent induction of TTP by iron chelation.

Conclusion: Our work describes a novel pathway by which cells coordinate iron availability with AA homeostasis and mTOR activity. Understanding the coordinated regulation of nutrient signaling and cellular metabolism by iron and mTOR could provide for the rational design of novel cardiomyocyte-targeted therapeutics for heart failure.

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