The pheromone and pheromone receptor mating-type locus is involved in controlling uniparental mitochondrial inheritance in Cryptococcus

Mitochondria are inherited uniparentally during sexual reproduction in the majority of eukaryotic species studied, including humans, mice, nematodes, as well as many fungal species. Mitochondrial uniparental inheritance (mito-UPI) could be beneficial in that it avoids possible genetic conflicts between organelles with different genetic backgrounds, as recently shown in mice; and it could prevent the spread of selfish genetic elements in the mitochondrial genome. Despite the prevalence of observed mito-UPI, the underlying mechanisms and the genes involved in controlling this non-mendelian inheritance are poorly understood in many species. InCryptococcus neoformans, a human pathogenic basidiomyceteous fungus, mating types (MATα andMATa) are defined by alternate alleles at the singleMATlocus that evolved from fusion of the twoMATloci (P/Rencoding pheromones and pheromone receptors,HDencoding homeodomain transcription factors) that are the ancestral state in the basidiomycota. Mitochondria are inherited uniparentally from theMATaparent inC. neoformansand this requires theSXI1α andSXI2aHD factors encoded byMAT. However, there is evidence additional genes contribute to control of mito-UPI inCryptococcus. Here we show that inCryptococcus amylolentus, a sibling species ofC. neoformanswith unlinkedP/RandHD MATloci, mitochondrial uniparental inheritance is controlled by theP/Rlocus, and is independent of theHDlocus. Consistently, by replacing theMATα alleles of the pheromones (MF) and pheromone receptor (STE3) with theMATaalleles, we show that theseP/Rlocus defining genes indeed affect mito-UPI inC. neoformansduring sexual reproduction. Additionally, we show that during early stages ofC. neoformanssexual reproduction, conjugation tubes are always produced by theMATα cells, resulting in unidirectional migration of theMATα nucleus into theMATacell during zygote formation. This process is controlled by theP/Rlocus and could serve to physically restrict movement ofMATα mitochondria in the zygotes, and thereby contribute to mito-UPI. We propose a model in which both physical and genetic mechanisms function in concert to prevent the coexistence of mitochondria from the two parents in the zygote and subsequently in the meiotic progeny, thus ensuring mito-UPI in pathogenicCryptococcus, as well as in closely related non-pathogenic species. The implications of these findings are discussed in the context of the evolution of mito-UPI in fungi and other more diverse eukaryotes.