Iron drives anabolic metabolism through active histone demethylation and mTORC1

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 susta...

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Published in:	Nature cell biology Vol. 25; no. 10; pp. 1478 - 1494
Main Authors:	Shapiro, Jason S., Chang, Hsiang-Chun, Tatekoshi, Yuki, Zhao, Zibo, Waxali, Zohra Sattar, Hong, Bong Jin, Chen, Haimei, Geier, Justin A., Bartom, Elizabeth T., De Jesus, Adam, Nejad, Farnaz K., Mahmoodzadeh, Amir, Sato, Tatsuya, Ramos-Alonso, Lucia, Romero, Antonia Maria, Martinez-Pastor, Maria Teresa, Jiang, Shang-Chuan, Sah-Teli, Shiv K., Li, Liming, Bentrem, David, Lopaschuk, Gary, Ben-Sahra, Issam, O’Halloran, Thomas V., Shilatifard, Ali, Puig, Sergi, Bergelson, Joy, Koivunen, Peppi, Ardehali, Hossein
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-10-2023 Nature Publishing Group
Subjects:	13/1 13/106 13/109 13/2 13/31 13/44 13/51 13/89 13/95 14/19 14/34 14/35 14/63 38/109 38/70 45 631/443/319 631/80/83 64/60 82 82/58 82/80 Binding Biomedical and Life Sciences Cancer Research Cell Biology Critical components Demethylation Developmental Biology Enhancers Eukaryotes Gene silencing Histones Histones - genetics Histones - metabolism Iron Iron - metabolism Iron deficiency Leucine Leucine - metabolism Life Sciences Mechanistic Target of Rapamycin Complex 1 - genetics Mechanistic Target of Rapamycin Complex 1 - metabolism Metabolism Nutrient deficiency Regulatory-Associated Protein of mTOR - metabolism Signal Transduction Stem Cells
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Summary:	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 H3K9me 2 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. Shapiro, Chang, et al. identify a conserved role for the iron-binding histone demethylase KDM3B in sensing iron levels and regulating mTORC1 through transcriptional repression of key mTORC1 pathway components.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceptualization: J.S.S., H.C.C., and H.A.; Methodology: J.S.S., H.C.C., Z.Z., B.J.H., Z.S.W., H.C., E.T.B., S.P., S.C.J., S.S.T., L.L., I.B.S., T.V.O, J.B., P.K.; Investigation: J.S.S., H.C.C., Z.Z., Y.T., B.J.H., Z.S.W., H.C., J.A.G., E.T.B., A.D.J., Z.S., F.K.N., A.M., T.S., L.R.A., A.M.R., M.T.M., S.C.J., S.S.T., G.L.; Resources:, S.P., L.L., D.B., G.L., I.B.S., T.V.O., A.S., J.B., P.K., and H.A.; Writing – Original Draft, J.S.S., H.A.; Writing – Review and Editing: All authors; Visualization: J.S.S., J.A.G.; Supervision: H.A.; Funding Acquisition: J.S.S., S.P., T.V.O., and H.A. Author Contribution These authors contributed equally to this work
ISSN:	1465-7392 1476-4679 1476-4679
DOI:	10.1038/s41556-023-01225-6