CHICAGO, July 21 (Xinhua) -- Researchers at Northwestern University (NU) Medicine have discovered that a protein called tristetraprolin (TTP) is activated during iron deficiency, and lowers iron usage to match availability and prevents mitochondrial dysfunction,
NU researchers examined regulatory interactions between TTP and mitochondrial proteins. The researchers had previously found TTP to be upregulated in iron deficiency, and therefore knew TTP played a part in the protective mechanism.
In the new study, the researchers found TTP directly regulates a specific protein in complex III of the "mitochondrial electron transport chain," a system which transports electrons through a chain of proteins and pumps out protons. If the mitochondria is an assembly line, complex III is in the middle of the process, transforming raw materials into parts required for manufacturing the end product: energy for the cell, in the form of ATP.
However, complex III requires iron in the form of iron-sulfur cofactor, and iron deficiency can cause it to stop working. In iron-deficient mitochondria without TTP, electrons are shuttled to complex III but left unused, causing electrons to leak into the intermembrane space of the mitochondria.
"That causes damage because these leaked electrons can lead to production of reactive oxygen species, which can be toxic to the cell," said Hossein Ardehali, professor of Medicine in the Division of Cardiology and senior author of the study.
To prevent this, TTP degrades a specific protein in complex III, which results in the lack of formation of an "apo-complex III" without the required iron-sulfur cofactor. This in turn results in less electron transport, less potential electron leakage and avoids production of toxic compounds.
"It's not a complete shutdown of the mitochondria, this just makes them work less," Ardehali said. "It's using the iron more efficiently."
The findings suggest that intravenous injections of iron, a clinical treatment that's gained popularity in recent years, may be unnecessary, said Ardehali.
Ardehali believes reducing mitochondrial iron in heart cells could treat patients with heart failure, with preliminary data to support the hypothesis.
"We're working with our chemistry department to identify novel iron chelators to reduce mitochondrial iron in patients with heart failure," Ardehali said. "We're hoping at some point we will have a novel treatment."
The study has been published in the Proceedings of the National Academy of Sciences.
