# Mss2 shapes the virulence of Candida albicans through reactive oxygen species (ROS) and calcium signaling, independent of direct transcriptional control

## TL;DR

This study shows that the protein Mss2 in Candida albicans affects its ability to cause disease by controlling calcium and reactive oxygen species, not through direct gene control.

## Contribution

The study is the first to show that Mss2 regulates virulence via a calcium-ROS circuit, independent of transcriptional control.

## Key findings

- Mss2 deletion impairs invasive growth on solid media but not hyphal formation in liquid media.
- Mss2 regulates invasive growth through calcium and ROS homeostasis, confirmed by restoring phenotypes with exogenous ROS.
- Mss2-regulated genes like UME6 and SAC1 are linked to calcium and ROS levels, and their deletion causes virulence defects.

## Abstract

Mitochondrial function is essential for virulence in Candida albicans, yet the mechanism by which mitochondria influence pathogenesis remains largely undefined. Here, we reveal that the mitochondrial-associated factor Mss2 controls invasive growth through the regulation of calcium–reactive oxygen species (ROS) homeostasis. Deletion of MSS2 results in impaired invasive growth on solid media without affecting hyphal formation in liquid media, indicating that Mss2 controls contact-specific responses. We demonstrate that the regulation of these processes by Mss2 is linked to the regulation of cytosolic calcium levels and cellular ROS production. Furthermore, transcriptomic profiling identified MSS2-regulated genes, including UME6, SAC1, RIM8, and ORF19.1841, whose expression is dependent on calcium and ROS levels. Restoration of invasive phenotypes through exogenous ROS confirms the functional significance of this calcium-ROS circuit. In systemic infection models, similar to mss2Δ, the Mss2 downstream genes exhibit severe virulence defects. Together, this work is the first to show that mitochondrial regulation of a coordinated calcium-ROS circuit is required for invasive hyphal growth and virulence in C. albicans. These findings refine our understanding of fungal invasion and virulence and reveal that targeting mitochondrial signaling could be an important area for antifungal therapeutic interventions.