Ferrostatin-1, a ferroptosis inhibitor, shows potential as therapeutic agent for mitochondrial cardiomyopathies, including Friedreich ataxia (FA), according to an abstract presented at the American Physiology Summit 2023 meeting.
Treatment with ferrostatin-1 improved cardiac function in mice with a cardiomyocyte-specific knockout of sirtuin 3 (SIRT3-cKO)—a deacetylase that participates in mitochondrial metabolism.
The underlying molecular mechanism involves reducing mitochondrial ferroptosis, which has been recognized as a contributor to several disease states, including FA, and improving iron homeostasis. These actions were specific to the mitochondria, suggesting that ferrostatin-1 may be a mitochondria-targeting agent.
SIRT3-cKO mice had severely impaired systolic function, as demonstrated by reduced ejection fraction and fractional shortening percentages in echocardiographic evaluation of ventricular function, when compared with SIRT3 wild-type (SIRT3wt) mice.
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After injecting the mice with ferrostatin-1 (1mg/kg/day) for 14 days, the researchers observed a significant improvement in SIRT3-cKO mice, albeit the alterations were not entirely normalized with ferrostatin-1 treatment.
Moreover, gene expression analysis revealed a decrease in the expression levels of mitochondrial GPX4, frataxin, and aconitase in the heart of SIRT3-cKO mice. Conversely, the expression level of 4-hydroxynonenal, a product of lipid peroxidation, was increased. Altogether, these results suggest that ferroptosis is occurring in the mitochondria and that iron homeostasis is impaired, as well as disclose similarities between this heart failure phenotype and the mitochondrial cardiomyopathy associated with FA.
Treatment with ferrostatin-1 upregulated mitochondrial GPX4 and aconitase, but did not alter the expression levels of frataxin. These findings support a role for ferrostatin-1 in improving iron homeostasis and suggest that ferroptosis may occur downstream of frataxin deficiency.
These alterations were not observed in the cytosol of SIRT3-cKO mice following ferrostatin-1 treatment.
Cantrell A, Besanson J, Zeng H, Williams Q, Chen J-X. Potential role of ferrostatin-1 as a mitochondrial-targeting agent for treatment of mitochondrial cardiomyopathy. Physiology. Published online May 23, 2023. doi:10.1152/physiol.2023.38.S1.5723310