title: Inhibition of Candida parapsilosis fatty acid synthase (Fas2) induces mitochondrial cell death in serum.
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.
authors.affiliation: Department of Medicine (Division of Infectious Diseases), Albert Einstein College of Medicine, New York, New York, United States of America. ngnlong@gmail.com
authors.forename: Long Nam
authors.initials: LN
authors.lastname: Nguyen
authors.forename: Gabriele Vargas
authors.initials: GV
authors.lastname: Cesar
authors.forename: Giang Thi Thu
authors.initials: GT
authors.lastname: Le
authors.forename: David L
authors.initials: DL
authors.lastname: Silver
authors.forename: Leonardo
authors.initials: L
authors.lastname: Nimrichter
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Nosanchuk
mesh_terms: D000818:Animals; D002175:Candida / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development; D002177:Candidiasis / Q000382:microbiology*; D003470:Culture Media; D004271:DNA, Fungal / Q000032:analysis / Q000235:genetics; D004272:DNA, Mitochondrial / Q000032:analysis / Q000235:genetics; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000096:biosynthesis*; D005260:Female; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000382:microbiology / Q000473:pathology; D051379:Mice; D050296:Microbial Viability / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D044967:Serum; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D003470:Culture Media; D004271:DNA, Fungal; D004272:DNA, Mitochondrial; D045222:Electron Transport Chain Complex Proteins; D005227:Fatty Acids; D005656:Fungal Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D011500:Protein Synthesis Inhibitors; D017382:Reactive Oxygen Species; D064429:Fatty Acid Synthases; D005947:Glucose