Heterochromatin epimutations impose mitochondrial dysfunction to confer antifungal resistance

Fellas, A., Pidoux, A.L., Tong, P., Hewes, H.H., Wallace, E.C., and Allshire, R.C.

By Maya Rowley, Marston and Deegan Labs.

Antifungal resistance is a growing concern in global health, agriculture, and biodiversity. Epigenetic mechanisms allow fungal pathogens to develop and propagate semi-stable adaptations to rapidly gain drug resistance. However, the mechanisms that enable these changes to confer resistance are incompletely understood. 

Previously, the Allshire lab identified several epimutants in fission yeast that displayed heterochromatin-dependent caffeine resistance. Many of these epimutants were also resistant to azoles, a class of antifungal drugs, suggesting a common pathway for overcoming these environmental insults.  

In this latest study, Fellas et al. characterise the mechanisms underlying fungal resistance in epimutants of two genes repressed by ectopic heterochromatin islands. These genes, cup1 and ppr4, are involved in the assembly of electron transport chain (ETC) complexes. They find that the mitochondrial dysfunction triggered by their silencing leads to an accumulation of reactive oxygen species (ROS). This in turn activates multiple stress response pathways, including that mediated by the transcription factor Pap1. Transcriptome remodelling caused by Pap1 nuclear retention was shown to increase cellular efflux and upregulate antioxidant-encoding genes, allowing cells to tolerate caffeine and azole exposure. 

Characteristic to the epimutants was their cell-to-cell heterogeneity in respiration competence and drug resistance. This 'best of both worlds' strategy allows the population to benefit from the resistance conferred by mitochondrial dysfunction while maintaining respiratory fitness. Thus, this paper demonstrates how cells can exploit the instability of epimutations to make induction of oxidative stress a viable option for acquiring drug resistance. 

These findings open the door for identification of similar epigenetic pathways that may be employed by fungal pathogens to adapt to antifungal agents.

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