Lucas Jae: How Mitochondria Sense Heme Scarcity to Regulate Heme and Globin Production
Lucas Jae, Professor at Ludwig Maximilian University of Munich, shared a post on LinkedIn about a recent article he and his colleagues co-authored, published in Nature, adding:
“Check out our new Nature paper showing that heme scarcity is surprisingly sensed in mitochondria by the DELE1 pathway.
This also reveals the molecular mechanism by which DELE1 activates HRI, the kinase that translates this mitochondrial reading into a cellular response.
Inactive HRI dimers recruit up to two S-DELE1 molecules to their heme-binding amino-terminal domains.
There, the first helix of S-DELE1 (TPR1) is required to release inhibitory heme that would otherwise remain largely bound to HRI, even amid heme starvation.
This enables critical structural rearrangements and HRI autophosphorylation, including within its extensive disordered kinase insert, allowing the kinase to recruit and phosphorylate eIF2α.
The mitochondrial DELE1-HRI system is conserved all the way to Hydra, a simple life form that lacks blood and hemoglobin-based oxygen transport.
Direct heme inhibition of HRI appears to be a later evolutionary innovation.
In the human system, the pathway safeguards red blood cell precursors against hemoglobin-related proteotoxicity, and its manipulation, for which we show proof of principle by targeting the DELE1-HRI interaction, can boost fetal globin expression, a therapeutic goal in hemoglobinopathies.
The ancient system takes the heme reading in the very organelle that produces this key metabolite.”
Title: An ancient mitochondrial program tunes translation to haem availability
Authors: Xiang Zhang, Max-Hinderk Schuler, Gonca Çetin, Eva-Maria Eckl, Lara Rheinemann, Julia Mergner, Barbara Steigenberger, Andreas Pichlmair, Lucas T. Jae
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