Abstract 17382: Jumonji-C Histone Demethylases Are Cellular Iron Sensors That Control mTORC1 and Mitophagy

Iron is an essential nutrient and is critical for cellular growth and metabolism. Here, we delineate a novel mechanism by which iron alters amino acid homeostasis and mTOR activity by remodeling the cellular epigenetic landscape. We find that iron deficiency inactivates Jumonji-C domain containing histone-demethylases, resulting in histone hyper-methylation and silencing of the leucine transporter LAT3 and obligatory mTORC1 cofactor RAPTOR. Additionally, we identify that mTOR-mediated regulation of RNA stability through tristetraprolin (TTP) is a novel and requisite step in selective-autophagy. In the absence of TTP, mitochondria damaged by the loss of iron cannot undergo fission, rendering the mitochondria too large for engulfment and subsequent recycling. Accumulation of damaged mitochondria leads to defective oxidative metabolism and impairs hepatic gluconeogenesis in response to fasting. These studies uncover a novel pathway that integrates iron sensing with cellular metabolism, mitochondrial dynamics and autophagy.