Abstract
We have recently observed that a fatty acid auxotrophic mutant (fatty acid synthase, Fas2Δ/Δ) of the emerging human pathogenic yeast Candida parapsilosis dies after incubation in various media including serum. In the present study we describe the mechanism for cell death induced by serum and glucose containing media. We show that Fas2Δ/Δ yeast cells are profoundly susceptible to glucose leading us to propose that yeast cells lacking fatty acids exhibit uncontrolled metabolism in response to glucose. We demonstrate that incubation of Fas2Δ/Δ yeast cells with serum leads to cell death, and this process can be prevented with inhibition of protein or DNA synthesis, indicating that newly synthesized cellular components are detrimental to the mutant cells. Furthermore, we have found that cell death is mediated by mitochondria. Suppression of electron transport enzymes using inhibitors such as cyanide or azide prevents ROS overproduction and Fas2Δ/Δ yeast cell death. Additionally, deletion of mitochondrial DNA, which encodes several subunits for enzymes of the electron transport chain, significantly reduces serum-induced Fas2Δ/Δ yeast cell death. Therefore, our results show that serum and glucose media induce Fas2Δ/Δ yeast cell death by triggering unbalanced metabolism, which is regulated by mitochondria. To our knowledge, this is the first study to critically define a link between cytosolic fatty acid synthesis and mitochondrial function in response to serum stress in C. parapsilosis.
Highlights
Fatty acid biosynthesis plays a significant role in the growth and survival of diverse organisms
Since suppression of protein synthesis by CHX had been shown to inhibit cell death induced by serum in a C. albicans homoserine kinase mutant [26] or induced by fatty acid starvation in S. cerevisiae [27], we examined the effect of CHX on cell death in C. parapsilosis
Fas2D/D yeast cells displayed enhanced metabolic activity resulting in mitochondrial dysfunction Our results indicated that C. parapsilosis Fas2D/D cell death in serum and glucose containing media is an active process and that metabolic activity might be intimately involved in cell death
Summary
Fatty acid biosynthesis plays a significant role in the growth and survival of diverse organisms. The de novo fatty acid synthesis pathway produces and regulates essential fatty acid species such as saturated (SFA) and unsaturated (UFA) fatty acids that are required for generation and maintenance of cell membranes. Inhibition of enzymes in this pathway, such as fatty acid synthase and fatty acid desaturase, impedes yeast cell growth unless appropriate exogenous fatty acids are provided [1,2,3]. Targeting bacterial fatty acid synthesis pathways has recently been criticized after a study showed that Gram-positive fatty acid synthesis deletion mutants could overcome the lack of de novo fatty acid synthesis using exogenous fatty acids from serum [8]. The potential of exploiting the fatty acid biosynthesis pathway for targeting microbial infections is still in debate, these studies suggest the importance of evaluating the efficacy of drugs in more complex media such as serum
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