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Zhang, X.* ; Schuler, M.H.* ; Çetin, G.* ; Eckl, E.M.* ; Rheinemann, L.* ; Mergner, J.* ; Steigenberger, B.* ; Pichlmair, A. ; Jae, L.T.*

An ancient mitochondrial program tunes translation to haem availability.

Nature, DOI: 10.1038/s41586-026-10885-x (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Anaemia is a major global health burden that affects one-quarter of the human population and annually accounts for over 50 million years of healthy life lost1. It arises from nutritional iron deficiency, hereditary disorders (including thalassaemia and sickle cell disease) and malaria, and is characterized by haemoglobin imbalances2. Haem-the active component of haemoglobin-is both essential and potentially toxic, which necessitates tight control of levels. However, the molecular circuitry that monitors haem levels remains obscure. The cytosolic eIF2α kinase HRI counteracts anaemia amid iron deficiency or thalassaemia3,4 by acting as a gatekeeper of translation during erythroid differentiation, which has been attributed to its haem-binding ability5. Here we uncover that haem scarcity is sensed inside mitochondria through an OMA1-DELE1 axis. Mechanistically, haem deficiency triggers OMA1-dependent mitochondrial release of DELE1. In the cytosol, DELE1 releases inhibitory haem from HRI, which enables modifications in a crucial disordered segment of the kinase. We demonstrate that this sensor-actuator operates across human tissues, including erythroid progenitors, and is evolutionarily conserved down to bloodless invertebrates, thus predating the emergence of haemoglobin-based oxygen transport. Notably, pharmacological manipulation of this system enhances fetal globin expression-a central therapeutic objective in haemoglobinopathies. Together, these results reveal a primordial sentinel system that safeguards against haem-related toxicity from the single-cell to the organismic scale.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Regulated Eif2-alpha Kinase; Factor 2-alpha Kinase; N-terminal Domain; Computational Platform; Eif-2-alpha Kinase; Globin-synthesis; Initiation; Binding; Autophosphorylation; Phosphorylation
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Zeitschrift Nature
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Virology (VIRO)
Förderungen German Research Foundation
German Research Foundation (DFG)
Alfried Krupp von Bohlen und Halbach Foundation
Vallee Foundation
EMBO fellowship
Peter and Traudl Engelhorn Foundation - Bavarian State Ministry of Science and Arts
Danish National Research Foundation
Marie Curie Postdoctoral fellowship
European Research Council