The δ subunit of F₁F_o-ATP synthase is required for pathogenicity of Candida albicans

Area of Science:

• Mycology
• Biochemistry
• Infectious Diseases

Background:

• Fungal infections like candidiasis and aspergillosis have high mortality rates.
• Fungal growth and survival depend on ATP, primarily synthesized via oxidative phosphorylation using F1F0-ATP synthase.
• The delta (δ) subunit of F1F0-ATP synthase is crucial for its function.

Purpose of the Study:

• To investigate the role of the Candida albicans F1F0-ATP synthase delta subunit (ATP16) in fungal pathogenicity.
• To identify potential therapeutic targets for invasive fungal infections.

Main Methods:

• Gene deletion of ATP16 in Candida albicans.
• Assessment of fungal growth, ATP levels, and virulence in vitro and in vivo.
• Structure-based virtual screening to identify small molecule inhibitors of fungal F1F0-ATP synthases.
• Phenotypic analysis of a targeted compound in vitro and in a mouse model.

Main Results:

• Deletion of ATP16 abrogated lethal systemic candidiasis in a mouse model.
• ATP16 deletion did not significantly impact in vitro growth or ATP levels due to compensatory glycolysis.
• The mutant showed reduced phosphofructokinase activity, lower fructose 1,6-bisphosphate, impaired cAMP-PKA signaling, and downregulated virulence factors.
• A screened compound mimicked the mutant's in vitro phenotype and protected mice from invasive candidiasis.

Conclusions:

• The F1F0-ATP synthase delta subunit is essential for Candida albicans virulence and lethal infection.
• Targeting the delta subunit of F1F0-ATP synthase presents a promising therapeutic strategy for invasive fungal infections.
• Inhibiting this subunit disrupts fungal pathogenicity through metabolic and signaling pathway alterations.