Heterochromatin epimutations impose mitochondrial dysfunction to confer antifungal resistance

Antifungal resistance in pathogenic fungi endanger global health and food supply. Wild-type fission yeast, Schizosaccharomyces pombe, can gain resistance to insults including caffeine and antifungal compounds through reversible epimutations. Resistant epimutants exhibit ectopic histone-H3K9 methylation-dependent heterochromatin islands, repressing underlying genes. Two genes whose heterochromatin island-induced repression causes resistance encode mitochondrial proteins: LYR-domain protein Cup1 and Cox1 translation regulator Ppr4. Genetic mutations, cup1-tt and ppr4Δ, that phenocopy epimutants, cause mitochondrial dysfunction, including respiratory deficiency, poor growth on non-glucose carbon sources, and elevated reactive oxygen species. Transcriptomic analyses indicate cup1-tt and ppr4Δ cells activate Pap1 transcription factor-dependent oxidative stress response and mitonuclear retrograde pathways. Pap1 nuclear localisation and recruitment to promoters of oxidoreductase and membrane transporter genes is increased, causing increased efflux activity. cup1 and ppr4 epimutants likewise show mitochondrial dysfunction phenotypes and increased efflux, explaining how heterochromatin-island epimutations cause drug resistance. Thus, wild-type cells harness epimutations that impose mitochondrial dysfunction to bypass external insults. As mitochondrial dysfunction is linked to antifungal resistance in several fungi, similar epimutations likely contribute to development of resistance in fungal pathogens.