Iron-induced Cell Death May Play Key Role in FA, Study Suggests
Iron-induced cell death may contribute to the progression of Friedreich’s ataxia, a study in human and mice cells shows.
Inhibition of this degenerative mechanism may represent a new therapeutic strategy for people affected by this rare disease, researchers suggest.
The study, “Ferroptosis as a novel therapeutic target for Friedreich’s ataxia,” was published in the Journal of Pharmacology and Experimental Therapeutics.
Friedreich’s ataxia is a genetic disease caused by the loss or impaired activity of frataxin protein. Although the protein’s function is still not fully understood, studies suggest that it may be involved in the regulation of iron metabolism in cells.
Cells lacking frataxin were found to accumulate iron, and evidence has shown that iron is deposited and accumulated in frataxin-deficient flies, cardiac muscles from frataxin-deficient mice, and Friedreich’s ataxia patients.
Iron accumulation can be toxic to cells and tissues, as it may lead to increased production and buildup of oxygen-reactive elements. It could also induce the production of some particular fatty molecules, which could trigger the degeneration of nerve cells.
Despite the potential risk that iron overload could represent in Friedreich’s ataxia, its underlying disease-related mechanism is still poorly understood, and may be much more complex than initially thought.
Some of the main cellular and molecular features of Friedreich’s ataxia, in particular mitochondrial iron accumulation, increased oxidative stress, and lipid peroxidation, are also the hallmark features of a cell death pathway called ferroptosis.
Ferroptosis was first described in 2012 and has been implicated in nerve cells’ degeneration in Parkinson’s and Alzheimer’s disease. Now, a team led by researchers from the Children’s Hospital of Philadelphia explored the role of ferroptosis in Friedreich’s ataxia.
The team found that cells derived from a patient with Friedreich’s ataxia were very sensitive to ferroptosis. After they chemically induced ferroptosis, only 4-10% of the Friedreich’s ataxia cells survived, compared to 34-55% of the healthy control cells. A similar result was observed in cells collected from a mouse model of Friedreich’s ataxia.
Using two well-described chemical inhibitors of ferroptosis, called Fer-1 and SRS11-92, the team could rescue both mice and human-derived cells and prevent their ferroptosis-induced death.
In addition, using another inhibitor that specifically acts on the mitochondria — the cell’s powerhouses that are known to play an important role in Friedreich’s ataxia — the team got similar cell survival recovery.
Next, the team genetically manipulated healthy human cells to lack frataxin protein, similar to what happens in Friedreich’s ataxia patients. Loss of the protein led the cells to die; however, treatment with SRS11-92 prevented cell death by 33% compared to a placebo.
Supported by these findings the team believes that ferroptosis inhibitors can effectively protect Friedreich’s ataxia cells.