Ancient Mitochondrial Signaling Pathway Regulates Vital Cellular Heme Levels

Heme, a bioactive form of iron, has numerous essential functions in the cell. As a key component of hemoglobin, it enables oxygen transport in the blood. In addition, it performs important functions in other proteins in processes ranging from energy conversion to signal transduction. However, it is potentially toxic when present at high concentrations as free heme. Cells must therefore carefully monitor heme levels and adapt accordingly.

A team led by Professor Lucas Jae from LMU's Gene Center Munich has now discovered that mitochondria, the powerhouses of the cell, play a critical role in this process – and have done so for over 700 million years, as the researchers report in the journal Nature.

To keep their metabolism in balance, cells have to throttle protein production, including that of heme binding partners, when faced with heme deficiency. How this is achieved across diverse cell types with vastly different heme levels remained a mystery.

Our study now provides the surprising answer: Heme deficiency is recognized by mitochondria – descendants of bacteria whose incorporation into ancestral cells was a milestone in the evolution of complex life."

Professor Lucas Jae, LMU's Gene Center Munich 

Mitochondrial Protein Activates Switch

Critical steps in heme production take place in the mitochondria. When heme is scarce, a mitochondrial protein called DELE1 is released into the cytosol, where it encounters an important molecular switch for protein production called HRI. This switch itself binds heme, which normally keeps it inactive. DELE1 displaces heme from the switch, thereby activating it and reducing protein production. This is particularly important in developing red blood cells, where the HRI switch prevents the excessive production of globin, heme's protein counterpart in hemoglobin. Otherwise, excess globin would aggregate in the absence of heme and damage the cell.

Mechanism has Deep Evolutionary Roots

This system is active in all human tissues investigated and has deep evolutionary roots, as the researchers discovered: "We were able to trace it across 700 million years of evolutionary divergence to very simple lifeforms such as Hydra vulgaris, a tiny bloodless creature. This underscores how fundamental cellular heme sensing is for life and how little the system has changed," says Jae. A later innovation is the ability of heme to suppress the HRI switch in humans. "We believe this could help boost hemoglobin production in developing red blood cells, when the mitochondria are highly active and heme is abundant," adds Dr. Max-Hinderk Schuler, co-first author of the study alongside Dr. Xiang Zhang.

Placing the sensor in the mitochondria, where heme is also produced, is remarkably elegant. The researchers hypothesize that linking production, sensing, and response could enable more comprehensive metabolic adaptations. "Modulation of the system could also be useful in the treatment of globin disorders and open up new perspectives for research into heme biology in malaria," says Zhang. "Moreover, our work provides proof of principle for the selective manipulation of the newly identified heme-sensing pathway."