# Longer Ubiquinone Side Chains Contribute to Enhanced Farnesol Resistance in Yeasts
## 4 Discussion  
The fungal pathogen _C. albicans_ exhibits a remarkably greater ability to withstand oxidative stress than do the model yeasts _S. cerevisiae_ and Schizosaccharomyces pombe [34; 35]. The distinctive and robust stress tolerance mechanisms in _C. albicans_ coevolved with host niche-specificity in order to evade the oxidative killing pressures exerted by hostile immune protective mechanisms [35; 36; 37]. However, the greater stress tolerance of _C. albicans_ cannot be attributed solely to transcriptional regulation of stress responsive genes since the antioxidant genes (CAT1, GPX, SOD) and the ROS scavenging systems (glutathione/glutaredoxin, thioredoxin) are equally upregulated in all yeasts [37; 38; 39]. Thus, the remarkable tolerance to farnesol to _C. albicans_ compared with _S. cerevisiae_ suggests the evolution of specific structural adaptations as well as the general antioxidant responses just described. Here we have shown that the structural differences inherent in having membrane bound UQ9 rather than UQ6 provides a significant advantage in tolerating farnesol and the oxidative stress induced by farnesol. The added protection provided by UQ9 appears to be specific for farnesol and due to the UQ9 itself, i.e., it is not a secondary effect. These conclusions are based on the fact that the UQ6 and UQ9 cells had equivalent osmotolerance (to 1 M NaCl) and redox tolerance (to 5 mM H\({}_{2}\)O\({}_{2}\) and 1 mM menadione) (Figure 6). They also had equivalent levels of catalase activity (Figure 7) and preliminary analysis showed that they had equivalent amounts of total and phosphorylated Hog1p both before and after stress with 10 mM H\({}_{2}\)O\({}_{2}\) or 50-100 \(\upmu\)M farnesol (data not shown). These findings support our suggestion that the UQ9 side chains have evolved as a structural adaptation to farnesol rather than as a superior general stress mechanism. According to our findings, it is very unlikely that transcriptional regulation of oxidative protection is affected by the type of endogenous UQ present. Also identifying the contribution of UQ9 side chains to high farnesol resistance in _C. albicans_ points to polyprenyl diphosphate synthase (Coq1p) as a potential target to control the dimorphic pathogenicity of this fungus. Figure 7: Change in UQ side chain length does not alter transcriptional regulation of the oxidative stress response. Catalase activity (units/liter) measured 60 min after addition of sub-lethal farnesol (20 \(\upmu\)M). Average of 3 replicates. Farnesol's interaction with the mitochondrial membrane is likely responsible for the increased toxicity (Figure 3) and excess ROS production (Figure 5) associated with UQ6 yeasts. This connection between farnesol, ROS, and mitochondrial respiration is consistent with prior reports that some petite mutants of _S. cerevisiae_ are farnesol resistant [10; 15] while anaerobically grown _C. albicans_ did not produce farnesol and did not respond to exogenous farnesol at concentrations ranging from 0 to 1.2 mM [27]. Note that 1.2 mM farnesol represents the maximum solubility of farnesol in water [27]. The enhanced resistance to farnesol was also observed for _S. cerevisiae_\(\Delta\)_eq_1::pYES strains (Figure 5). This strain lacks a complete aerobic respiration and is unable to grow in media containing only non-fermentable carbon sources such as glycerol, thus is considered as a petite. [PERSON] et al. [10] showed that for _S. cerevisiae_ farnesol generated reactive oxygen species (ROS) by interacting with the mitochondrial electron transport chain. Here we corroborate their findings while providing the added suggestion that UQ release or solvent exposure is one of the mechanisms for ROS formation. [PERSON] et al. [32] produced mutants of _S. cerevisiae_ which synthesized UQ with chain lengths varying from UQ5 up to UQ10. These mutants had roughly equivalent growth rates and respiration rates [32]. Although _S. cerevisiae_ has frequently been used as a model for _C.