# Longer Ubiquinone Side Chains Contribute to Enhanced Farnesol Resistance in Yeasts
## 1 Introduction  
_Candida albicans_, a member of normal human flora has become the most common nosocomial fungal pathogen in humans [1]. This yeast shows remarkable diversity in its morphology and secretes farnesol, a quorum-sensing molecule which mediates yeast to hyphae dimorphism in a cell density-dependent manner without influencing growth rate [2]. Farnesol is a 15-carbon sesquiterpene which is formed from farnesyl pyrophosphate, an intermediate in the ergosterol biosynthetic pathway [3]. In vivo, this lipophilic molecule acts as a virulence factor which enhances systemic candidiasis in mice [4] and stimulates immune recognition by host macrophages [5]. Farnesol stimulated an 8.5-fold increase in macrophage migration in vitro and a 3-fold increase of peritoneal infiltration by mouse macrophages in vivo [5]. Wild type _C. albicans_ tolerates up to 300-500 \(\upmu\)M farnesol [3, 6] while farnesol production can varyfrom 0.5 uM to 50 uM, depending on strain differences as well as planktonic or biofilm growth [2; 7; 8; 9]. The ability of _C. albicans_ to tolerate such high concentrations of farnesol is remarkable because much lower concentrations of farnesol (<20-25 uM) are antimicrobial towards other microorganisms including both bacteria and fungi. The growth of _S. cerevisiae_, a distant cousin of _C. albicans_, is inhibited by <25 uM farnesol which causes cell cycle arrest and/or mitochondrial dysfunction [10; 11]. Farnesol can also induce apoptotic cell death in filamentous fungi such as _Aspergillus nidulans_ and _Aspergillus fumigatus_[12] as well as _Fusarium graminearum_[13]. Farnesol also induces reactive oxygen inside macrophages leading to increased intracellular oxidative stress [14]. The juxtaposition of these observations poses the question of the mechanisms whereby _C. albicans_ tolerates farnesol doses that are lethal to other fungi; what adaptations has it made to be able to use farnesol as a quorum-sensing molecule and a virulence factor? Current best evidence is that farnesol kills cells by generating superoxide radicals, the major reactive oxygen species (ROS), by interacting with the mitochondrial electron transport chain during respiratory growth of _S. cerevisiae_[10; 12; 15]. ROS production is a normal byproduct of respiration and mitochondria have their own antioxidant mechanisms for the efficient elimination of superoxide anions [16] which can be localized either in the mitochondrial matrix, inner membrane/outer side, outer membrane/inner side, or intermembrane space [16]. Presumably farnesol enhances ROS production to a level such that the cell can no longer cope. Thus, it is reasonable to speculate that a cell or organism could increase its farnesol tolerance by structural adaptations to mitochondrial membranes or other components in order to avoid leakage of electrons, thus minimizing cell damage and/or reduced proton motive force. One of the major sites responsible for electron leakage in the mitochondrial electron transport chain is ubiquinone, especially when electrons translocate to complex III via reduction of ubiquinone to ubiquinol [15; 16]. Ubiquunces (UQ) are critical membrane-localized electron carriers, which 'ubiquitously' exist in the mitochondrial electron transport chain in all living organisms. They are involved in the transfer of electrons from NADH-ubiquinone oxidoreductase (complex I) and succinate-ubiquinone reductase (complex II) to ubiquinol-cytochrome \(c\) oxidoreductase (complex III) [15; 16]. They have a redox active benzoquinone ring attached to a lipophilic side chain consisting of a variable number of isoprene units (Figure 1). The number of isoprenoid units varies among species, ranging from 4 to 14, where the number of isoprenoid units is numerically designated following the abbreviation UQ or Q for ubiquinone. The hydrophobic isoprene tail is derived from successive head-to-tail condensations of isoprene units [isoprenyl diphosphate (IPP)] catalyzed by prenyl diphosphate synthase [17].