Pathogenic fungi represent a growing concern for human health, necessitating a deeper understanding of their molecular mechanisms of virulence to formulate effective antifungal strategies. Recent research has increasingly highlighted the role of phospholipid components in fungal cell membranes, which are not only vital for maintaining cellular integrity but also significantly influence fungal pathogenicity. This review focuses on the impact of membrane phospholipid composition on fungal growth, morphogenesis, stress responses, and interactions with host cells. To be specific, membrane phospholipid composition critically influences fungal virulence by modulating growth dynamics and morphogenesis, such as the transition from yeast to hyphal forms, which enhances tissue invasion. Additionally, phospholipids mediate stress adaptation, enabling fungi to withstand host-derived oxidative and osmotic stresses, crucial for survival within hostile host environments. Phospholipid asymmetry also impacts interactions with host cells, including adhesion, phagocytosis evasion, and the secretion of virulence factors like hydrolytic enzymes. These adaptations collectively enhance fungal pathogenicity by promoting colonization, immune evasion, and damage to host tissues, directly linking membrane architecture to infection outcomes. By elucidating the molecular mechanisms involved, we aim to underscore the potential of targeting phospholipid metabolic pathways as a promising avenue for antifungal therapy. A comprehensive understanding of how membrane phospholipid composition regulates the virulence of pathogenic fungi can provide valuable insights for developing novel antifungal strategies.

Mitochondria, as the core metabolic organelles, play a crucial role in aerobic respiration/biosynthesis in fungi. Numerous studies have demonstrated a close relationship between mitochondria and Candida albicans virulence and drug resistance. Here, we report an octapeptide-aminopeptidase located in the mitochondrial matrix named Oct1p. Its homolog in the model fungus Saccharomyces cerevisiae is one of the key proteins in maintaining mitochondrial respiration and protein stability. In this study, we utilized evolutionary tree analysis, gene knockout experiments, mitochondrial function detection, and other methods to demonstrate the impact of Oct1p on the mitochondrial function of C. albicans. Furthermore, through transcriptome analysis, real-time quantitative PCR, and morphological observation, we discovered that the absence of Oct1p results in functional abnormalities in C. albicans, affecting hyphal growth, cell adhesion, and biofilm formation. Finally, the in vivo results of the infection of Galleria mellonella larvae and vulvovaginal candidiasis in mice indicate that the loss of Oct1p led to the decreased virulence of C. albicans. In conclusion, this study provides a solid theoretical foundation for treating Candida diseases, developing new targeted drugs, and serves as a valuable reference for investigating the connection between mitochondria and virulence in other pathogenic fungi.

The mitochondrial membrane protein UPS1, a conserved intermembrane space protein in Saccharomyces cerevisiae, possesses phosphatidic acid transfer activity and plays a positive regulatory role in processes such as cardiolipin metabolism and transport. The role of UPS1 protein in pathogenic fungi such as Candida albicans has not been explored, especially in relation to its influence on virulence factors like hyphal growth and biofilm formation, which are crucial for the pathogenicity of C. albicans. The research investigated the function of the UPS1 protein in C. albicans by using gene knockout techniques, analyzing mitochondrial function, and conducting tests for hyphal and biofilm development. The results revealed that deletion of the UPS1 gene leads to altered mitochondrial morphology, increased reactive oxygen species levels, and reduced intracellular ATP content, thereby causing severe growth defects in C. albicans. In addition, transcriptomic analysis indicated that loss of UPS1 significantly represses the expression of genes associated with hyphal growth and biofilm formation. Functional assays further confirmed that UPS1 deficiency markedly impairs cell adhesion capability, hyphal development, and biofilm formation of C. albicans. Notably, deletion of the UPS1 protein markedly reduces the susceptibility of C. albicans to membrane-targeted antifungal drugs. Finally, infection models using Galleria mellonella larvae and a murine vulvovaginal candidiasis model verified that UPS1 gene knockout attenuates the pathogenicity of C. albicans. In summary, our findings demonstrate that UPS1 protein modulates the pathogenicity of C. albicans by regulating mitochondrial function, hyphal growth, and biofilm formation.