Heterochromatin epimutations impose mitochondrial dysfunction to confer antifungal resistance (NCBI Gene Expression Omnibus Series GSE304438)

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.