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

Abstract

SummaryMitochondria 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.

The hypoxia‐induced dehydrogenase HorA is required for coenzyme Q10 biosynthesis, azole sensitivity and virulence of Aspergillus fumigatus

“…Several other reports also described the connection between mitochondria dysfunction and drug resistance in fungi. For instance, a recent study of mitochondria dynamics showed that mitochondrial fission mutants of A. fumigatus exhibited increased azole Virulence-associated oxidoreductase in A. fumigatus 101 resistance that was suggested to be linked to lanosterol 14a-demethylation activity (Neubauer et al, 2015). Similarly, the A. fumigatus DhorA mutant strain showed an increased resistance against voriconazole and amphotericin B.…”

Exploiting mitochondria as targets for the development of new antifungals

“…Of these 7 genes, the fusion genes Ugo1, Fzo1 and Mgm1 are partially conserved from S. cerevisiae to Aspergillus spp, and mutants are essential for viability of A. fumigatus, and avirulent in a Galleria mellonella infection model. 38 Growth and sporulation of each fission mutant was substantially reduced compared to WT cells but unexplainably not essential for virulence. Also, the fission mutants demonstrated resistance to voriconazole and posaconizole but not caspofungin antifungals.…”

“…Mitochondrial dynamics of fusion/fission have been recently reported in Aspergillus fumigatus. 38 Fusion genes included Mgm1, Ugo1 and Fzo1 while fission genes studied were Drp1, Mdv1, Caf2, and Fis1. Of these 7 genes, the fusion genes Ugo1, Fzo1 and Mgm1 are partially conserved from S. cerevisiae to Aspergillus spp, and mutants are essential for viability of A. fumigatus, and avirulent in a Galleria mellonella infection model.…”

Distinct Contributions of the Peroxisome-Mitochondria Fission Machinery During Sexual Development of the Fungus Podospora anserina

“…In addition, we also observed that mitochondria were segregated during the formation of different cell types, including ascospores and spermatia (microconidia), when FIS1 or DRP1 were missing. Similarly, Fis1 and Dnm1 are dispensable for mitochondria inheritance into conidia in Aspergillus fumigatus (Neubauer et al, 2015). This indicates that P. anserina is able to divide mitochondria during the formation of these cells in absence of FIS1 or DNM1.…”