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Bioscience Reports Jun 2007Mitochondrial diseases are a group of disorders due to a mitochondrial respiratory chain deficiency. They may depend on mitochondrial genome (mtDNA-related disorders) as... (Review)
Review
Mitochondrial diseases are a group of disorders due to a mitochondrial respiratory chain deficiency. They may depend on mitochondrial genome (mtDNA-related disorders) as well as on a nuclear genome defect (nDNA-related disorders). mtDNA-related disorders encompass an increasing number of clinical pictures associated with more than 250 different provisional or confirmed pathogenic changes in mtDNA. Although some clinical syndromes are nosologically defined, most of the cases present with polymorphous phenotypes ranging from pure myopathy to multi-system involvement. Complexity of mitochondrial genetics is in part responsible for the extreme clinical intra- and inter-familial heterogeneity of this group of diseases. In this review, we briefly report an updated classification and overview the main clinical pictures of this class of diseases.
Topics: DNA, Mitochondrial; Gene Deletion; Gene Duplication; Genes, Mitochondrial; Humans; Mitochondrial Diseases; Mitochondrial Proteins; Mutation; Point Mutation
PubMed: 17484046
DOI: 10.1007/s10540-007-9035-2 -
Current Opinion in Genetics &... Jun 2023In contrast with nuclear genes that are passed on through both parents, mitochondrial genes are maternally inherited in most species, most of the time. The genetic... (Review)
Review
In contrast with nuclear genes that are passed on through both parents, mitochondrial genes are maternally inherited in most species, most of the time. The genetic conflict stemming from this transmission asymmetry is well-documented, and there is an abundance of population-genetic theory associated with it. While occasional or aberrant paternal inheritance occurs, there are only a few cases where exclusive paternal inheritance of mitochondrial genomes is the evolved state. Why this is remains poorly understood. By examining commonalities between species with exclusive paternal inheritance, we discuss what they may tell us about the evolutionary forces influencing mitochondrial inheritance patterns. We end by discussing recent technological advances that make exploring the causes and consequences of paternal inheritance feasible.
Topics: Paternal Inheritance; Mitochondria; Inheritance Patterns; Genes, Mitochondrial; Genome, Mitochondrial; DNA, Mitochondrial
PubMed: 37245242
DOI: 10.1016/j.gde.2023.102053 -
Scientific Reports Feb 2020In most sexual eukaryotes, mitochondrial (mt) DNA is uniparentally inherited, although the detailed mechanisms underlying this phenomenon remain controversial. The most...
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 α-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 α-parent (α-mitochondria) was studied by fluorescence microscopy and single cell analysis using optical tweezers, which revealed that α-mitochondria are preferentially reduced by the following three steps: (1) preferential reduction of α-mitochondrial (mt) nucleoids and α-mtDNA, (2) degradation of the α-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 α-mitochondria lacking mt nucleoids persisted in Δatg8 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 α-mt nucleoids.
Topics: Autophagy-Related Protein 8 Family; Cryptococcus neoformans; DNA, Mitochondrial; Endonucleases; Fungal Proteins; Genes, Mitochondrial; Germ Cells; Optical Tweezers; Zygote
PubMed: 32051468
DOI: 10.1038/s41598-020-59277-9 -
Genome Research 2022Mitochondrial DNA (mtDNA) is a cytoplasmic genome that is essential for respiratory metabolism. Although uniparental mtDNA inheritance is most common in animals and...
Mitochondrial DNA (mtDNA) is a cytoplasmic genome that is essential for respiratory metabolism. Although uniparental mtDNA inheritance is most common in animals and plants, distinct mtDNA haplotypes can coexist in a state of heteroplasmy, either because of paternal leakage or de novo mutations. mtDNA integrity and the resolution of heteroplasmy have important implications, notably for mitochondrial genetic disorders, speciation, and genome evolution in hybrids. However, the impact of genetic variation on the transition to homoplasmy from initially heteroplasmic backgrounds remains largely unknown. Here, we use yeasts, fungi with constitutive biparental mtDNA inheritance, to investigate the resolution of mtDNA heteroplasmy in a variety of hybrid genotypes. We previously designed 11 crosses along a gradient of parental evolutionary divergence using undomesticated isolates of and Each cross was independently replicated 48 to 96 times, and the resulting 864 hybrids were evolved under relaxed selection for mitochondrial function. Genome sequencing of 446 MA lines revealed extensive mtDNA recombination, but the recombination rate was not predicted by parental divergence level. We found a strong positive relationship between parental divergence and the rate of large-scale mtDNA deletions, which led to the loss of respiratory metabolism. We also uncovered associations between mtDNA recombination, mtDNA deletion, and genome instability that were genotype specific. Our results show that hybridization in yeast induces mtDNA degeneration through large-scale deletion and loss of function, with deep consequences for mtDNA evolution, metabolism, and the emergence of reproductive isolation.
Topics: Animals; DNA, Mitochondrial; Genes, Mitochondrial; Mitochondria; Hybridization, Genetic; Genotype; Saccharomyces cerevisiae
PubMed: 36351770
DOI: 10.1101/gr.276885.122 -
Mycologia 2019Mitochondrial inheritance in Fusarium zanthoxyli and F. continuum, two canker-inducing pathogens of prickly ash (Zanthoxylum bungeanum) in northern China, was...
Mitochondrial inheritance in Fusarium zanthoxyli and F. continuum, two canker-inducing pathogens of prickly ash (Zanthoxylum bungeanum) in northern China, was investigated by genotyping ascospore progeny obtained from laboratory crosses. Polymorphic regions of the mitochondrial genomes (mitogenomes) that contained indels and single-nucleotide polymorphisms (SNPs) were identified via comparative analyses of the complete mitogenomes of the parents used in the intraspecific crosses. A reciprocal genetic cross of F. zanthoxyli NRRL 66714 × NRRL 66285, and a separate cross of F. continuum ♀ NRRL 66286 × ♂ NRRL 66218, revealed that mitochondria were only inherited from the maternal parent. In addition, the reciprocal cross demonstrated that mitochondrial inheritance is not linked to mating type. Gene order in the circular mitogenomes of the prickly ash pathogens was identical to that previously reported for other fusaria and members of the Hypocreales, except that the TRNL tRNAs were duplicated in F. zanthoxyli NRRL 66714. The genomes contained 14 polypeptide-encoding genes involved in oxidative respiration, one intron-encoded ribosomal protein (rps3) gene, two ribosomal RNA (rRNA) genes, and 26-28 tRNA genes. The F. zanthoxyli mitogenomes were 80.9 and 98.7 kb in length, whereas those of F. continuum were considerably shorter and nearly identical in length at 63.4 kb. The significant differences in mitogenome length were primarily due to variable numbers of introns and open reading frames (ORFs) encoding hypothetical proteins.
Topics: China; Crosses, Genetic; DNA, Mitochondrial; Fusarium; Genes, Mitochondrial; Genome, Mitochondrial; Genotype; Genotyping Techniques; Mycological Typing Techniques; Polymorphism, Genetic; Sequence Analysis, DNA; Zanthoxylum
PubMed: 30896371
DOI: 10.1080/00275514.2018.1562269 -
ELife Oct 2019Oogenesis features an enormous increase in mitochondrial mass and mtDNA copy number, which are required to furnish mature eggs with an adequate supply of mitochondria...
Oogenesis features an enormous increase in mitochondrial mass and mtDNA copy number, which are required to furnish mature eggs with an adequate supply of mitochondria and to curb the transmission of deleterious mtDNA variants. Quiescent in dividing germ cells, mtDNA replication initiates upon oocyte determination in the ovary, which necessitates active mitochondrial respiration. However, the underlying mechanism for this dynamic regulation remains unclear. Here, we show that an feedforward insulin-Myc loop promotes mitochondrial respiration and biogenesis by boosting the expression of electron transport chain subunits and of factors essential for mtDNA replication and expression, and for the import of mitochondrial proteins. We further reveal that transient activation of JNK enhances the expression of the insulin receptor and initiates the insulin-Myc signaling loop. This signaling relay promotes mitochondrial biogenesis in the ovary, and thereby plays a role in limiting the transmission of deleterious mtDNA mutations. Our study demonstrates cellular mechanisms that couple mitochondrial biogenesis and inheritance with oocyte development.
Topics: Animals; DNA-Binding Proteins; Drosophila; Drosophila Proteins; Electron Transport Chain Complex Proteins; Genes, Mitochondrial; Insulin; MAP Kinase Kinase 4; Mitochondria; Organelle Biogenesis; Receptor Protein-Tyrosine Kinases; Signal Transduction; Transcription Factors
PubMed: 31612862
DOI: 10.7554/eLife.49309 -
Nature Sep 2015
Topics: Animals; Bioethical Issues; CRISPR-Cas Systems; Female; Genes, Mitochondrial; Humans; Male; Mitochondria; Mitochondrial Diseases; Practice Guidelines as Topic; United Kingdom
PubMed: 26399789
DOI: 10.1038/525425b -
The Journal of Biological Chemistry Jan 2011Mitochondria undergo continuous cycles of homotypic fusion and fission, which play an important role in controlling organelle morphology, copy number, and mitochondrial...
Mitochondria undergo continuous cycles of homotypic fusion and fission, which play an important role in controlling organelle morphology, copy number, and mitochondrial DNA maintenance. Because mitochondria cannot be generated de novo, the motility and distribution of these organelles are essential for their inheritance by daughter cells during division. Mitochondrial Rho (Miro) GTPases are outer mitochondrial membrane proteins with two GTPase domains and two EF-hand motifs, which act as receptors to regulate mitochondrial motility and inheritance. Here we report that although all of these domains are biochemically active, only the GTPase domains are required for the mitochondrial inheritance function of Gem1p (the yeast Miro ortholog). Mutations in either of the Gem1p GTPase domains completely abrogated mitochondrial inheritance, although the mutant proteins retained half the GTPase activity of the wild-type protein. Although mitochondrial inheritance was not dependent upon Ca(2+) binding by the two EF-hands of Gem1p, a functional N-terminal EF-hand I motif was critical for stable expression of Gem1p in vivo. Our results suggest that basic features of Miro protein function are conserved from yeast to humans, despite differences in the cellular machinery mediating mitochondrial distribution in these organisms.
Topics: Amino Acid Motifs; Amino Acid Sequence; Animals; Calcium; DNA, Mitochondrial; Genes, Mitochondrial; Humans; Hydrolysis; Mitochondria; Mutation; Nucleotides; Protein Stability; Protein Structure, Tertiary; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Structure-Activity Relationship; rho GTP-Binding Proteins
PubMed: 21036903
DOI: 10.1074/jbc.M110.180034 -
Physiological Genomics Jul 2023Mitochondrial dysfunction has been implicated in pregnancy-induced hypertension (PIH). The role of mitochondrial gene dysregulation in PIH, and consequences for...
Mitochondrial dysfunction has been implicated in pregnancy-induced hypertension (PIH). The role of mitochondrial gene dysregulation in PIH, and consequences for maternal-fetal interactions, remain elusive. Here, we investigated mitochondrial gene expression and dysregulation in maternal and placental tissues from pregnancies with and without PIH; further, we measured circulating mitochondrial DNA (mtDNA) mutational load, an index of mtDNA integrity. Differential gene expression analysis followed by Time Course Gene Set Analysis (TcGSA) was conducted on publicly available high throughput sequencing transcriptomic data sets. Mutational load analysis was carried out on peripheral mononuclear blood cells from healthy pregnant individuals and individuals with preeclampsia. Thirty mitochondrial differentially expressed genes (mtDEGs) were detected in the maternal cell-free circulating transcriptome, whereas nine were detected in placental transcriptome from pregnancies with PIH. In PIH pregnancies, maternal mitochondrial dysregulation was associated with pathways involved in inflammation, cell death/survival, and placental development, whereas fetal mitochondrial dysregulation was associated with increased production of extracellular vesicles (EVs) at term. Mothers with preeclampsia did not exhibit a significantly different degree of mtDNA mutational load. Our findings support the involvement of maternal mitochondrial dysregulation in the pathophysiology of PIH and suggest that mitochondria may mediate maternal-fetal interactions during healthy pregnancy. This study identifies aberrant maternal and fetal expression of mitochondrial genes in pregnancies with gestational hypertension and preeclampsia. Mitochondrial gene dysregulation may be a common etiological factor contributing to the development of de novo hypertension in pregnancy-associated hypertensive disorders.
Topics: Pregnancy; Female; Humans; Hypertension, Pregnancy-Induced; Placenta; Pre-Eclampsia; Genes, Mitochondrial; DNA, Mitochondrial
PubMed: 37184228
DOI: 10.1152/physiolgenomics.00005.2023 -
Journal of Plant Research Mar 2010To analyze mitochondrial DNA (mtDNA)inheritance, differences in mtDNA between Chlamydomonas reinhardtii and Chlamydomonas smithii, respiration deficiency and antibiotic... (Review)
Review
To analyze mitochondrial DNA (mtDNA)inheritance, differences in mtDNA between Chlamydomonas reinhardtii and Chlamydomonas smithii, respiration deficiency and antibiotic resistance were used to distinguish mtDNA origins. The analyses indicated paternal inheritance. However, these experiments raised questions regarding whether paternal inheritance occurred normally.Mitochondrial nucleoids were observed in living zygotes from mating until 3 days after mating and then until progeny formation. However, selective disappearance of nucleoids was not observed. Subsequently, experimental serial backcrosses between the two strains demonstrated strict paternal inheritance. The fate of mt+ and mt- mtDNA was followed using the differences in mtDNA between the two strains. The slow elimination of mt+ mtDNA through zygote maturation in darkness was observed, and later the disappearance of mt+ mtDNA was observed at the beginning of meiosis. To explain the different fates of mtDNA, methylation status was investigated; however, no methylation was detected. Variously constructed diploid cells showed biparental inheritance. Thus, when the mating process occurs normally, paternal inheritance occurs. Mutations disrupting mtDNA inheritance have not yet been isolated. Mutations that disrupt maternal inheritance of chloroplast DNA (cpDNA) do not disrupt inheritance of mtDNA. The genes responsible for mtDNA inheritance are different from those of chloroplasts.
Topics: Chlamydomonas; DNA, Mitochondrial; Diploidy; Genes, Mitochondrial; Genome, Mitochondrial
PubMed: 20069335
DOI: 10.1007/s10265-009-0295-8