ER–mitochondria encounter structure connections determine drug sensitivity and virulence of Cryptococcus neoformans

Cryptococcus neoformans is a common fungal pathogen, causing fatal meningoencephalitis in immunocompromised individuals. The limited availability of antifungals and increasing resistance in pathogens including C. neoformans emphasize the need to find new drugs. Mitochondria have long been associated with drug resistance in fungi. They are connected to the endoplasmic reticulum (ER) via a multiprotein complex, the ER–mitochondria encounter structure (ERMES), which is unique in the fungal kingdom. In this study on C. neoformans, the four subunits of the ERMES complex, namely, Mmm1, Mdm12, Mdm10 and Mdm34, were deleted to generate the strains Δmmm1, Δmdm12, Δmdm10 and Δmdm34, respectively. These mutants had impaired mitochondria and were sensitive to antifungals, including echinocandins, due to lower chitin content. Virulence factors, including capsule formation and melanin production, were debilitated in the mutants. The partner organelle ER was also affected by compromised ERMES contact, as the activity of several ER-synthesized enzymes involved in virulence was impacted. The in vivo studies in Caenorhabditis elegans model of cryptococcosis confirmed the reduced virulence of the mutants. These results indicate that the impairment of the ERMES complex is crucial for the virulence and pathogenesis of C. neoformans. © 2025 Elsevier B.V., All rights reserved.