RNA sequencing of the budding yeast Saccharomyces cerevisiae strains missing YFH1, an ortholog of the human FXN gene affected in people with Friedreich ataxia (FA), revealed overlapping transcriptional responses to deferiprone and metformin treatments, according to an article published in Yeast.
In this study, the researchers used haploid alpha FY1679 as the control strain and YFH1Δ as the mutant strain. They evaluated the transcriptional rewiring of a yeast FA model through RNA‐sequencing experiments as well as the effects of potential treatments with deferiprone and metformin through transcriptome analyses.
According to the results, YFH1 deletion in yeast may transcriptionally upregulate iron import and downregulate respiration‐related genes. The mutant cells exhibited impaired oxidative stress tolerance, which was likely due to the downregulation of “cellular oxidant detoxification” processes. Moreover, mutant cells showed a notable accumulation of mtDNA lesions.
A series of experiments in both liquid and solid media with different drug concentrations indicated that both deferiprone and metformin had a limited effect on mutant cells’ respiration deficiency. However, a dose‐dependent increase in the chronological lifespan of mutant cells could be observed with both tested medications.
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Viability experiments showed that deferiprone dosage increases may hinder the viability of mutant cells upon hydrogen peroxide exposure, with an optimum concentration of 100 μM. On the other hand, treatment with 200 μM of metformin caused the highest increase in mutant cell viability.
Upon conducting RNA sequencing experiments with the optimum dosages of both medications, the transcriptome analyses revealed an overlap of the mutant replicates. The investigation of significantly expressed genes showed that both drugs led to the downregulation of 296 shared genes. In addition, metformin use upregulated 446 genes while deferiprone treatment had the same effect on 393 genes.
“The two drugs trigger nuclear genes’ expressions taking part in aerobic respiration, although mitochondrially encoded complex IV’s genes’ expressions, such as COX1, are not upregulated,” Börklü noted. “This result hints that both drugs exert their beneficial effects by restoring the impaired mitochondria‐to‐nucleus signaling. Metformin, a copper‐binding agent currently in use for antidiabetes treatment, may have a potential use also in FA trials as a promising drug since it generates a transcriptional response similar to that of deferiprone”.
In the absence of YFH1, yeast exhibit cellular phenotypic traits typically seen in FA, such as impaired respiration, problems in iron homeostasis, decreased oxidative stress tolerance, and shorter life span.
Reference
Börklü E. Insights from yeast: transcriptional reprogramming following metformin treatment is similar to that of deferiprone in a yeast Friedreich’s ataxia model. Yeast. Published online February 8, 2023. doi:10.1002/yea.3845
