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International Journal of Molecular... Aug 2020Mitochondria are energy-producing intracellular organelles containing their own genetic material in the form of mitochondrial DNA (mtDNA), which codes for proteins and... (Review)
Review
Mitochondria are energy-producing intracellular organelles containing their own genetic material in the form of mitochondrial DNA (mtDNA), which codes for proteins and RNAs essential for mitochondrial function. Some mtDNA mutations can cause mitochondria-related diseases. Mitochondrial diseases are a heterogeneous group of inherited disorders with no cure, in which mutated mtDNA is passed from mothers to offspring via maternal egg cytoplasm. Mitochondrial replacement (MR) is a genome transfer technology in which mtDNA carrying disease-related mutations is replaced by presumably disease-free mtDNA. This therapy aims at preventing the transmission of known disease-causing mitochondria to the next generation. Here, a proof of concept for the specific removal or editing of mtDNA disease-related mutations by genome editing is introduced. Although the amount of mtDNA carryover introduced into human oocytes during nuclear transfer is low, the safety of mtDNA heteroplasmy remains a concern. This is particularly true regarding donor-recipient mtDNA mismatch (mtDNA-mtDNA), mtDNA-nuclear DNA (nDNA) mismatch caused by mixing recipient nDNA with donor mtDNA, and mtDNA replicative segregation. These conditions can lead to mtDNA genetic drift and reversion to the original genotype. In this review, we address the current state of knowledge regarding nuclear transplantation for preventing the inheritance of mitochondrial diseases.
Topics: Gene Editing; Genes, Mitochondrial; Genetic Drift; Humans; Mitochondrial Replacement Therapy; Nuclear Transfer Techniques; Oocytes
PubMed: 32824295
DOI: 10.3390/ijms21165880 -
Molecular Biology and Evolution Nov 2023Genetic elements encoded in nuclear DNA determine the sex of an individual in many animals. In certain bivalve lineages that possess doubly uniparental inheritance...
Genetic elements encoded in nuclear DNA determine the sex of an individual in many animals. In certain bivalve lineages that possess doubly uniparental inheritance (DUI), mitochondrial DNA (mtDNA) has been hypothesized to contribute to sex determination. In these cases, females transmit a female mtDNA to all offspring, while male mtDNA (M mtDNA) is transmitted only from fathers to sons. Because M mtDNA is inherited in the same way as Y chromosomes, it has been hypothesized that mtDNA may be responsible for sex determination. However, the role of mitochondrial and nuclear genes in sex determination has yet to be validated in DUI bivalves. In this study, we used DNA, RNA, and mitochondrial short noncoding RNA (sncRNA) sequencing to explore the role of mitochondrial and nuclear elements in the sexual development pathway of the freshwater mussel Potamilus streckersoni (Bivalvia: Unionida). We found that the M mtDNA sheds a sncRNA partially within a male-specific mitochondrial gene that targets a pathway hypothesized to be involved in female development and mitophagy. RNA-seq confirmed the gene target was significantly upregulated in females, supporting a direct role of mitochondrial sncRNAs in gene silencing. These findings support the hypothesis that M mtDNA inhibits female development. Genome-wide patterns of genetic differentiation and heterozygosity did not support a nuclear sex-determining region, although we cannot reject that nuclear factors are involved with sex determination. Our results provide further evidence that mitochondrial loci contribute to diverse, nonrespiratory functions and additional insights into an unorthodox sex-determining system.
Topics: Female; Animals; Bivalvia; DNA, Mitochondrial; Mitochondria; Genes, Mitochondrial; RNA, Small Untranslated
PubMed: 37935058
DOI: 10.1093/molbev/msad240 -
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 -
Comptes Rendus Biologies 2016Genomes and genes continuously evolve. Gene sequences undergo substitutions, deletions or nucleotide insertions; mobile genetic elements invade genomes and interleave in... (Review)
Review
Genomes and genes continuously evolve. Gene sequences undergo substitutions, deletions or nucleotide insertions; mobile genetic elements invade genomes and interleave in genes; chromosomes break, even within genes, and pieces reseal in reshuffled order. To maintain functional gene products and assure an organism's survival, two principal strategies are used - either repair of the gene itself or of its product. I will introduce common types of gene aberrations and how gene function is restored secondarily, and then focus on systematically fragmented genes found in a poorly studied protist group, the diplonemids. Expression of their broken genes involves restitching of pieces at the RNA-level, and substantial RNA editing, to compensate for point mutations. I will conclude with thoughts on how such a grotesquely unorthodox system may have evolved, and why this group of organisms persists and thrives since tens of millions of years.
Topics: Animals; Biological Evolution; DNA Fragmentation; Genes, Mitochondrial; Genetics; Humans; RNA; RNA Editing; Targeted Gene Repair
PubMed: 27180109
DOI: 10.1016/j.crvi.2016.04.004 -
Molecular Biology and Evolution Nov 2022Mitochondrial (mt) and nuclear-encoded proteins are integrated in aerobic respiration, requiring co-functionality among gene products from fundamentally different...
Mitochondrial (mt) and nuclear-encoded proteins are integrated in aerobic respiration, requiring co-functionality among gene products from fundamentally different genomes. Different evolutionary rates, inheritance mechanisms, and selection pressures set the stage for incompatibilities between interacting products of the two genomes. The mitonuclear coevolution hypothesis posits that incompatibilities may be avoided if evolution in one genome selects for complementary changes in interacting genes encoded by the other genome. Nuclear compensation, in which deleterious mtDNA changes are offset by compensatory nuclear changes, is often invoked as the primary mechanism for mitonuclear coevolution. Yet, direct evidence supporting nuclear compensation is rare. Here, we used data from 58 mammalian species representing eight orders to show strong correlations between evolutionary rates of mt and nuclear-encoded mt-targeted (N-mt) proteins, but not between mt and non-mt-targeted nuclear proteins, providing strong support for mitonuclear coevolution across mammals. N-mt genes with direct mt interactions also showed the strongest correlations. Although most N-mt genes had elevated dN/dS ratios compared to mt genes (as predicted under nuclear compensation), N-mt sites in close contact with mt proteins were not overrepresented for signs of positive selection compared to noncontact N-mt sites (contrary to predictions of nuclear compensation). Furthermore, temporal patterns of N-mt and mt amino acid substitutions did not support predictions of nuclear compensation, even in positively selected, functionally important residues with direct mitonuclear contacts. Overall, our results strongly support mitonuclear coevolution across ∼170 million years of mammalian evolution but fail to support nuclear compensation as the major mode of mitonuclear coevolution.
Topics: Animals; DNA, Mitochondrial; Genes, Mitochondrial; Mammals; Cell Nucleus; Mitochondrial Proteins; Genomics
PubMed: 36288802
DOI: 10.1093/molbev/msac233 -
Neurobiology of Aging May 2017Although mitochondrial dysfunction is a consistent feature of Alzheimer's disease in the brain and blood, the molecular mechanisms behind these phenomena are unknown....
Although mitochondrial dysfunction is a consistent feature of Alzheimer's disease in the brain and blood, the molecular mechanisms behind these phenomena are unknown. Here we have replicated our previous findings demonstrating reduced expression of nuclear-encoded oxidative phosphorylation (OXPHOS) subunits and subunits required for the translation of mitochondrial-encoded OXPHOS genes in blood from people with Alzheimer's disease and mild cognitive impairment. Interestingly this was accompanied by increased expression of some mitochondrial-encoded OXPHOS genes, namely those residing closest to the transcription start site of the polycistronic heavy chain mitochondrial transcript (MT-ND1, MT-ND2, MT-ATP6, MT-CO1, MT-CO2, MT-C03) and MT-ND6 transcribed from the light chain. Further we show that mitochondrial DNA copy number was unchanged suggesting no change in steady-state numbers of mitochondria. We suggest that an imbalance in nuclear and mitochondrial genome-encoded OXPHOS transcripts may drive a negative feedback loop reducing mitochondrial translation and compromising OXPHOS efficiency, which is likely to generate damaging reactive oxygen species.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Cognitive Dysfunction; Female; Gene Expression; Genes, Mitochondrial; Humans; Male; Mitochondria; Oxidative Phosphorylation; Reactive Oxygen Species; Transcription, Genetic
PubMed: 28208064
DOI: 10.1016/j.neurobiolaging.2016.12.029 -
Scientific Reports Jun 2022Mito-nuclear phylogenetic discordance in Bivalvia is well known. In particular, the monophyly of Amarsipobranchia (Heterodonta + Pteriomorphia), retrieved from...
Mito-nuclear phylogenetic discordance in Bivalvia is well known. In particular, the monophyly of Amarsipobranchia (Heterodonta + Pteriomorphia), retrieved from mitochondrial markers, contrasts with the monophyly of Heteroconchia (Heterodonta + Palaeoheterodonta), retrieved from nuclear markers. However, since oxidative phosphorylation nuclear markers support the Amarsipobranchia hypothesis instead of the Heteroconchia one, interacting subunits of the mitochondrial complexes ought to share the same phylogenetic signal notwithstanding the genomic source, which is different from the signal obtained from other nuclear markers. This may be a clue of coevolution between nuclear and mitochondrial genes. In this work we inferred the phylogenetic signal from mitochondrial and nuclear oxidative phosphorylation markers exploiting different phylogenetic approaches and added two more datasets for comparison: genes of the glycolytic pathway and genes related to the biogenesis of regulative small noncoding RNAs. All trees inferred from mitochondrial and nuclear subunits of the mitochondrial complexes support the monophyly of Amarsipobranchia, regardless of the phylogenetic pipeline. However, not every single marker agrees with this topology: this is clearly visible in nuclear subunits that do not directly interact with the mitochondrial counterparts. Overall, our data support the hypothesis of a coevolution between nuclear and mitochondrial genes for the oxidative phosphorylation. Moreover, we suggest a relationship between mitochondrial topology and different nucleotide composition between clades, which could be associated to the highly variable gene arrangement in Bivalvia.
Topics: Animals; Artifacts; Bivalvia; Caricaceae; DNA, Mitochondrial; Gene Order; Genes, Mitochondrial; Phylogeny
PubMed: 35773462
DOI: 10.1038/s41598-022-15076-y -
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 -
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 -
Ageing Research Reviews Jan 2017As regulators of bioenergetics in the cell and the primary source of endogenous reactive oxygen species (ROS), dysfunctional mitochondria have been implicated for... (Review)
Review
As regulators of bioenergetics in the cell and the primary source of endogenous reactive oxygen species (ROS), dysfunctional mitochondria have been implicated for decades in the process of aging and age-related diseases. Mitochondrial DNA (mtDNA) is replicated and repaired by nuclear-encoded mtDNA polymerase γ (Pol γ) and several other associated proteins, which compose the mtDNA replication machinery. Here, we review evidence that errors caused by this replication machinery and failure to repair these mtDNA errors results in mtDNA mutations. Clonal expansion of mtDNA mutations results in mitochondrial dysfunction, such as decreased electron transport chain (ETC) enzyme activity and impaired cellular respiration. We address the literature that mitochondrial dysfunction, in conjunction with altered mitochondrial dynamics, is a major driving force behind aging and age-related diseases. Additionally, interventions to improve mitochondrial function and attenuate the symptoms of aging are examined.
Topics: Aging; DNA Replication; DNA, Mitochondrial; Genes, Mitochondrial; Humans; Mitochondria; Mutagenesis; Mutation; Reactive Oxygen Species
PubMed: 27143693
DOI: 10.1016/j.arr.2016.04.006