Iron drives anabolic metabolism through active histone demethylation and mTORC1

Jason S. Shapiro, Hsiang Chun Chang, Yuki Tatekoshi, Zibo Zhao, Zohra Sattar Waxali, Bong Jin Hong, Haimei Chen, Justin A. Geier, Elizabeth T. Bartom, Adam De Jesus, Farnaz K. Nejad, Amir Mahmoodzadeh, Tatsuya Sato, Lucia Ramos-Alonso, Antonia Maria Romero, Maria Teresa Martinez-Pastor, Shang Chuan Jiang, Shiv K. Sah-Teli, Liming Li, David BentremGary Lopaschuk, Issam Ben-Sahra, Thomas V. O’Halloran, Ali Shilatifard, Sergi Puig, Joy Bergelson, Peppi Koivunen, Hossein Ardehali

Research output: Contribution to journalArticlepeer-review


All eukaryotic cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here we report a previously undescribed eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway. Specifically, we identify the iron-binding histone-demethylase KDM3B as an intrinsic iron sensor that regulates mTORC1 activity by demethylating H3K9me2 at enhancers of a high-affinity leucine transporter, LAT3, and RPTOR. By directly suppressing leucine availability and RAPTOR levels, iron deficiency supersedes other nutrient inputs into mTORC1. This process occurs in vivo and is not an indirect effect by canonical iron-utilizing pathways. Because ancestral eukaryotes share homologues of KDMs and mTORC1 core components, this pathway probably pre-dated the emergence of the other kingdom-specific nutrient sensors for mTORC1.

Original languageEnglish (US)
Pages (from-to)1478-1494
Number of pages17
JournalNature Cell Biology
Issue number10
StatePublished - Oct 2023

ASJC Scopus subject areas

  • Cell Biology


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