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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 -
IUBMB Life Dec 2018Mitochondria are the sandbox of evolution as exemplified most particularly by the diplonemids, a group of marine microeukaryotes. These protists are uniquely... (Review)
Review
Mitochondria are the sandbox of evolution as exemplified most particularly by the diplonemids, a group of marine microeukaryotes. These protists are uniquely characterized by their highly multipartite mitochondrial genome and systematically fragmented genes whose pieces are spread out over several dozens of chromosomes. The type species Diplonema papillatum was the first member of this group in which the expression of fragmented mitochondrial genes was investigated experimentally. We now know that gene expression involves separate transcription of gene pieces (modules), RNA editing of module transcripts, and module joining to mature mRNAs and rRNAs. The mechanism of cognate module recognition and ligation is distinct from known intron splicing and remains to be uncovered. Here, we review the current status of research on mitochondrial genome architecture, as well as gene complement, structure, and expression modes in diplonemids. Further, we discuss the potential molecular mechanisms of posttranscriptional processing, and finally reflect on the evolutionary trajectories and trends of mtDNA evolution as seen in this protist group. © 2018 IUBMB Life, 70(12):1197-1206, 2018.
Topics: Aquatic Organisms; DNA, Mitochondrial; Euglenozoa; Genes, Mitochondrial; Genome, Mitochondrial; Introns; Mitochondria
PubMed: 30304578
DOI: 10.1002/iub.1927 -
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 -
Trends in Biochemical Sciences Aug 2017Perturbation of mitochondrial DNA (mtDNA) gene expression can lead to human pathologies. Therefore, a greater appreciation of the basic mechanisms of mitochondrial gene... (Review)
Review
Perturbation of mitochondrial DNA (mtDNA) gene expression can lead to human pathologies. Therefore, a greater appreciation of the basic mechanisms of mitochondrial gene expression is desirable to understand the pathophysiology of associated disorders. Although the purpose of the mitochondrial gene expression machinery is to provide only 13 proteins of the oxidative phosphorylation (OxPhos) system, recent studies have revealed its remarkable and unexpected complexity. We review here the latest breakthroughs in our understanding of the post-transcriptional processes of mitochondrial gene expression, focusing on advances in analyzing the mitochondrial epitranscriptome, the role of mitochondrial RNA granules (MRGs), the benefits of recently obtained structures of the mitochondrial ribosome, and the coordination of mitochondrial and cytosolic translation to orchestrate the biogenesis of OxPhos complexes.
Topics: Animals; Gene Expression Regulation; Genes, Mitochondrial; Humans; Mitochondria; Mitochondrial Ribosomes; Oxidative Phosphorylation; RNA Processing, Post-Transcriptional
PubMed: 28285835
DOI: 10.1016/j.tibs.2017.02.003 -
G3 (Bethesda, Md.) Aug 2022The expression of nuclear and mitochondrial genes, as well as their coordinated control, regulates cell proliferation, individual development, and disease in animals....
The expression of nuclear and mitochondrial genes, as well as their coordinated control, regulates cell proliferation, individual development, and disease in animals. However, the potential coregulation between nuclear and mitochondrial genes is unclear in triploid fishes. The two triploids (R2C and RC2) with distinct mitochondrial genomes but similar nuclear genomes exhibit different embryonic development times and growth rates. They are an excellent model for studying how nuclear and mitochondrial genes coordinate. Here, we performed the mRNA-seq of four stages of embryonic development (blastula, gastrula, segmentation, and hatching periods) in the two triploids (R2C and RC2) and their diploid inbred parents (red crucian carp and common carp). After establishing the four patterns of mitochondrial and nuclear gene expression, 270 nuclear genes regulated by mitochondrial genes were predicted. The expression levels of APC16 and Trim33 were higher in RC2 than in R2C, suggesting their potential effects on regulating embryonic development time. In addition, 308 differentially expressed genes filtered from the list of nuclear-encoded mitochondrial genes described by Mercer et al. in 2011 were considered potential genes for which nuclear genes regulate mitochondrial function. The findings might aid in our understanding of the correlation between mitochondrial and nuclear genomes as well as their synergistic effects on embryonic development.
Topics: Animals; Carps; Cell Nucleus; Diploidy; Genes, Mitochondrial; Triploidy
PubMed: 35924985
DOI: 10.1093/g3journal/jkac197 -
Ageing Research Reviews Apr 2011There is substantial evidence that mitochondria are involved in the aging process. Mitochondrial function requires the coordinated expression of hundreds of nuclear... (Review)
Review
There is substantial evidence that mitochondria are involved in the aging process. Mitochondrial function requires the coordinated expression of hundreds of nuclear genes and a few dozen mitochondrial genes, many of which have been associated with either extended or shortened life span. Impaired mitochondrial function resulting from mtDNA and nuclear DNA variation is likely to contribute to an imbalance in cellular energy homeostasis, increased vulnerability to oxidative stress, and an increased rate of cellular senescence and aging. The complex genetic architecture of mitochondria suggests that there may be an equally complex set of gene interactions (epistases) involving genetic variation in the nuclear and mitochondrial genomes. Results from Drosophila suggest that the effects of mtDNA haplotypes on longevity vary among different nuclear allelic backgrounds, which could account for the inconsistent associations that have been observed between mitochondrial DNA (mtDNA) haplogroups and survival in humans. A diversity of pathways may influence the way mitochondria and nuclear-mitochondrial interactions modulate longevity, including: oxidative phosphorylation; mitochondrial uncoupling; antioxidant defenses; mitochondrial fission and fusion; and sirtuin regulation of mitochondrial genes. We hypothesize that aging and longevity, as complex traits having a significant genetic component, are likely to be controlled by nuclear gene variants interacting with both inherited and somatic mtDNA variability.
Topics: Aging; Cell Nucleus; DNA, Mitochondrial; Epistasis, Genetic; Genes, Mitochondrial; Genetic Variation; Haplotypes; Humans; Longevity; Mitochondria; Mutation; Oxidative Phosphorylation; Oxidative Stress; Polymorphism, Genetic
PubMed: 20601194
DOI: 10.1016/j.arr.2010.06.003 -
Neurogenetics Oct 2021The term SCA refers to a phenotypically and genetically heterogeneous group of autosomal dominant spinocerebellar ataxias. Phenotypically they present as gait ataxia... (Review)
Review
The term SCA refers to a phenotypically and genetically heterogeneous group of autosomal dominant spinocerebellar ataxias. Phenotypically they present as gait ataxia frequently in combination with dysarthria and oculomotor problems. Additional signs and symptoms are common and can include various pyramidal and extrapyramidal signs and intellectual impairment. Genetic causes of SCAs are either repeat expansions within disease genes or common mutations (point mutations, deletions, insertions etc.). Frequently the two types of mutations cause indistinguishable phenotypes (locus heterogeneity). This article focuses on SCAs caused by common mutations. It describes phenotype and genotype of the presently 27 types known and discusses the molecular pathogenesis in those 21 types where the disease gene has been identified. Apart from the dominant types, the article also summarizes findings in a variant caused by mutations in a mitochondrial gene. Possible common disease mechanisms are considered based on findings in the various SCAs described.
Topics: Humans; Genes, Mitochondrial; Genotype; Mutation; Phenotype; Spinocerebellar Ataxias
PubMed: 34401960
DOI: 10.1007/s10048-021-00662-5 -
Open Biology Mar 2019The mitochondrial genome is an evolutionarily persistent and cooperative component of metazoan cells that contributes to energy production and many other cellular... (Review)
Review
The mitochondrial genome is an evolutionarily persistent and cooperative component of metazoan cells that contributes to energy production and many other cellular processes. Despite sharing the same host as the nuclear genome, the multi-copy mitochondrial DNA (mtDNA) follows very different rules of replication and transmission, which translate into differences in the patterns of selection. On one hand, mtDNA is dependent on the host for its transmission, so selections would favour genomes that boost organismal fitness. On the other hand, genetic heterogeneity within an individual allows different mitochondrial genomes to compete for transmission. This intra-organismal competition could select for the best replicator, which does not necessarily give the fittest organisms, resulting in mito-nuclear conflict. In this review, we discuss the recent advances in our understanding of the mechanisms and opposing forces governing mtDNA transmission and selection in bilaterians, and what the implications of these are for mtDNA evolution and mitochondrial replacement therapy.
Topics: Animals; DNA, Mitochondrial; Evolution, Molecular; Genes, Mitochondrial; Genetic Fitness; Genome, Mitochondrial; Humans; Mitochondrial Diseases; Mutation; Selection, Genetic
PubMed: 30890027
DOI: 10.1098/rsob.180267 -
Genes & Development Aug 2009It is now clear that mitochondrial defects are associated with a plethora of clinical phenotypes in man and mouse. This is the result of the mitochondria's central role... (Review)
Review
It is now clear that mitochondrial defects are associated with a plethora of clinical phenotypes in man and mouse. This is the result of the mitochondria's central role in energy production, reactive oxygen species (ROS) biology, and apoptosis, and because the mitochondrial genome consists of roughly 1500 genes distributed across the maternal mitochondrial DNA (mtDNA) and the Mendelian nuclear DNA (nDNA). While numerous pathogenic mutations in both mtDNA and nDNA mitochondrial genes have been identified in the past 21 years, the causal role of mitochondrial dysfunction in the common metabolic and degenerative diseases, cancer, and aging is still debated. However, the development of mice harboring mitochondrial gene mutations is permitting demonstration of the direct cause-and-effect relationship between mitochondrial dysfunction and disease. Mutations in nDNA-encoded mitochondrial genes involved in energy metabolism, antioxidant defenses, apoptosis via the mitochondrial permeability transition pore (mtPTP), mitochondrial fusion, and mtDNA biogenesis have already demonstrated the phenotypic importance of mitochondrial defects. These studies are being expanded by the recent development of procedures for introducing mtDNA mutations into the mouse. These studies are providing direct proof that mtDNA mutations are sufficient by themselves to generate major clinical phenotypes. As more different mtDNA types and mtDNA gene mutations are introduced into various mouse nDNA backgrounds, the potential functional role of mtDNA variation in permitting humans and mammals to adapt to different environments and in determining their predisposition to a wide array of diseases should be definitively demonstrated.
Topics: Animals; Disease Models, Animal; Energy Metabolism; Genes, Mitochondrial; Humans; Mice; Mitochondria; Mitochondrial Diseases; Mutation; Oxidative Phosphorylation; Reactive Oxygen Species
PubMed: 19651984
DOI: 10.1101/gad.1784909 -
JCI Insight Sep 2021Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving more than 1000 nuclear-encoded proteins. Transcriptional networks...
Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving more than 1000 nuclear-encoded proteins. Transcriptional networks controlling the nuclear-encoded mitochondrial genes remain to be fully elucidated. Here, we show that histone demethylase LSD1 KO from adult mouse liver (LSD1-LKO) reduces the expression of one-third of all nuclear-encoded mitochondrial genes and decreases mitochondrial biogenesis and function. LSD1-modulated histone methylation epigenetically regulates nuclear-encoded mitochondrial genes. Furthermore, LSD1 regulates gene expression and protein methylation of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), which controls the final step of NAD+ synthesis and limits NAD+ availability in the nucleus. Lsd1 KO reduces NAD+-dependent SIRT1 and SIRT7 deacetylase activity, leading to hyperacetylation and hypofunctioning of GABPβ and PGC-1α, the major transcriptional factor/cofactor for nuclear-encoded mitochondrial genes. Despite the reduced mitochondrial function in the liver, LSD1-LKO mice are protected from diet-induced hepatic steatosis and glucose intolerance, partially due to induction of hepatokine FGF21. Thus, LSD1 orchestrates a core regulatory network involving epigenetic modifications and NAD+ synthesis to control mitochondrial function and hepatokine production.
Topics: Animals; Cells, Cultured; Epigenesis, Genetic; Fatty Liver; Fibroblast Growth Factors; Gene Expression Regulation; Genes, Mitochondrial; Histone Demethylases; Liver; Mice; RNA; Signal Transduction
PubMed: 34314389
DOI: 10.1172/jci.insight.147692