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Bio-energetics Investigation of Candida albicans Using Real-time Extracellular Flux Analysis
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ER-mitochondria encounter structure connections determine drug sensitivity and virulence of Cryptococcus neoformans

Deepika Kumari1, Mohit Kumar2, Naseem A Gaur2

  • 1Department of Biochemistry, Maharshi Dayanand University, Rohtak, Haryana 124001, India.

Journal of Cell Science
|April 3, 2025
PubMed

Insights

Disrupting the ER-mitochondria encounter structure (ERMES) in Cryptococcus neoformans impairs fungal mitochondria, reduces antifungal drug resistance, and debilitates virulence factors, highlighting ERMES as a key target for new antifungal therapies.

Area of Science:

  • Mycology
  • Cell Biology
  • Pathogenesis

Background:

  • Cryptococcus neoformans causes life-threatening meningoencephalitis in immunocompromised individuals.
  • Antifungal resistance necessitates novel therapeutic targets.
  • The ER-mitochondria encounter structure (ERMES) is a unique fungal complex crucial for mitochondrial function.

Purpose of the Study:

  • To investigate the role of the ERMES complex in C. neoformans virulence and antifungal susceptibility.
  • To determine the impact of ERMES subunit deletion on fungal cell biology and pathogenesis.

Main Methods:

  • Generation of C. neoformans deletion mutants for each ERMES subunit (Mmm1, Mdm12, Mdm10, Mdm34).
  • Assessment of mitochondrial function, antifungal susceptibility (echinocandins), chitin content, capsule formation, and melanin production in mutants.
  • Evaluation of endoplasmic reticulum (ER) enzyme activity and in vivo virulence in a Caenorhabditis elegans cryptococcosis model.

Main Results:

  • ERMES mutants exhibited impaired mitochondria and increased susceptibility to antifungals, linked to reduced chitin synthesis.
  • Virulence factors such as capsule and melanin production were significantly debilitated in the ERMES mutants.
  • Compromised ERMES function affected ER-synthesized virulence enzymes and reduced overall pathogenicity in vivo.

Conclusions:

  • The ERMES complex is essential for maintaining mitochondrial integrity and function in C. neoformans.
  • Disruption of ERMES compromises fungal virulence and antifungal resistance.
  • Targeting the ERMES complex represents a promising strategy for developing new antifungal treatments against C. neoformans infections.
Keywords:
Caenorhabditis elegansCryptococcus neoformansIn vivo activityBiofilmsCell wallDrug resistanceDrugsERMESER–mitochondria encounter structureMitochondriaVirulence

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