Distribution Of mtDNA Research Articles

Anti-neuroinflammation ameliorates systemic inflammation-induced mitochondrial DNA impairment in the nucleus of the solitary tract and cardiovascular reflex dysfunction

BackgroundDecreased heart rate variability (HRV) leads to cardiovascular diseases and increased mortality in clinical studies. However, the underlying mechanisms are still inconclusive. Systemic inflammation-induced neuroinflammation is known to impair the autonomic center of cardiovascular regulation. The dynamic stability of blood pressure and heart rate (HR) is regulated by modulation of the reciprocal responses of sympathetic and parasympathetic tone by the baroreflex, which is controlled by the nucleus of the solitary tract (NTS).MethodsSystemic inflammation was induced by E. coli lipopolysaccharide (LPS, 1.2 mg/kg/day, 7 days) peritoneal infusion via an osmotic minipump in normotensive Sprague-Dawley rats. Systolic blood pressure (SBP) and HR were measured by femoral artery cannulation and recorded on a polygraph under anesthesia. The low-frequency (LF; 0.25–0.8 Hz) and high-frequency (HF; 0.8–2.4 Hz) components of SBP were adopted as the indices for sympathetic vasomotor tone and parasympathetic vasomotor tone, while the baroreflex effectiveness index (BEI) was adopted from the analysis of SBP and pulse interval (PI). The plasma levels of proinflammatory cytokines and mitochondrial DNA (mtDNA) oxidative damage were analyzed by ELISA. Protein expression was evaluated by Western blot. The distribution of oxidative mtDNA was probed by immunofluorescence. Pharmacological agents were delivered via infusion into the cisterna magna with an osmotic minipump.ResultsThe suppression of baroreflex sensitivity was concurrent with increased SBP and decreased HR. Neuroinflammatory factors, including TNF-α, CD11b, and Iba-1, were detected in the NTS of the LPS group. Moreover, indices of mtDNA damage, including 8-OHdG and γ-H2AX, were significantly increased in neuronal mitochondria. Pentoxifylline or minocycline intracisternal (IC) infusion effectively prevented mtDNA damage, suggesting that cytokine and microglial activation contributed to mtDNA damage. Synchronically, baroreflex sensitivity was effectively protected, and the elevated blood pressure was significantly relieved. In addition, the mtDNA repair mechanism was significantly enhanced by pentoxifylline or minocycline.ConclusionThese results suggest that neuronal mtDNA damage in the NTS induced by neuroinflammation could be the core factor in deteriorating baroreflex desensitization and subsequent cardiovascular dysfunction. Therefore, the enhancement of base excision repair (BER) signaling in mitochondria could be a potential therapeutic strategy for cardiovascular reflex dysregulation.

Mitochondrial fusion is required for regulation of mitochondrial DNA replication.

Mitochondrial dynamics is an essential physiological process controlling mitochondrial content mixing and mobility to ensure proper function and localization of mitochondria at intracellular sites of high-energy demand. Intriguingly, for yet unknown reasons, severe impairment of mitochondrial fusion drastically affects mtDNA copy number. To decipher the link between mitochondrial dynamics and mtDNA maintenance, we studied mouse embryonic fibroblasts (MEFs) and mouse cardiomyocytes with disruption of mitochondrial fusion. Super-resolution microscopy revealed that loss of outer mitochondrial membrane (OMM) fusion, but not inner mitochondrial membrane (IMM) fusion, leads to nucleoid clustering. Remarkably, fluorescence in situ hybridization (FISH), bromouridine labeling in MEFs and assessment of mitochondrial transcription in tissue homogenates revealed that abolished OMM fusion does not affect transcription. Furthermore, the profound mtDNA depletion in mouse hearts lacking OMM fusion is not caused by defective integrity or increased mutagenesis of mtDNA, but instead we show that mitochondrial fusion is necessary to maintain the stoichiometry of the protein components of the mtDNA replisome. OMM fusion is necessary for proliferating MEFs to recover from mtDNA depletion and for the marked increase of mtDNA copy number during postnatal heart development. Our findings thus link OMM fusion to replication and distribution of mtDNA.

Mitochondrial DNA: Distribution, Mutations, and Elimination.

Mitochondrion harbors its own DNA (mtDNA), which encodes many critical proteins for the assembly and activity of mitochondrial respiratory complexes. mtDNA is packed by many proteins to form a nucleoid that uniformly distributes within the mitochondrial matrix, which is essential for mitochondrial functions. Defects or mutations of mtDNA result in a range of diseases. Damaged mtDNA could be eliminated by mitophagy, and all paternal mtDNA are degraded by endonuclease G or mitophagy during fertilization. In this review, we describe the role and mechanism of mtDNA distribution and elimination. In particular, we focus on the regulation of paternal mtDNA elimination in the process of fertilization.

Role of mitochondrial fusion in cardiac energy metabolism

Mitochondrial dynamics is an essential physiological process controlling mitochondrial content mixing and mobility to ensure proper function and localization of mitochondria at intracellular sites of high-energy demand. Intriguingly, for yet unknown reasons, severe impairment of mitochondrial fusion drastically affects mtDNA copy number. The goal of our work was to determine the importance of mitochondrial fusion on heart energy homeostasis. To decipher the link between mitochondrial dynamics and mtDNA maintenance and heart energy metabolism, we studied heart conditional knockout mouse and mouse embryonic fibroblasts (MEFs) with disruption of mitochondrial fusion. Super-resolution microscopy analyses revealed that loss of outer mitochondrial membrane (OMM) fusion, but not inner mitochondrial membrane (IMM) fusion, leads to clustering and loss of nucleoids. Remarkably, fluorescence in situ hybridization (FISH) in MEFs, bromouridine labeling of MEFs and assessment of mitochondrial transcription in tissue homogenates revealed that abolished OMM fusion does not affect transcription. The profound mtDNA depletion in hearts lacking OMM fusion is not caused by defective integrity or increased mutagenesis of mtDNA, but, instead, we show that mitochondrial fusion is necessary to maintain the stoichiometry of the protein components of the mtDNA replisome. OMM fusion is necessary for proliferating MEFs to recover from mtDNA depletion and for the marked increase of mtDNA copy number during postnatal heart development. Our findings thus link OMM fusion to replication and distribution of mtDNA.

The evolutionary history and global phylogeography of the green turtle (Chelonia mydas)

AbstractAimTo examine the genetic structure and global phylogeography of the endangered green sea turtle, Chelonia mydas, in light of past climatic events and current conservation needs.LocationTropical and subtropical beaches around the world.MethodsWe analysed 386 base pairs of the mitochondrial (mt)DNA control region of 4,878 individual nesting green turtle samples from 127 rookeries globally. We used phylogeographic analysis to assess how demographic history, dispersal and barriers to gene flow have led to the current distribution of mtDNA lineages.ResultsWe identified 11 divergent lineages that were tied to specific biogeographical regions. The phylogenetic analyses revealed an ancient origin for the species centred in the Indo‐Pacific and more recent colonization of the Central/Eastern Pacific as well as the Atlantic Basin. Overall the phylogeographic structure was strong but with a clear pattern of regional connectivity among rookeries. A Large genetic separation was found where there were obvious barriers to dispersal such as between the Atlantic and Pacific oceans and across the Pacific Ocean, as well as less obvious barriers to dispersal. Admixture of mtDNA haplotype lineages was detected at latitudinal extremes across the Indian Ocean and western Pacific Ocean resulting in these areas being nucleotide diversity hotspots. The highest regional genetic diversity and high endemic richness was observed in the SW Pacific, NW Pacific, SW Indian and NW Indian oceans.Main conclusionsPast climatic fluctuations greatly affected the distribution of genetic diversity in the highly migratory green turtle. Our data suggest that past climatic events influenced local populations in different ways and the species appears to have survived the last glaciations in multiple glacial refugia.

Matching Mitochondrial DNA Haplotypes for Circumventing Tissue-Specific Segregation Bias

SummaryMitochondrial DNA (mtDNA) segregation associated with donor-recipient mtDNA mismatch in mitochondria replacement therapy leads to unknown risks. Here, to explore whether matching mtDNA haplotypes contributes to ameliorating segregation, we reproduced various degrees of heteroplasmic mice with three single nucleotide polymorphisms to monitor segregation severity. “Segregation” presented in tissues of heteroplasmic mice containing low-level donor mtDNA heteroplasmy, and disappeared as donor mtDNA heteroplasmy levels ascended. Meanwhile, we found that distribution of donor mtDNA among the blastomeres of preimplantation embryos from the heteroplasmic mice shared the same tendency as that in adult tissues. Statistical analysis showed that no selective replication of donor mtDNA occurred during lifespan. Tracking donor mtDNA distribution showed that uneven distribution of donor mtDNA among embryonic blastomeres gradually became even as donor mtDNA heteroplasmy increased, indicating that the “segregation” in tissues was inherited from the uneven distribution. Our finding suggested that donor-recipient mtDNA matching could circumvent segregation in mitochondria replacement therapy.

Visualization of mitochondrial DNA in living cells with super-resolution microscopy using thiophene-based terpyridine Zn(ii) complexes.

We present a thiophene-based terpyridine Zn(ii) complex (namely LC) which could specifically target live cell mitochondria via binding with mitochondrial DNA (mtDNA). Due to its high biocompatibility, red emission and photo-stability, mtDNA distribution within mitochondrial cristae and inner matrix in living cells was successfully visualized using stimulated emission depletion (STED) nanoscopy with unprecedented resolution.

MtDNAmap: Geographic representation of mtDNA Haplogroups

Mitochondrial DNA is inherited maternally and is thought to be evolved stepwise from one population to another population in the history of mankind. Haplogroup for any mtDNA provides us a solution for the logical classification of the mitochondrial DNA based on established phylogenetic principles. There is a huge amount of scattered mtDNA sequence data from different global and regional populations. It demands a professional platform for representation of data to draw meaningful and simple-to-understand information about mtDNA distribution. Here, mtDNAmap provides geographical representation of mtDNA haplogroups’ frequencies in various populations all over the world according to their present day reported locations. It is a haplogroup frequency database of different populations calculated from the published data using their reported valid mtDNA sequences. Publicly available MtDNA sequences, processed through mtDNAprofiler for SNP determinations based on revised Cambridge Reference Sequence and followed by Haplogrep 2.0 for the determination of the haplogroups on the basis of most updated Phylotree version-17, are graphically represented on the dynamic map in the form of frequencies. mtDNAmap provides the open access to the whole or part of published high-quality curated data. The tool is not only useful for researchers from forensic and anthropology backgrounds but also in general public.

ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells.

Mitochondrial DNA (mtDNA) encodes RNAs and proteins critical for cell function. In human cells, hundreds to thousands of mtDNA copies are replicated asynchronously, packaged into protein-DNA nucleoids, and distributed within a dynamic mitochondrial network. The mechanisms that govern how nucleoids are chosen for replication and distribution are not understood. Mitochondrial distribution depends on division, which occurs at endoplasmic reticulum (ER)-mitochondria contact sites. These sites were spatially linked to a subset of nucleoids selectively marked by mtDNA polymerase and engaged in mtDNA synthesis--events that occurred upstream of mitochondrial constriction and division machine assembly. Our data suggest that ER tubules proximal to nucleoids are necessary but not sufficient for mtDNA synthesis. Thus, ER-mitochondria contacts coordinate licensing of mtDNA synthesis with division to distribute newly replicated nucleoids to daughter mitochondria.

How the ER manages mitochondrial division

Mitochondria It has been unclear how mitochondrial DNA (mtDNA) replication is spatially controlled in mammalian cells and how the mitochondrial nucleoid—the protein-DNA structure that is the unit of mtDNA inheritance—is distributed at the cellular level. Lewis et al. now show that homeostatic mtDNA synthesis in mitochondrial nucleoids in mammalian cells is spatially linked to a small subset of endoplasmic reticulum (ER)-mitochondria contact sites that are specifically destined for mitochondrial division. Successive events of mtDNA replication, mitochondrial division, and mitochondrial motility function together to ensure the accurate distribution of mtDNA in cells. Furthermore, ER-mitochondria contacts coordinate the licensing of mtDNA replication with division to distribute newly replicated nucleoids to daughter mitochondria. Science , this issue p. [261][1] [1]: /lookup/doi/10.1126/science.aaf5549

MtDNA Heteroplasmy in Monozygotic Twins Discordant for Schizophrenia

Although monozygotic (MZ) twins have theoretically identical nuclear DNA sequences, there may be phenotypic differences between them caused by somatic mutations and epigenetic changes affecting each genome. In this study, we collected eight families of MZ twins discordant for schizophrenia with the aim of investigating the potential role of mitochondrial DNA (mtDNA) heteroplasmy in causing the phenotypic differences between the twin pairs. Next-generation sequencing (NGS) technology was used to screen the whole mitochondrial genome of the twin pairs and their parents. The mtDNA heteroplasmy level was found to be nearly identical between the twin pairs but was distinctly different between each mother and their offspring. These results suggest that the discordance of schizophrenia between MZ twins may not be attributable to the difference in mtDNA heteroplasmy, and the high concordance of mtDNA heteroplasmy between MZ twins may indicate the relatively equal distribution of mtDNA during embryo separation of MZ twins and/or the modulation effect from the same nuclear genetic background. Furthermore, we observed an overrepresentation of heteroplasmy in noncoding regions and an elevated ratio of nonsynonymous heteroplasmy, suggesting the possible effects of a purifying selection in shaping the pattern of mtDNA heteroplasmy.

Geography has a greater effect than Wolbachia infection on population genetic structure in the spider mite, Tetranychus pueraricola.

Wolbachia is an intracellular symbiotic bacterium that infects various spider mite species and is associated with alterations in host reproduction, which indicates the potential role in mite evolution. However, studies of Wolbachia infections in the spider mite Tetranychus pueraricola, a major agricultural pest, are limited. Here, we used multilocus sequence typing to determine Wolbachia infection status and examined the relationship between Wolbachia infection status and mitochondrial diversity in T. pueraricola from 12 populations in China. The prevalence of Wolbachia ranged from 2.8 to 50%, and three strains (wTpue1, wTpue2, and wTpue3) were identified. We also found double infections (wTpue1 + wTpue3) within the same individuals. Furthermore, the wTpue1 strain caused weak cytoplasmic incompatibility (CI) (egg hatchability ~55%), whereas another widespread strain, wTpue3, did not induce CI. There was no reduction in mitochondrial DNA (mtDNA) or nuclear DNA diversity among infected individuals, and mtDNA haplotypes did not correspond to specific Wolbachia strains. Phylogenetic analysis and analysis of molecular variance revealed that the distribution of mtDNA and nuclear DNA haplotypes were significantly associated with geography. These findings indicate that Wolbachia infection in T. pueraricola is complex, but T. pueraricola genetic differentiation likely resulted from substantial geographic isolation.

Systematics of the Artiodactyla of China in the 21(st) century.

In this paper, I have introduced the concept of the Evolutionary Species, and shown how it affects the taxonomy of the Artiodactyla of China. The "traditional" taxonomy of the Artiodactyla, which has remained almost unchanged for 100 years, relies on ill-formulated notions of species and subspecies, only slightly modified by the population-thinking of the 1930s. Species are populations (or metapopulations) differentiated by the possession of fixed heritable differences from other such populations (or metapopulations). In the Artiodactyla, there are many more species than "traditionally" recognised; this is by no means a drawback, as it enables the units of biodiversity to be identified in a testable fashion, and brings the taxonomy of large mammals into line with that long practised for small mammals. Species are likely to differentiate where there are natural gaps in the distribution of a genus, such as mountain blocks (for example in the genus Budorcas) or otherwise dissected habitat (for example in the genus Cervus). Natural hybridisation between distinct species is not an uncommon phenomenon, again illustrated well in the genus Cervus, where hybridisation between the elaphus and nippon groups occurs today and evidently occurred in the past, as shown by the distribution of mtDNA.

Linking between genetic structure and geographical distance: Study of the maternal gene pool in the Ethiopian population

Background The correlation between genetics and geographical distance has already been examined through the study of the dispersion of human populations, especially in terms of uniparental genetic markers.Aim The present work characterises, at the level of the mitochondrial DNA (mtDNA), two new samples of Amhara and Oromo populations from Ethiopia to evaluate the possible pattern of distribution for mtDNA variation and to test the hypothesis of the Isolation-by-Distance (IBD) model among African, European and Middle-Eastern populations.Subjects and methods This study analysed 173 individuals belonging to two ethnic groups of Ethiopia, Amhara and Oromo, by assaying HVS-I and HVS-II of mtDNA D-loop and informative coding region SNPs of mtDNA.Results The analysis suggests a relationship between genetic and geographic distances, affirming that the mtDNA pool of Africa, Europe and the Middle East might be coherent with the IBD model. Moreover, the mtDNA gene pools of the Sub-Saharan African and Mediterranean populations were very different.Conclusion In this study the pattern of mtDNA distribution, beginning with the Ethiopian plateau, was tested in the IBD model. It could be affirmed that, on a continent scale, the mtDNA pool of Africa, Europe and the Middle East might fall under the IBD model.

Interaction of human mitochondrial transcription factor A in mitochondria: its involvement in the dynamics of mitochondrial DNA nucleoids.

Mitochondrial transcription factor A (TFAM) is a key regulator of mitochondrial DNA (mtDNA). TFAM interacts with itself and forms dimers; however, the precise interaction domain in vivo has not yet been determined. We herein showed that human TFAM formed oligomers in mitochondria by in situ chemical cross-linking. We used the separated fluorescent protein, monomeric Kusabira-Green, as a reporter to monitor their self-association in mitochondria. This reporter successfully detected the TFAM-TFAM interaction in cells as fluorescent signals on mitochondria. We also found that the N-terminal high-mobility group box domain was sufficient for this interaction. The expression of the dimer-defective mutant induced enlarged mtDNA nucleoids, suggesting the importance of dimerization in the distribution of mtDNA. The reporter system also supported the association and mixture between independent nucleoids through TFAM by a cell fusion assay using hemagglutinating virus of Japan. We here, for the first time, visualized the interaction of TFAM molecules in mitochondria and proposed its implications for the dynamics of mtDNA nucleoids.

Distribution of paternally inherited foreign mtDNA in early mouse embryos

Transmission of foreign mtDNA of paternal origin to the offspring of F0 males, as well as its distribution in early embryos, was studied in a mouse model. It was shown that F0 male mice obtained by microinjection of human mitochondria into a mouse zygote can transmit foreign mtDNA to their progeny. Apparently, transmission of foreign mtDNA depended considerably on individual characteristics of the males. The distribution of paternally inherited foreign mtDNA among blastomeres was different from the distribution of foreign mtDNA of maternal origin.

Less Pollen-Mediated Gene Flow for More Signatures of Glacial Lineages: Congruent Evidence from Balsam Fir cpDNA and mtDNA for Multiple Refugia in Eastern and Central North America

The phylogeographic structure and postglacial history of balsam fir (Abies balsamea), a transcontinental North American boreal conifer, was inferred using mitochondrial DNA (mtDNA) and chloroplast DNA (cpDNA) markers. Genetic structure among 107 populations (mtDNA data) and 75 populations (cpDNA data) was analyzed using Bayesian and genetic distance approaches. Population differentiation was high for mtDNA (dispersed by seeds only), but also for cpDNA (dispersed by seeds and pollen), indicating that pollen gene flow is more restricted in balsam fir than in other boreal conifers. Low cpDNA gene flow in balsam fir may relate to low pollen production due to the inherent biology of the species and populations being decimated by recurrent spruce budworm epidemics, and/or to low dispersal of pollen grains due to their peculiar structural properties. Accordingly, a phylogeographic structure was detected using both mtDNA and cpDNA markers and population structure analyses supported the existence of at least five genetically distinct glacial lineages in central and eastern North America. Four of these would originate from glacial refugia located south of the Laurentide ice sheet, while the last one would have persisted in the northern Labrador region. As expected due to reduced pollen-mediated gene flow, congruence between the geographic distribution of mtDNA and cpDNA lineages was higher than in other North American conifers. However, concordance was not complete, reflecting that restricted but nonetheless detectable cpDNA gene flow among glacial lineages occurred during the Holocene. As a result, new cpDNA and mtDNA genome combinations indicative of cytoplasmic genome capture were observed.

Integrity of the yeast mitochondrial genome, but not its distribution and inheritance, relies on mitochondrial fission and fusion

Mitochondrial DNA (mtDNA) is essential for mitochondrial and cellular function. In Saccharomyces cerevisiae, mtDNA is organized in nucleoprotein structures termed nucleoids, which are distributed throughout the mitochondrial network and are faithfully inherited during the cell cycle. How the cell distributes and inherits mtDNA is incompletely understood although an involvement of mitochondrial fission and fusion has been suggested. We developed a LacO-LacI system to noninvasively image mtDNA dynamics in living cells. Using this system, we found that nucleoids are nonrandomly spaced within the mitochondrial network and observed the spatiotemporal events involved in mtDNA inheritance. Surprisingly, cells deficient in mitochondrial fusion and fission distributed and inherited mtDNA normally, pointing to alternative pathways involved in these processes. We identified such a mechanism, where we observed fission-independent, but F-actin-dependent, tip generation that was linked to the positioning of mtDNA to the newly generated tip. Although mitochondrial fusion and fission were dispensable for mtDNA distribution and inheritance, we show through a combination of genetics and next-generation sequencing that their absence leads to an accumulation of mitochondrial genomes harboring deleterious structural variations that cluster at the origins of mtDNA replication, thus revealing crucial roles for mitochondrial fusion and fission in maintaining the integrity of the mitochondrial genome.

Mathematical Modeling of the Role of Mitochondrial Fusion and Fission in Mitochondrial DNA Maintenance

Accumulation of mitochondrial DNA (mtDNA) mutations has been implicated in a wide range of human pathologies, including neurodegenerative diseases, sarcopenia, and the aging process itself. In cells, mtDNA molecules are constantly turned over (i.e. replicated and degraded) and are also exchanged among mitochondria during the fusion and fission of these organelles. While the expansion of a mutant mtDNA population is believed to occur by random segregation of these molecules during turnover, the role of mitochondrial fusion-fission in this context is currently not well understood. In this study, an in silico modeling approach is taken to investigate the effects of mitochondrial fusion and fission dynamics on mutant mtDNA accumulation. Here we report model simulations suggesting that when mitochondrial fusion-fission rate is low, the slow mtDNA mixing can lead to an uneven distribution of mutant mtDNA among mitochondria in between two mitochondrial autophagic events leading to more stochasticity in the outcomes from a single random autophagic event. Consequently, slower mitochondrial fusion-fission results in higher variability in the mtDNA mutation burden among cells in a tissue over time, and mtDNA mutations have a higher propensity to clonally expand due to the increased stochasticity. When these mutations affect cellular energetics, nuclear retrograde signalling can upregulate mtDNA replication, which is expected to slow clonal expansion of these mutant mtDNA. However, our simulations suggest that the protective ability of retrograde signalling depends on the efficiency of fusion-fission process. Our results thus shed light on the interplay between mitochondrial fusion-fission and mtDNA turnover and may explain the mechanism underlying the experimentally observed increase in the accumulation of mtDNA mutations when either mitochondrial fusion or fission is inhibited.

Origins of the Iberomaurusian in NW Africa: New AMS radiocarbon dating of the Middle and Later Stone Age deposits at Taforalt Cave, Morocco

Recent genetic studies based on the distribution of mtDNA of haplogroup U6 have led to subtly different theories regarding the arrival of modern human populations in North Africa. One proposes that groups of the proto-U6 lineage spread from the Near East to North Africa around 40–45 ka (thousands of years ago), followed by some degree of regional continuity. Another envisages a westward human migration from the Near East, followed by further demographic expansion at ∼22 ka centred on the Maghreb and associated with a microlithic bladelet culture known as the Iberomaurusian. In evaluating these theories, we report on the results of new work on the Middle (MSA) and Later Stone (LSA) Age deposits at Taforalt Cave in Morocco. We present 54 AMS radiocarbon dates on bone and charcoals from a sequence of late MSA and LSA occupation levels of the cave. Using Bayesian modelling we show that an MSA non-Levallois flake industry was present until ∼24.5 ka Cal BP (calibrated years before present), followed by a gap in occupation and the subsequent appearance of an LSA Iberomaurusian industry from at least 21,160 Cal BP. The new dating offers fresh light on theories of continuity versus replacement of populations as presented by the genetic evidence. We examine the implications of these data for interpreting the first appearance of the LSA in the Maghreb and providing comparisons with other dated early blade and bladelet industries in North Africa.