Mitochondrial anchor protein Num11 is key to pathogenicity of Candida albicans by affecting mitochondrial function and cell wall masking.

The mitochondrial anchoring protein Num1 directly affects mitochondrial redox function, cell division, and growth in unicellular fungi. However, the functional characterization of Num11, its Candida albicans homolog, remains elusive. Our investigation revealed that Num11 deletion in C. albicans caused profound cellular defects: (1) Disrupted cell cycle progression and mitochondrial dysfunction manifesting as mitochondrial morphological aggregation, ATP depletion, membrane potential collapse, and ROS overproduction; (2) Hypersensitivity to cell wall-perturbing agents accompanied by thicker cell walls and increased surface exposure of β-glucan/chitin; (3) Enhanced macrophage phagocytosis and proinflammatory cytokine release. These cellular alterations translated to significantly attenuated virulence in both Galleria mellonella and systematic mice infection models. Mechanistically, transcriptome profiling and protein interaction analyses demonstrated Num11 deficiency hyperactivates the Cdc42-Cek1 MAPK cascade (phospho-Cek1 increased), driving cell wall remodeling. Our findings establish Num11's dual closely connected regulatory roles in C. albicans pathogenesis: as a mitochondrial scaffold maintaining bioenergetic homeostasis to attenuate growth and as a negative regulator of the Cdc42-Cek1 axis controlling cell wall architecture through affection on mitochondria. These coordinated actions collectively underscore Num11's critical role in mediating host-pathogen interactions during invasive candidiasis.