Mitochondrial retrograde control of transcription evolves with respiratory stress, metabolic adaptation, and virulence in budding yeasts.

The pathway involving the paralogous transcription factors Rtg1 and Rtg3 was first described in Saccharomyces cerevisiae as the retrograde regulation that adapts cellular metabolism in response to the state of mitochondrial respiration. We investigated the evolution of this pathway by studying its target genes in respiratory-deficient mutants of Candida albicans-a phylogenetically distant and metabolically distinct yeast species. We show that in C. albicans the Rtg pathway is also responsible for adaptation to cellular stresses related to respiratory dysfunction, but the repertoire of its target genes is different than in S. cerevisiae, and includes genes encoding proteins involved in alternative respiration, oxidative stress, mitophagy, and other aspects of metabolism. We also traced the evolution of the main components of the Rtg pathway and its target genes in the budding yeast (Saccharomycotina) subphylum. We show that the system originated within this clade following a single duplication of the gene encoding the ancestor of Rtg1 and Rtg3, but employs other factors, like the regulatory proteins Rtg2 and Mks1 that were likely present in the last common ancestor of budding yeasts. The regulation of the Rtg transcription factors in C. albicans is different than in S. cerevisiae, as both Rtg2 and Mks1 were lost in the majority of Serinales. Among the target genes, of particular interest is the evolution of the alternative oxidase (Aox), which was either lost or duplicated in multiple independent events. The presence of Aox strongly correlates with the mitochondrially encoded Complex I-a major source of oxidative stress.