Inhibition of Candida parapsilosis Fatty Acid Synthase (Fas2) Induces Mitochondrial Cell Death in Serum

PLoS Pathogens

Long Nam Nguyen¹  Giang Thi Thu Le²  Joshua D. Nosanchuk²  Gabriele Vargas Cesar³  Leonardo Nimrichter³  David L. Silver⁴ 

[1] Department of Medicine (Division of Infectious Diseases), Albert Einstein College of Medicine, New York, New York, United States of America;Laboratório de Estudos Integrados em Bioquímica Microbiana, Instituto de Microbiologia Professor Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil;Signature Research Program in Cardiovascular & Metabolic Disorders, DUKE-NUS Graduate Medical School, Singapore;University of Hamburg, Biocenter Klein Flottbek, Department of Molecular Phytopathology and Genetics, Hamburg, Germany

关键词: Cell death;    Mitochondria;    Fatty acids;    Yeast;    Glucose;    Saccharomyces cerevisiae;    Yeast infections;    C;    ida albicans;   

DOI  :  10.1371/journal.ppat.1002879

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY