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Step-wise elimination of ?-mitochondrial nucleoids and mitochondrial structure as a basis for the strict uniparental inheritance in Cryptococcus neoformans.

ABSTRACT: In most sexual eukaryotes, mitochondrial (mt) DNA is uniparentally inherited, although the detailed mechanisms underlying this phenomenon remain controversial. The most widely accepted explanations include the autophagic elimination of paternal mitochondria in the fertilized eggs and the active degradation of paternal mitochondrial DNA. To decode the precise program for the uniparental inheritance, we focused on Cryptococcus neoformans as a model system, in which mtDNA is inherited only from the a-parent, although gametes of a- and ?-cells are of equal size and contribute equal amounts of mtDNA to the zygote. In this research, the process of preferential elimination of the mitochondria contributed by the ?-parent (?-mitochondria) was studied by fluorescence microscopy and single cell analysis using optical tweezers, which revealed that ?-mitochondria are preferentially reduced by the following three steps: (1) preferential reduction of ?-mitochondrial (mt) nucleoids and ?-mtDNA, (2) degradation of the ?-mitochondrial structure and (3) proliferation of remaining mt nucleoids during the zygote development. Furthermore, AUTOPHAGY RELATED GENE (ATG) 8 and the gene encoding mitochondrial endonuclease G (NUC1) were disrupted, and the effects of their disruption on the uniparental inheritance were scrutinized. Disruption of ATG8 (ATG7) and NUC1 did not have severe effects on the uniparental inheritance, but microscopic examination revealed that ?-mitochondria lacking mt nucleoids persisted in ?atg8 zygotes, indicating that autophagy is not critical for the uniparental inheritance per se but is responsible for the clearance of mitochondrial structures after the reduction of ?-mt nucleoids.

SUBMITTER: Nishimura Y

PROVIDER: S-EPMC7016115 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Step-wise elimination of α-mitochondrial nucleoids and mitochondrial structure as a basis for the strict uniparental inheritance in Cryptococcus neoformans.

Nishimura Yoshiki Y Shikanai Toshiharu T Kawamoto Susumu S Toh-E Akio A

Scientific reports 20200212 1

In most sexual eukaryotes, mitochondrial (mt) DNA is uniparentally inherited, although the detailed mechanisms underlying this phenomenon remain controversial. The most widely accepted explanations include the autophagic elimination of paternal mitochondria in the fertilized eggs and the active degradation of paternal mitochondrial DNA. To decode the precise program for the uniparental inheritance, we focused on Cryptococcus neoformans as a model system, in which mtDNA is inherited only from the ...[more]

PMID: 32051468

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Project description:UNLABELLED:Uniparental inheritance of mitochondrial DNA is pervasive in nonisogamic higher eukaryotes during sexual reproduction, and postzygotic and/or prezygotic factors are shown to be important in ensuring such an inheritance pattern. Although the fungus Cryptococcus neoformans undergoes sexual production with isogamic partners of opposite mating types a and ?, most progeny derived from such mating events inherit the mitochondrial DNA (mtDNA) from the a parent. The homeodomain protein complex Sxi1?/Sxi2a, formed in the zygote after a-? cell fusion, was previously shown to play a role in this uniparental mtDNA inheritance. Here, we defined the timing of the establishment of the mtDNA inheritance pattern during the mating process and demonstrated a critical role in determining the mtDNA inheritance pattern by a prezygotic factor, Mat2. Mat2 is the key transcription factor that governs the pheromone sensing and response pathway, and it is critical for the early mating events that lead to cell fusion and zygote formation. We show that Mat2 governs mtDNA inheritance independently of the postzygotic factors Sxi1?/Sxi2a, and the cooperation between these prezygotic and postzygotic factors helps to achieve stricter uniparental mitochondrial inheritance in this eukaryotic microbe. IMPORTANCE:Mitochondrial DNA is inherited uniparentally from the maternal parent in the majority of eukaryotes. Studies done on higher eukaryotes such as mammals have shown that the transmission of parental mitochondrial DNA is controlled at both the prefertilization and postfertilization stages to achieve strict uniparental inheritance. However, the molecular mechanisms underlying such uniparental mitochondrial inheritance have been investigated in detail mostly in anisogamic multicellular eukaryotes. Here, we show that in a simple isogamic microbe, Cryptococcus neoformans, the mitochondrial inheritance is controlled at the prezygotic level as well as the postzygotic level by regulators that are critical for sexual development. Furthermore, the cooperation between these two levels of control ensures stricter uniparental mitochondrial inheritance, echoing what has been observed in higher eukaryotes. Thus, the investigation of uniparental mitochondrial inheritance in this eukaryotic microbe could help advance our understanding of the convergent evolution of this widespread phenomenon in the eukaryotic domain.

Project description:Mitochondria are inherited uniparentally during sexual reproduction in the majority of eukaryotic species studied, including humans, mice, and 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. In Cryptococcus neoformans, a human pathogenic basidiomyceteous fungus, mating types (MATα and MAT a) are defined by alternate alleles at the single MAT locus that evolved from fusion of the two MAT loci (P/R encoding pheromones and pheromone receptors, and HD encoding homeodomain transcription factors) that are the ancestral state in the basidiomycota. Mitochondria are inherited uniparentally from the MAT a parent in C. neoformans, and this requires the SXI1α and SXI2 a HD factors encoded by MAT However, there is evidence that additional genes contribute to the control of mito-UPI in Cryptococcus Here, we show that in C. amylolentus, a sibling species of C. neoformans with unlinked P/R and HD MAT loci, mito-UPI is controlled by the P/R locus and is independent of the HD locus. Consistently, by replacing the MATα alleles of the pheromones (MF) and pheromone receptor (STE3) with the MAT a alleles, we show that these P/R locus-defining genes indeed affect mito-UPI in C. neoformans during sexual reproduction. Additionally, we show that during early stages of C. neoformans sexual reproduction, conjugation tubes are always produced by the MATα cells, resulting in unidirectional migration of the MATα nucleus into the MAT a cell during zygote formation. This process is controlled by the P/R locus and could serve to physically restrict movement of MATα 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 pathogenic Cryptococcus, as well as in closely related nonpathogenic species. The implications of these findings are discussed in the context of the evolution of mito-UPI in fungi and other more diverse eukaryotes.

Project description:The Cryptococcus complex consists of at least seven evolutionary divergent lineages and causes ?200,000 fatal human infections each year worldwide. The dominant lineage is Cryptococcus neoformans which consists of three haploid clades VNI, VNII, and VNB, their haploid hybrids, and various diploids derived from intra- and inter-clade mating events. In this study, we analyzed the mitogenomes of 184 strains of C. neoformans. Our analyses revealed that all 184 mitogenomes contained the same 15 protein-coding genes in the same gene order. However, their mitogenome sizes varied between 24,740 and 31,327 bp, primarily due to differences in the number and size of mitochondrial introns. Twelve nucleotide sites within five mitochondrial genes were found to contain introns in at least one of the 184 strains, ranging from 2 to 7 introns within each mitogenome. The concatenated mitochondrial exon sequences of the 15 protein-coding genes and two rRNA genes showed that VNI, VNII, and VNB strains were separated into distinct clades or sub-clades, largely consistent with results based on nuclear genome SNPs. However, several novel findings were observed. First, one strain of the VNB clade contained mitogenome exon sequences identical to the main VNI mitogenome type but was distant to other VNB mitogenomes. Second, hybrids among clades VNI, VNII, and VNB identified based on their nuclear genome SNPs contained mitogenomes from different clades, with evidence of their mitogenomes inherited from either the MAT a or the MAT ? parents. Third, the eight diploid VNB (C. neoformans) × VNIV (C. deneoformans) hybrids contained recombinant mitogenomes. Fourth, analyses of intron distribution and the paired exon-intron phylogenies for each of the 12 exon-intron pairs suggested frequent gains and losses of mitochondrial introns during the evolution of C. neoformans. The combined mitogenome exon-based phylogeny and intron distributions suggested that clades VNI, VNII and VNB could be further divided into sub-clades. Together, our results revealed a dynamic evolution of mitochondrial genomes in this important human fungal pathogen.

Dataset Information

Step-wise elimination of ?-mitochondrial nucleoids and mitochondrial structure as a basis for the strict uniparental inheritance in Cryptococcus neoformans.

Publications

Step-wise elimination of α-mitochondrial nucleoids and mitochondrial structure as a basis for the strict uniparental inheritance in Cryptococcus neoformans.

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