ER-mitochondrial crosstalk (ERMES) regulates cell wall composition in pathogenic fungi

Fungal infections pose a significant global health challenge, exacerbated by limited antifungal therapies and the rise of drug-resistant strains. The cell wall is a critical determinant of fungal pathogenicity, as it maintains structural integrity and mediates host-pathogen interactions. Notably, the cell wall compositions of Cryptococcus neoformans and Candida albicans differ substantially. In C. albicans, the inner layer is rich in chitin, β-1,3-glucans and β-1,6-glucans, while the outer layer comprises N-linked and O-linked mannoproteins. Conversely, C. neoformans includes additional components such as α-1,3-glucan and chitosan, and is characterized by an outermost capsule layer containing glucuronoxylomannan (GXM) and galactoxylomannan (GalXM), along with minor mannoproteins. In this study, we explored the role of a unique fungal multi-subunit complex known as the Endoplasmic Reticulum-Mitochondria Encounter Structure (ERMES) in regulating cell wall architecture. The ERMES complex is composed of four key subunits: Mmm1, Mdm10, Mdm12 and Mdm34. It plays critical roles across various fungal species, including maintaining mitochondrial morphology and function, facilitating phospholipid transport, supporting mitophagy and contributing to virulence. Notably, disruption of ERMES components has been linked to enhanced susceptibility of both planktonic and biofilm-forming fungal cells to echinocandin-class antifungal drugs. Our investigation revealed that deletion or impairment of ERMES subunits significantly alters the cell wall composition in C. neoformans and C. albicans, suggesting a previously underappreciated connection between mitochondrial contact sites and fungal cell wall integrity. Using staining techniques, we assessed changes in key cell wall components, including reduced β-1,3-glucans, chitin, chitosan and mannoproteins in deletion mutants (Δmmm1, Δmdm10, Δmdm12 and Δmdm34) of both species. Transmission electron microscopy (TEM) analysis confirmed alterations in cell wall thickness, with the most pronounced effects observed in Δmmm1 and Δmdm10 mutants. The ERMES mutants were also impaired in hyphal development. These findings underscore the essential role of ER-mitochondrial communication in regulating cell wall biosynthesis and structural remodeling.