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Hossain S, Veri AO, Liu Z, et al. Mitochondrial perturbation reduces susceptibility to xenobiotics through altered efflux in Candida albicans. Genetics. 2021;219(2)doi: 10.1093/genetics/iyab095.
Hossain, S., Veri, A. O., Liu, Z., Iyer, K. R., O'Meara, T. R., Robbins, N., & Cowen, L. E. (2021). Mitochondrial perturbation reduces susceptibility to xenobiotics through altered efflux in Candida albicans. Genetics, 219(2), . https://doi.org/10.1093/genetics/iyab095
Hossain, Saif, et al. "Mitochondrial perturbation reduces susceptibility to xenobiotics through altered efflux in Candida albicans." Genetics vol. 219,2 (2021). doi: https://doi.org/10.1093/genetics/iyab095
Hossain S, Veri AO, Liu Z, Iyer KR, O'Meara TR, Robbins N, Cowen LE. Mitochondrial perturbation reduces susceptibility to xenobiotics through altered efflux in Candida albicans. Genetics. 2021 Oct 02;219(2). doi: 10.1093/genetics/iyab095. PMID: 34143207.
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Genetics. 2021 Oct 02;219(2). doi: 10.1093/genetics/iyab095.

Mitochondrial perturbation reduces susceptibility to xenobiotics through altered efflux in Candida albicans.

Genetics

Saif Hossain, Amanda O Veri, Zhongle Liu, Kali R Iyer, Teresa R O'Meara, Nicole Robbins, Leah E Cowen

Affiliations

  1. Department of Molecular Genetics, University of Toronto, Toronto, ON M5S, Canada.
  2. Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

PMID: 34143207 DOI: 10.1093/genetics/iyab095

Abstract

Candida albicans is a leading human fungal pathogen, which can cause superficial infections or life-threatening systemic disease in immunocompromised individuals. The ability to transition between yeast and filamentous forms is a major virulence trait of C. albicans, and a key regulator of this morphogenetic transition is the molecular chaperone Hsp90. To explore the mechanisms governing C. albicans morphogenesis in response to Hsp90 inhibition, we performed a functional genomic screen using the gene replacement and conditional expression collection to identify mutants that are defective in filamentation in response to the Hsp90 inhibitor, geldanamycin. We found that transcriptional repression of genes involved in mitochondrial function blocked filamentous growth in response to the concentration of the Hsp90 inhibitor used in the screen, and this was attributable to increased resistance to the compound. Further exploration revealed that perturbation of mitochondrial function reduced susceptibility to two structurally distinct Hsp90 inhibitors, geldanamycin and radicicol, such that filamentous growth was restored in the mitochondrial mutants by increasing the compound concentration. Deletion of two representative mitochondrial genes, MSU1 and SHY1, enhanced cellular efflux and reduced susceptibility to diverse intracellularly acting compounds. Additionally, screening a C. albicans efflux pump gene deletion library implicated Yor1 in the efflux of geldanamycin and Cdr1, in the efflux of radicicol. Deletion of these transporter genes restored sensitivity to Hsp90 inhibitors in MSU1 and SHY1 homozygous deletion mutants, thereby enabling filamentation. Taken together, our findings suggest that mitochondrial dysregulation elevates cellular efflux and consequently reduces susceptibility to xenobiotics in C. albicans.

© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America. All rights reserved. For permissions, please email: [email protected].

Keywords: Candida albicans ; Hsp90; efflux; functional genomics; fungal pathogen; mitochondria; morphogenesis

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