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

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.