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Updated: Aug 7, 2026
06:05
An In Vitro Approach to Study Mitochondrial Dysfunction: A Cybrid Model
Published on: March 9, 2022
An ancient mitochondrial program tunes translation to haem availability
Xiang Zhang1, Max-Hinderk Schuler1, Gonca Çetin1
1Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
Nature
|August 5, 2026
Summary
A newly discovered mitochondrial OMA1-DELE1 pathway senses low heme levels, crucial for preventing anemia. This system, conserved across species, offers therapeutic targets for hemoglobinopathies.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Anemia is a significant global health issue affecting a quarter of the population.
- Heme is essential but toxic, requiring strict level control, yet the monitoring mechanism is unknown.
- The cytosolic kinase HRI (heme-regulated inhibitor) is known to counteract anemia by regulating translation during erythroid differentiation.
Purpose of the Study:
- To elucidate the molecular mechanisms by which cellular heme levels are monitored.
- To identify the signaling pathway involved in sensing heme scarcity.
- To explore the therapeutic potential of modulating this pathway for hemoglobinopathies.
Main Methods:
- Investigated heme sensing using cell-based assays in human tissues, including erythroid progenitors.
- Utilized genetic and biochemical approaches to dissect the OMA1-DELE1 signaling axis.
- Examined the evolutionary conservation of the pathway in various organisms.
Main Results:
- Discovered that heme deficiency is sensed within mitochondria via an OMA1-DELE1 pathway.
- Demonstrated that heme deficiency triggers the OMA1-dependent release of DELE1 from mitochondria.
- Showed that cytosolic DELE1 releases inhibitory heme from HRI, enabling kinase activation and subsequent translational control.
- Confirmed the pathway's operation in human tissues and its evolutionary conservation.
Conclusions:
- Identified a primordial mitochondrial sentinel system (OMA1-DELE1 axis) that monitors cellular heme levels.
- This system safeguards against heme toxicity from the cellular to the organismic level.
- Pharmacological targeting of this pathway enhances fetal globin expression, offering a therapeutic strategy for hemoglobinopathies.
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