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

Mitochondrial function is essential for virulence in <i>Candida albicans</i>, 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 <i>MSS2</i> 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 <i>MSS2</i>-regulated genes, including <i>UME6</i>, <i>SAC1</i>, <i>RIM8</i>, and <i>ORF19.1841</i>, 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 <i>mss2Δ</i>, 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 <i>C. albicans</i>. 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.