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Molecular Phylogenetics and Evolution Oct 2022Molecularly, the family Caryophylliidae is polyphyletic and different sets of genetic data converge towards a consensus that a taxonomic review of this family is...
Molecularly, the family Caryophylliidae is polyphyletic and different sets of genetic data converge towards a consensus that a taxonomic review of this family is necessary. Overall, the order of genes in the mitochondrial genome (mitogenome) together with DNA sequences have been used to successfully untangle evolutionary relationships in several groups of organisms. Published mitogenomes of two caryophylliid genera (Desmophyllum and Solenosmilia) present a transposition of the gene block containing cob, nad2, and nad6, which is located between nad5 5' exon and trnW, while that of Polycyathus chaishanensis presents the same gene order as the majority of scleractinian corals. In molecular-based evolutionary reconstructions, caryophylliids that have the mitochondrial gene rearrangement were recovered as a monophyletic lineage ("true" caryophylliids), while members of the genus Polycyathus were placed in a different position. In this study, additional mitogenomes of this family were assembled and included in evolutionary reconstructions of Scleractinia in order to improve our understanding on whether the mitogenome gene rearrangement is limited to and, therefore, could be a synapomorphy of the actual members of Caryophylliidae. Specimens of Caryophyllia scobinosa, Premocyathus sp., Heterocyathus sulcatus, and Trochocyathus caryophylloides, as well as Desmophyllum pertusum and Solenosmilia variabilis from the Southwest Atlantic were sequenced using Illumina platforms. Then, mitochondrial genomes were assembled and annotated, and nuclear datasets were recovered in-silico from assembled contigs using a previously published set of baits. Evolutionary reconstructions were performed using mitochondrial and nuclear datasets and based on Maximum Likelihood and Bayesian Inference. Obtained mitogenomes are circular and range between 15,816 and 18,225 bp in size and from 30.76% to 36.63% in GC content. The gene rearrangement is only seen in C. scobinosa, D. pertusum, Premocyathus sp., and S. variabilis, which were recovered as a monophyletic clade in both mitochondrial and nuclear phylogenies. On the other hand, the "caryophylliids" with the canonical mitogenome gene order were not recovered within this clade. Differences in features of the skeleton of "true" caryophylliids in comparison to traditional members of the family were observed and offer further support that the gene rearrangement might be seen as a synapomorphy of family Caryophylliidae.
Topics: Animals; Anthozoa; Bayes Theorem; Gene Order; Genes, Mitochondrial; Genome, Mitochondrial; Phylogeny
PubMed: 35787457
DOI: 10.1016/j.ympev.2022.107565 -
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 -
Journal of Internal Medicine Jun 2020The first draft human mitochondrial DNA (mtDNA) sequence was published in 1981, paving the way for two decades of discovery linking mtDNA variation with human disease.... (Review)
Review
The first draft human mitochondrial DNA (mtDNA) sequence was published in 1981, paving the way for two decades of discovery linking mtDNA variation with human disease. Severe pathogenic mutations cause sporadic and inherited rare disorders that often involve the nervous system. However, some mutations cause mild organ-specific phenotypes that have a reduced clinical penetrance, and polymorphic variation of mtDNA is associated with an altered risk of developing several late-onset common human diseases including Parkinson's disease. mtDNA mutations also accumulate during human life and are enriched in affected organs in a number of age-related diseases. Thus, mtDNA contributes to a wide range of human pathologies. For many decades, it has generally been accepted that mtDNA is inherited exclusively down the maternal line in humans. Although recent evidence has challenged this dogma, whole-genome sequencing has identified nuclear-encoded mitochondrial sequences (NUMTs) that can give the false impression of paternally inherited mtDNA. This provides a more likely explanation for recent reports of 'bi-parental inheritance', where the paternal alleles are actually transmitted through the nuclear genome. The presence of both mutated and wild-type variant alleles within the same individual (heteroplasmy) and rapid shifts in allele frequency can lead to offspring with variable severity of disease. In addition, there is emerging evidence that selection can act for and against specific mtDNA variants within the developing germ line, and possibly within developing tissues. Thus, understanding how mtDNA is inherited has far-reaching implications across medicine. There is emerging evidence that this highly dynamic system is amenable to therapeutic manipulation, raising the possibility that we can harness new understanding to prevent and treat rare and common human diseases where mtDNA mutations play a key role.
Topics: DNA, Mitochondrial; Genome, Mitochondrial; Humans; Mitochondrial Diseases; Mutation; Rare Diseases
PubMed: 32187761
DOI: 10.1111/joim.13047 -
Genes & Diseases Dec 2020Allotopic expression of mitochondrial genes is a deliberate functional relocation of mitochondrial genes into the nucleus followed by import of the gene-encoded... (Review)
Review
Allotopic expression of mitochondrial genes is a deliberate functional relocation of mitochondrial genes into the nucleus followed by import of the gene-encoded polypeptide from the cytoplasm into the mitochondria. For successful allotopic expression of a mitochondrial gene, several key aspects must be considered. These include the different codon dictionary used by the mitochondrial and nuclear genomes, different codon preferences between mitochondrial and nuclear-cytosolic translation systems, and the provision of an import signal to ensure that the newly translated protein in the cytosol is successfully imported into mitochondria. The allotopic expression strategy was first developed in yeast, a useful model organism for studying human and other eukaryotic cells. Currently, a number of mitochondrial genes have been successfully recoded and nuclearly expressed in yeast and human cells. In addition to its use in evolutionary and molecular biology studies, the allotopic expression strategy has been developed as a potential approach to treat mitochondrial genetic disorders. Substantial progress has been recently achieved, and the development of this technique for therapy of the mitochondrial disease Leber's hereditary optic neuropathy (LHON) has entered phase III clinical trials. However, a number of challenges remain to be overcome to accelerate the successful application of this technique. These include improvement of nuclear gene expression, import into mitochondria, processing, and functional integration of the allotopically expressed polypeptides into mitochondrial protein complexes. This review discusses the current basic strategy, progress, challenges, and prospects of the allotopic expression strategy for mitochondrial genes.
PubMed: 33335957
DOI: 10.1016/j.gendis.2019.08.001 -
Pharmacological Research Dec 2023Sorafenib, a multi-targeted tyrosine kinase inhibitor, is a first-line treatment for advanced solid tumors, but it induces many adverse cardiovascular events, including...
Sorafenib, a multi-targeted tyrosine kinase inhibitor, is a first-line treatment for advanced solid tumors, but it induces many adverse cardiovascular events, including myocardial infarction and heart failure. These cardiac defects can be mediated by alternative splicing of genes critical for heart function. Whether alternative splicing plays a role in sorafenib-induced cardiotoxicity remains unclear. Transcriptome of rat hearts or human cardiomyocytes treated with sorafenib was analyzed and validated to define alternatively spliced genes and their impact on cardiotoxicity. In rats, sorafenib caused severe cardiotoxicity with decreased left ventricular systolic pressure, elongated sarcomere, enlarged mitochondria and decreased ATP. This was associated with alternative splicing of hundreds of genes in the hearts, many of which were targets of a cardiac specific splicing factor, RBM20. Sorafenib inhibited RBM20 expression in both rat hearts and human cardiomyocytes. The splicing of RBM20's targets, SLC25A3 and FHOD3, was altered into fetal isoforms with decreased function. Upregulation of RBM20 during sorafenib treatment reversed the pathogenic splicing of SLC25A3 and FHOD3, and enhanced the phosphate transport into mitochondria by SLC25A3, ATP synthesis and cell survival.We envision this regulation may happen in many drug-induced cardiotoxicity, and represent a potential druggable pathway for mitigating sorafenib-induced cardiotoxicity.
Topics: Rats; Animals; Humans; Alternative Splicing; Sorafenib; Cardiotoxicity; Sarcomeres; Genes, Mitochondrial; RNA-Binding Proteins; Myocytes, Cardiac; Adenosine Triphosphate; Formins
PubMed: 38006979
DOI: 10.1016/j.phrs.2023.107017 -
Philosophical Transactions of the Royal... Jan 2020Finding causal links between genotype and phenotype is a major issue in biology, even more in mitochondrial biology. First of all, mitochondria form complex networks,...
Finding causal links between genotype and phenotype is a major issue in biology, even more in mitochondrial biology. First of all, mitochondria form complex networks, undergoing fission and fusion and we do not know how such dynamics influence the distribution of mtDNA variants across the mitochondrial network and how they affect the phenotype. Second, the non-Mendelian inheritance of mitochondrial genes can have sex-specific effects and the mechanism of mitochondrial inheritance is still poorly understood, so it is not clear how selection and/or drift act on mtDNA genetic variation in each generation. Third, we still do not know how mtDNA expression is regulated; there is growing evidence for a convoluted mechanism that includes RNA editing, mRNA stability/turnover, post-transcriptional and post-translational modifications. Fourth, mitochondrial activity differs across species as a result of several interacting processes such as drift, adaptation, genotype-by-environment interactions, mitonuclear coevolution and epistasis. This issue will cover several aspects of mitochondrial biology along the path from genotype to phenotype, and it is subdivided into four sections focusing on mitochondrial genetic variation, on the relationship among mitochondria, germ line and sex, on the role of mitochondria in adaptation and phenotypic plasticity, and on some future perspectives in mitochondrial research. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.
Topics: Genome, Mitochondrial; Genotype; Mitochondria; Phenotype
PubMed: 31787041
DOI: 10.1098/rstb.2019.0169 -
The New Phytologist Aug 2022Incongruent phylogenies have been widely observed between nuclear and plastid or mitochondrial genomes in terrestrial plants and animals. However, few studies have...
Incongruent phylogenies have been widely observed between nuclear and plastid or mitochondrial genomes in terrestrial plants and animals. However, few studies have examined these patterns in microalgae or the discordance between the two organelles. Here we investigated the nuclear-mitochondrial-plastid phylogenomic incongruence in Emiliania-Gephyrocapsa, a group of cosmopolitan calcifying phytoplankton with enormous populations and recent speciations. We assembled mitochondrial and plastid genomes of 27 strains from across global oceans and temperature regimes, and analyzed the phylogenomic histories of the three compartments using concatenation and coalescence methods. Six major clades with varying morphology and distribution are well recognized in the nuclear phylogeny, but such relationships are absent in the mitochondrial and plastid phylogenies, which also differ substantially from each other. The rampant phylogenomic discordance is due to a combination of organellar capture (introgression), organellar genome recombination, and incomplete lineage sorting of ancient polymorphic organellar genomes. Hybridization can lead to replacements of whole organellar genomes without introgression of nuclear genes and the two organelles are not inherited as a single cytoplasmic unit. This study illustrates the convoluted evolution and inheritance of organellar genomes in isogamous haplodiplontic microalgae and provides a window into the phylogenomic complexity of marine unicellular eukaryotes.
Topics: Animals; Genome, Mitochondrial; Genome, Plastid; Microalgae; Phylogeny; Plastids
PubMed: 35556250
DOI: 10.1111/nph.18219 -
PloS One 2022Transfer RNAs (tRNAs) are intermediate-sized non-coding RNAs found in all organisms that help translate messenger RNA into protein. Recently, the number of sequenced...
Transfer RNAs (tRNAs) are intermediate-sized non-coding RNAs found in all organisms that help translate messenger RNA into protein. Recently, the number of sequenced plant genomes has increased dramatically. The availability of this extensive data greatly accelerates the study of tRNAs on a large scale. Here, 8,768,261 scaffolds/chromosomes containing 229,093 giga-base pairs representing whole-genome sequences of 256 plant species were analyzed to identify tRNA genes. As a result, 331,242 nuclear, 3,216 chloroplast, and 1,467 mitochondrial tRNA genes were identified. The nuclear tRNA genes include 275,134 tRNAs decoding 20 standard amino acids, 1,325 suppressor tRNAs, 6,273 tRNAs with unknown isotypes, 48,475 predicted pseudogenes, and 37,873 tRNAs with introns. Efforts also extended to the creation of PltRNAdb (https://bioinformatics.um6p.ma/PltRNAdb/index.php), a data source for tRNA genes from 256 plant species. PltRNAdb website allows researchers to search, browse, visualize, BLAST, and download predicted tRNA genes. PltRNAdb will help improve our understanding of plant tRNAs and open the door to discovering the unknown regulatory roles of tRNAs in plant genomes.
Topics: Databases, Nucleic Acid; Genes, Mitochondrial; Genome, Plant; Plants; RNA; RNA, Plant; RNA, Transfer
PubMed: 35605006
DOI: 10.1371/journal.pone.0268904 -
Journal of Translational Medicine Feb 2023Mitochondria represent a major source of reactive oxygen species (ROS) in cells, and the direct increase in ROS content is the primary cause of oxidative stress, which...
BACKGROUND
Mitochondria represent a major source of reactive oxygen species (ROS) in cells, and the direct increase in ROS content is the primary cause of oxidative stress, which plays an important role in tumor proliferation, invasion, angiogenesis, and treatment. However, the relationship between mitochondrial oxidative stress-related genes and glioblastoma (GBM) remains unclear. This study aimed to investigate the value of mitochondria and oxidative stress-related genes in the prognosis and therapeutic targets of GBM.
METHODS
We retrieved mitochondria and oxidative stress-related genes from several public databases. The LASSO regression and Cox analyses were utilized to build a risk model and the ROC curve was used to assess its performance. Then, we analyzed the correlation between the model and immunity and mutation. Furthermore, CCK8 and EdU assays were utilized to verify the proliferative capacity of GBM cells and flow cytometry was used to analyze apoptosis rates. Finally, the JC-1 assay and ATP levels were utilized to detect mitochondrial function, and the intracellular ROS levels were determined using MitoSOX and BODIPY 581/591 C11.
RESULTS
5 mitochondrial oxidative stress-related genes (CTSL, TXNRD2, NUDT1, STOX1, CYP2E1) were screened by differential expression analysis and Cox analysis and incorporated in a risk model which yielded a strong prediction accuracy (AUC value = 0.967). Furthermore, this model was strongly related to immune cell infiltration and mutation status and could identify potential targeted therapeutic drugs for GBM. Finally, we selected NUDT1 for further validation in vitro. The results showed that NUDT1 was elevated in GBM, and knockdown of NUDT1 inhibited the proliferation and induced apoptosis of GBM cells, while knockdown of NUDT1 damaged mitochondrial homeostasis and induced oxidative stress in GBM cells.
CONCLUSION
Our study was the first to propose a prognostic model of mitochondria and oxidative stress-related genes, which provided potential therapeutic strategies for GBM patients.
Topics: Humans; Glioblastoma; Oxidative Stress; Prognosis; Reactive Oxygen Species; Genes, Mitochondrial
PubMed: 36814293
DOI: 10.1186/s12967-023-03970-6 -
Frontiers in Aging 2024The Mother's Curse hypothesis posits that mothers curse their sons with harmful mitochondria, because maternal mitochondrial inheritance makes selection blind to... (Review)
Review
The Mother's Curse hypothesis posits that mothers curse their sons with harmful mitochondria, because maternal mitochondrial inheritance makes selection blind to mitochondrial mutations that harm only males. As a result, mitochondrial function may be evolutionarily optimized for females. This is an attractive explanation for ubiquitous sex differences in lifespan and aging, given the prevalence of maternal mitochondrial inheritance and the established relationship between mitochondria and aging. This review outlines patterns expected under the hypothesis, and traits most likely to be affected, chiefly those that are sexually dimorphic and energy intensive. A survey of the literature shows that evidence for Mother's Curse is limited to a few taxonomic groups, with the strongest support coming from experimental crosses in . Much of the evidence comes from studies of fertility, which is expected to be particularly vulnerable to male-harming mitochondrial mutations, but studies of lifespan and aging also show evidence of Mother's Curse effects. Despite some very compelling studies supporting the hypothesis, the evidence is quite patchy overall, with contradictory results even found for the same traits in the same taxa. Reasons for this scarcity of evidence are discussed, including nuclear compensation, factors opposing male-specific mutation load, effects of interspecific hybridization, context dependency and demographic effects. Mother's Curse effects may indeed contribute to sex differences, but the complexity of other contributing factors make Mother's Curse a poor general predictor of sex-specific lifespan and aging.
PubMed: 38523670
DOI: 10.3389/fragi.2024.1361396