The ER-mitochondria encounter structure contributes to hyphal growth, mitochondrial morphology and virulence of the pathogenic mold Aspergillus fumigatus.

Aspergillus fumigatus is an opportunistic fungal pathogen and the primary causative species of invasive aspergillosis, a systemic disease associated with high mortality rates. Treatment of invasive fungal infection relies on a very limited number of antifungal drug classes. In order to extend the spectrum of antifungal drugs novel target structures have to be identified. The ER-mitochondria encounter structure (ERMES), a recently discovered tether that links mitochondria and endoplasmic reticulum, is a potential drug target based on its absence in Metazoa. Very recently, it was shown that ERMES is important for the fitness and immune evasion of the pathogenic yeast Candida albicans. We studied the role of the four ERMES core components Mdm10, Mdm12, Mdm34 and Mmm1 in the pathogenic mold A. fumigatus. By construction and characterizing conditional mutants of all four core components and deletion mutants of mdm10 and mdm12, we show that each component is of significant importance for growth of the fungal pathogen. While markedness of the individual mutant phenotypes differed slightly, all components are important for maintenance of the mitochondrial morphology and the intra-organellar distribution of nucleoids. Characterization of the Mmm1 ERMES mutant in a Galleria mellonella infection model indicates that ERMES contributes to virulence of A. fumigatus. Our results demonstrate that pharmacologic inhibition of ERMES could exert antifungal activity against this important pathogen.

Mitochondrial dynamics in the pathogenic mold Aspergillus fumigatus: therapeutic and evolutionary implications.

Mitochondria within eukaryotic cells continuously fuse and divide. This phenomenon is called mitochondrial dynamics and crucial for mitochondrial function and integrity. We performed a comprehensive analysis of mitochondrial dynamics in the pathogenic mold Aspergillus fumigatus. Phenotypic characterization of respective mutants revealed the general essentiality of mitochondrial fusion for mitochondrial genome maintenance and the mold's viability. Surprisingly, it turned out that the mitochondrial rhomboid protease Pcp1 and its processing product, s-Mgm,1 which are crucial for fusion in yeast, are dispensable for fusion, mtDNA maintenance and viability in A. fumigatus. In contrast, mitochondrial fission mutants show drastically reduced growth and sporulation rates and increased heat susceptibility. However, reliable inheritance of mitochondria to newly formed conidia is ensured. Strikingly, mitochondrial fission mutants show a significant and growth condition-dependent increase in azole resistance. Parallel disruption of fusion in a fission mutant partially rescues growth and sporulation defects and further increases the azole resistance phenotype. Taken together, our results indicate an emerging dispensability of the mitochondrial rhomboid protease function in mitochondrial fusion, the suitability of mitochondrial fusion machinery as antifungal target and the involvement of mitochondrial dynamics in azole susceptibility.