Aspergillus fumigatus mitogenomes and their influence on azole-resistant and -susceptible populations

The role of the fungal mitochondria goes far beyond energy metabolism. The genomes of 318 Aspergillus fumigatus clinical and environmental isolates from different geographic origins were analyzed aiming to study the mitochondrial sequences from populations sensitive and resistant to azoles. Our results show that A. fumigatus mitogenomic sequences are very conserved and only show variation in small intergenic regions and one intronic sequence in the cox3 gene. Furthermore, a genome-wide association analysis of accessory mitochondrial genes revealed potential mitochondria-based genotypes that may interact synergistically with the ergosterol biosynthesis pathway to confer the resistant phenotype. This includes a mutation in the AMID-like mitochondrial oxidoreductase (aifA, AFUA_3G01290) and the absence of the mitochondrial carrier protein (pet8, AFUA_8G01400). Deletion of these genes did not change the azole-susceptibility but increased the azole-persistence, suggesting mitochondrial genes could be involved in azole-persistence. Our work opens new hypotheses for the involvement of mitochondria in A. fumigatus azole-resistance.