# Mitochondrial complex III subunit Qcr8 regulates the virulence and adhesion of Candida albicans by modulating mitochondrial function

## TL;DR

This study identifies Qcr8, a mitochondrial complex III subunit, as a key regulator of Candida albicans virulence and adhesion, offering a new potential drug target.

## Contribution

The study reveals Qcr8 as a novel virulence determinant in C. albicans and links it to the Ras/cAMP/PKA pathway.

## Key findings

- QCR8 deletion in C. albicans significantly reduces virulence in infection models.
- Qcr8 deletion disrupts mitochondrial function and lowers cAMP levels, affecting the Ras/cAMP/PKA pathway.
- Exogenous cAMP partially restores adhesion in QCR8-deleted strains.

## Abstract

Invasive fungal infections caused by Candida albicans pose significant clinical challenges due to their high mortality rates and emerging drug resistance. In this study, we established Qcr8, an accessory subunit of mitochondrial complex III, as a critical virulence determinant in C. albicans. The deletion of QCR8 markedly attenuated virulence in both Galleria mellonella and murine infection models, concomitant with impaired adhesion to biotic (human umbilical vein endothelial cells) and abiotic surfaces. Mechanistically, QCR8 deletion disrupted mitochondrial homeostasis, evidenced by elevated reactive oxygen species levels, diminished membrane potential (ΔΨm), and reduced ATP levels. Notably, cAMP levels decreased in mutant strains, resulting in the pronounced downregulation of Ras/cAMP/protein kinase A (PKA) pathway components (RAS1, CYR1, TPK1/2, EFG1, and FLO8), while exogenous cAMP supplementation partially restored the adhesion capacity. Our findings indicate that Qcr8 plays a vital role in mitochondrial complex III, highlighting its therapeutic potential as a fungus-specific drug target.

We identified Qcr8, an accessory subunit of mitochondrial complex III for C. albicans full virulence. This study indicates that the accessory subunit of complex III, in addition to the structural subunits that have been previously the focus of study, also plays a significant role in the regulation of virulence. We also elucidated that Qcr8 promotes virulence via the Ras/cAMP/PKA pathway. Our findings established Qcr8 as a potential therapeutic target for treating C. albicans infections, which is particularly relevant, given the rising concern about antifungal resistance.