SOD Enzymes in a Human Fungal Pathogen: Oxidative Stress Protection Versus Cellular Signaling

Candida albicans is a human opportunistic pathogen of important public health relevance. The capacity of this organism to adapt to drastic changes in nutrient availability in the host allows C. albicans to be a successful pathogen. More specifically C. albicans adapts to fluctuations in bioavailability of the metal nutrient copper by substituting a copper requiring superoxide dismutase enzyme (Cu/Zn SOD1) with a non-copper alternative (Mn SOD3). Both are antioxidant enzymes that remove superoxide free radicals. However, the exact function of these two SOD enzymes inside the cell and whether they perform redundant or diverging roles remained largely unknown, and is the focus of investigation in this thesis. We found that Cu/Zn SOD1 but not Mn SOD3 enters the mitochondria intermembrane space to protect against mitochondrial oxidative stress (Chapter 2). During copper starvation when cells repress Cu/Zn SOD1, C. albicans induces an iron requiring alternative oxidase (AOX) to maintain mitochondrial superoxide at low levels. We find that this replacement of Cu/Zn SOD1 with non-copper alternatives (Mn SOD3 and Fe AOX) helps spare copper for cytochrome c oxidase respiration, which is essential for pathogenesis. Both Cu/Zn SOD1 and Mn SOD3 localize to the cytosol and in Chapter 3 we investigate their possible role in cell signaling involving reactive oxygen species (ROS). In the related yeast Saccharomyces cerevisiae, Cu/Zn SOD1 participates in a cell signaling process involving ROS that promotes glucose uptake and represses respiration. Whether C. albicans Cu/Zn SOD1 and/or Mn SOD3 were capable of similar cytosolic cellular signaling was unknown. We established that both SODs of C. albicans participate in glucose signaling, however as a fungal pathogen, C. albicans has rewired the SODs such that they signal repression of glucose uptake, rather than activation of glucose uptake as is seen in the fermentative yeast S. cerevisiae. C. albicans heavily relies on respiration, not fermentation for pathogenesis, consistent with the repurposing of its SODs in glucose signaling. Altogether, this work illustrates unique mechanisms in C. albicans for responding to changes in nutrients, specifically copper and glucose. These traits likely reflect the need to adapt rapidly to changes in environment within the human host