Iron-mediated cell death could be heart disease management target
Inhibiting ferroptosis improved heart function in mice, study finds
Inhibiting ferroptosis, a type of iron-dependent cell death, could be a promising therapeutic strategy for heart disease management in people with Friedreich’s ataxia, a study found.
Through a series of experiments, scientists found that mice lacking a protein called SIRT3 in heart cells showed cellular properties similar to what’s seen in FA-associated heart disease, including signs of increased ferroptosis due directly to dysfunction of mitochondria, cells’ energy production centers. Blocking ferroptosis in those mice eased signs of heart disease.
The study, “Ferrostatin-1 specifically targets mitochondrial iron-sulfur clusters and aconitase to improve cardiac function in Sirtuin 3 cardiomyocyte knockout mice,” was published in the Journal of Molecular and Cellular Cardiology.
The heart needs high energy to function properly. Dysfunction of mitochondria, the organelles largely responsible for generating cellular energy, is a recognized driver of cardiac disease.
FA patients are lacking in a mitochondrial protein called frataxin, which is important for regulating iron dynamics and mitochondrial function. Cardiomyopathy, a disease of the heart’s pumping muscle, is a leading cause of death in the rare disease.
Stronger effects on male mice
It’s believed that a lack of frataxin leads to iron overload in mitochondria that leave cells susceptible to a type of iron-dependent cell death called ferroptosis. This is likely a key driver of FA-associated cardiomyopathy.
In previous experiments, the researchers found that eliminating a protein called SIRT3 from heart muscle cells (cardiomyocytes) led to severe heart dysfunction and death in mice.
SIRT3 is found mostly in mitochondria, and its expression reduced in the hearts of FA mouse models. It has been suggested that it might play a role in iron overload-mediated ferroptosis, as seen in FA, but this has not been fully explored.
To learn more, the researchers examined the cardiac profiles of mice lacking SIRT3 in cardiomyocytes. They found that these mice, especially males, developed severe heart disease that was at least partly attributable to mitochondrial ferroptosis.
This was accompanied by alterations in mitochondrial protein expression, increases in ferroptosis-associated proteins, and altered iron dynamics in the heart. Also observed were decreases in calcium, which is needed for certain energy-producing functions in mitochondria and for heart muscle contractions.
The researchers believed the ferroptosis associated with SIRT3 loss to be a direct consequence of mitochondrial dysfunction. Frataxin was also diminished in cardiac mitochondria in the mouse model, leading to a cardiac profile that overall seems similar to what’s seen in FA.
The researchers examined whether treatment with a ferroptosis inhibitor called ferrostatin-1 (Fer-1) might be able to improve heart function in the mice. Over two weeks of treatment, the mice showed progressive improvements in heart function, although not all aspects of heart function were completely rescued.
This was accompanied by signs of improved mitochondrial function, normalized iron dynamics, and reduced signs of ferroptosis. Frataxin levels were not restored with treatment.
The researchers noted that the cellular changes occurring with Fer-1 treatment “are almost exclusive to the mitochondria, suggesting for the first time that mitochondrial dysfunction may be a major driver of ferroptosis in the heart.”
Given the similarities between these mice and the FA heart, “Fer-1 may be a potential therapeutic for treatment of [FA], although more studies are necessary to fully elucidate the mechanisms by which Fer-1 inhibits ferroptosis,” wrote.
Once the sex differences in heart function were identified, only male mice were used for subsequent studies. The researchers said experiments in female mice “will be beneficial to evaluate how sex can impact cardiac function in the context of cardiomyocyte SIRT3 deficiency.”
The longer-term safety and efficacy of Fer-1 will also need to be investigated in order to fully understand its potential for treating FA and other heart conditions, according to the scientists.
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