Mitochondria influence CDR1 efflux pump activity, Hog1-mediated oxidative stress pathway, iron homeostasis, and ergosterol levels in Candida albicans

Edwina Thomas, Elvira Roman, Steven M Claypool, Nikhat Manzoor, Jesús Pla, Sneh Lata Panwar

Research output: Contribution to journalArticle

Abstract

Mitochondrial dysfunction in Candida albicans is known to be associated with drug susceptibility, cell wall integrity, phospholipid homeostasis, and virulence. In this study, we deleted CaFZO1, a key component required during biogenesis of functional mitochondria. Cells with FZO1 deleted displayed fragmented mitochondria, mitochondrial genome loss, and reduced mitochondrial membrane potential and were rendered sensitive to azoles and peroxide. In order to understand the cellular response to dysfunctional mitochondria, genome-wide expression profiling of fzo1Δ/Δ cells was performed. Our results show that the increased susceptibility to azoles was likely due to reduced efflux activity of CDR efflux pumps, caused by the missorting of Cdr1p into the vacuole. In addition, fzo1Δ/Δ cells showed upregulation of genes involved in iron assimilation, in iron-sufficient conditions, characteristic of iron-starved cells. One of the consequent effects was downregulation of genes of the ergosterol biosynthesis pathway with a commensurate decrease in cellular ergosterol levels. We therefore connect deregulated iron metabolism to ergosterol biosynthesis pathway in response to dysfunctional mitochondria. Impaired activation of the Hog1 pathway in the mutant was the basis for increased susceptibility to peroxide and increase in reactive oxygen species, indicating the importance of functional mitochondria in controlling Hog1-mediated oxidative stress response. Mitochondrial phospholipid levels were also altered as indicated by an increase in phosphatidylserine and phosphatidylethanolamine and decrease in phosphatidylcholine in fzo1Δ/Δ cells. Collectively, these findings reinforce the connection between functional mitochondria and azole tolerance, oxidant- mediated stress, and iron homeostasis in C. albicans.

Original languageEnglish (US)
Pages (from-to)5580-5599
Number of pages20
JournalAntimicrobial Agents and Chemotherapy
Volume57
Issue number11
DOIs
StatePublished - Nov 2013

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Ergosterol
Candida albicans
Mitochondria
Oxidative Stress
Homeostasis
Iron
Azoles
Peroxides
Phospholipids
Mitochondrial Genome
Mitochondrial Membrane Potential
Phosphatidylserines
Vacuoles
Phosphatidylcholines
Oxidants
Cell Wall
Genes
Virulence
Reactive Oxygen Species
Up-Regulation

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Mitochondria influence CDR1 efflux pump activity, Hog1-mediated oxidative stress pathway, iron homeostasis, and ergosterol levels in Candida albicans. / Thomas, Edwina; Roman, Elvira; Claypool, Steven M; Manzoor, Nikhat; Pla, Jesús; Panwar, Sneh Lata.

In: Antimicrobial Agents and Chemotherapy, Vol. 57, No. 11, 11.2013, p. 5580-5599.

Research output: Contribution to journalArticle

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