Insights from yeast: transcriptional reprogramming following metformin treatment is similar to that of deferiprone in a yeast Friedreich's ataxia model

Abstract

In the absence of YFH1, the yeast ortholog of the human FXN gene, budding yeast Saccharomyces cerevisiae experience similar problems to those of cells with Friedreich's ataxia (FRDA). The comparable phenotypic traits consist of impaired respiration, problems in iron homeostasis, decreased oxidative stress tolerance, and diminished iron-sulfur cluster synthesis, rendering yeast of potential use in FRDA modeling and drug trials. Deferiprone, an iron chelator, is one of the long-term studied potential drugs for FRDA, whereas metformin is a biguanide prescribed to treat type 2 diabetes. In the present study, the effects of deferiprone and metformin treatment on the yeast FRDA model are explored via RNA-sequencing analyses. The comparative inquiry of transcriptome data reveals new promising roles for metformin in FRDA treatment since deferiprone and metformin treatments produce overlapping transcriptional and phenotypic responses in YFH1 Delta cells. The results revealed that both deferiprone and metformin treatment does not rescue aerobic respiration in YFH1 Delta cells, but they alleviate the FRDA phenotype probably by triggering the retrograde mitochondria-to-nucleus signaling.