Dysfunction of Prohibitin 2 Results in Reduced Susceptibility to Multiple Antifungal Drugs via Activating the Oxidative Stress Responsive Transcription Factor Pap1 in Fission Yeast [Mechanisms of Resistance]

The fight against resistance to antifungal drugs requires a better understanding of the underlying cellular mechanisms. To gain insight into the mechanisms leading to antifungal drug resistance, we performed a genetic screen to identify genes whose overexpression caused resistance to the antifungal drugs including clotrimazole and terbinafine using a model organism, Schizosaccharomyces pombe (S. pombe), and identified the phb2⁺ gene encoding a highly conserved mitochondrial protein prohibitin Phb2, as a novel determinant of multidrug resistance. Unexpectedly, deletion of the phb2⁺ gene also exhibited antifungal drug resistance. Overexpression of the phb2⁺ gene failed to cause the drug resistance when the pap1⁺ gene encoding an oxidative stress responsive transcription factor was deleted. Furthermore, pap1⁺ mRNA expression was significantly increased when the phb2⁺ gene was overexpressed or deleted. Importantly, either overexpression of phb2⁺ or deletion of its gene stimulated NO and ROS synthesis as measured by a cell-permeant fluorescent NO probe DAF-FM DA and a ROS probe DCFH-DA, respectively. Altogether, these results suggest that dysfunction of Phb2 results in multidrug resistance via increasing NO and ROS synthesis due to dysfunctional mitochondria, thereby activating transcription factor Pap1 in fission yeast.

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