Articoli di riviste: "MtDNA segregation"

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Takeda, Kumiko, Seiya Takahashi, Akira Onishi, Hirofumi Hanada e Hiroshi Imai. "Replicative Advantage and Tissue-Specific Segregation of RR Mitochondrial DNA Between C57BL/6 and RR Heteroplasmic Mice". Genetics 155, n. 2 (1 giugno 2000): 777–83. http://dx.doi.org/10.1093/genetics/155.2.777.

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Abstract To investigate the interactions between mtDNA and nuclear genomes, we produced heteroplasmic maternal lineages by transferring the cytoplasts between the embryos of two mouse strains, C57BL/6 (B6) and RR. A total of 43 different nucleotides exist in the displacement-loop (D-loop) region of mtDNA between B6 and RR. Heteroplasmic embryos were reconstructed by electrofusion using a blastomere from a two-cell stage embryo of one strain and an enucleated blastomere from a two-cell stage embryo of the other strain. Equivalent volumes of both types of mtDNAs were detected in blastocyst stage embryos. However, the mtDNA from the RR strain became biased in the progeny, regardless of the source of the nuclear genome. The RR mtDNA population was very high in most of the tissues examined but was relatively low in the brain and the heart. An age-related increase of RR mtDNA was also observed in the blood. The RR mtDNAs in the reconstructed embryos and in the embryos collected from heteroplasmic mice showed a different segregation pattern during early embryonic development. These results suggest that the RR mtDNA has a replicative advantage over B6 mtDNA during embryonic development and differentiation, regardless of the type of nuclear genome.

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Lechuga-Vieco, Ana Victoria, Ana Latorre-Pellicer, Iain G. Johnston, Gennaro Prota, Uzi Gileadi, Raquel Justo-Méndez, Rebeca Acín-Pérez et al. "Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics". Science Advances 6, n. 31 (luglio 2020): eaba5345. http://dx.doi.org/10.1126/sciadv.aba5345.

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Heteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development. Engineered heteroplasmic mice with nonpathological mtDNA variants reveal a nonrandom tissue-specific mtDNA segregation pattern, with few tissues that do not show segregation. The driving force for this dynamic complex pattern has remained unexplained for decades, challenging our understanding of this fundamental biological problem and hindering clinical planning for inherited diseases. Here, we demonstrate that the nonrandom mtDNA segregation is an intracellular process based on organelle selection. This cell type–specific decision arises jointly from the impact of mtDNA haplotypes on the oxidative phosphorylation (OXPHOS) system and the cell metabolic requirements and is strongly sensitive to the nuclear context and to environmental cues.

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Røyrvik, Ellen C., e Iain G. Johnston. "MtDNA sequence features associated with ‘selfish genomes’ predict tissue-specific segregation and reversion". Nucleic Acids Research 48, n. 15 (27 luglio 2020): 8290–301. http://dx.doi.org/10.1093/nar/gkaa622.

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Abstract Mitochondrial DNA (mtDNA) encodes cellular machinery vital for cell and organism survival. Mutations, genetic manipulation, and gene therapies may produce cells where different types of mtDNA coexist in admixed populations. In these admixtures, one mtDNA type is often observed to proliferate over another, with different types dominating in different tissues. This ‘segregation bias’ is a long-standing biological mystery that may pose challenges to modern mtDNA disease therapies, leading to substantial recent attention in biological and medical circles. Here, we show how an mtDNA sequence’s balance between replication and transcription, corresponding to molecular ‘selfishness’, in conjunction with cellular selection, can potentially modulate segregation bias. We combine a new replication-transcription-selection (RTS) model with a meta-analysis of existing data to show that this simple theory predicts complex tissue-specific patterns of segregation in mouse experiments, and reversion in human stem cells. We propose the stability of G-quadruplexes in the mtDNA control region, influencing the balance between transcription and replication primer formation, as a potential molecular mechanism governing this balance. Linking mtDNA sequence features, through this molecular mechanism, to cellular population dynamics, we use sequence data to obtain and verify the sequence-specific predictions from this hypothesis on segregation behaviour in mouse and human mtDNA.

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Tsang, William Y., e Bernard D. Lemire. "Stable heteroplasmy but differential inheritance of a large mitochondrial DNA deletion in nematodes". Biochemistry and Cell Biology 80, n. 5 (1 ottobre 2002): 645–54. http://dx.doi.org/10.1139/o02-135.

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Many human mitochondrial diseases are associated with defects in the mitochondrial DNA (mtDNA). Mutated and wild-type forms of mtDNA often coexist in the same cell in a state called heteroplasmy. Here, we report the isolation of a Caenorhabditis elegans strain bearing the 3.1-kb uaDf5 deletion that removes 11 genes from the mtDNA. The uaDf5 deletion is maternally transmitted and has been maintained for at least 100 generations in a stable heteroplasmic state in which it accounts for ~60% of the mtDNA content of each developmental stage. Heteroplasmy levels vary between individual animals (from ~20 to 80%), but no observable phenotype is detected. The total mtDNA copy number in the uaDf5 mutant is approximately twice that of the wild type. The maternal transmission of the uaDf5 mtDNA is controlled by at least two competing processes: one process promotes the increase in the average proportion of uaDf5 mtDNA in the offspring, while the second promotes a decrease. These two forces prevent the segregation of the mtDNAs to homoplasmy.Key words: mtDNA deletion, Caenorhabditis elegans, heteroplasmy, inheritance, mtDNA copy number.

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Ling, Feng, Rong Niu, Hideyuki Hatakeyama, Yu-ichi Goto, Takehiko Shibata e Minoru Yoshida. "Reactive oxygen species stimulate mitochondrial allele segregation toward homoplasmy in human cells". Molecular Biology of the Cell 27, n. 10 (15 maggio 2016): 1684–93. http://dx.doi.org/10.1091/mbc.e15-10-0690.

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Mitochondria that contain a mixture of mutant and wild-type mitochondrial (mt) DNA copies are heteroplasmic. In humans, homoplasmy is restored during early oogenesis and reprogramming of somatic cells, but the mechanism of mt-allele segregation remains unknown. In budding yeast, homoplasmy is restored by head-to-tail concatemer formation in mother cells by reactive oxygen species (ROS)–induced rolling-circle replication and selective transmission of concatemers to daughter cells, but this mechanism is not obvious in higher eukaryotes. Here, using heteroplasmic m.3243A > G primary fibroblast cells derived from MELAS patients treated with hydrogen peroxide (H2O2), we show that an optimal ROS level promotes mt-allele segregation toward wild-type and mutant mtDNA homoplasmy. Enhanced ROS level reduced the amount of intact mtDNA replication templates but increased linear tandem multimers linked by head-to-tail unit-sized mtDNA (mtDNA concatemers). ROS-triggered mt-allele segregation correlated with mtDNA-concatemer production and enabled transmission of multiple identical mt-genome copies as a single unit. Our results support a mechanism by which mt-allele segregation toward mt-homoplasmy is mediated by concatemers.

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Zelenaya-Troitskaya, Olga, Scott M. Newman, Koji Okamoto, Philip S. Perlman e Ronald A. Butow. "Functions of the High Mobility Group Protein, Abf2p, in Mitochondrial DNA Segregation, Recombination and Copy Number in Saccharomyces cerevisiae". Genetics 148, n. 4 (1 aprile 1998): 1763–76. http://dx.doi.org/10.1093/genetics/148.4.1763.

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Abstract Previous studies have established that the mitochondrial high mobility group (HMG) protein, Abf2p, of Saccharomyces cerevisiae influences the stability of wild-type (ρ+) mitochondrial DNA (mtDNA) and plays an important role in mtDNA organization. Here we report new functions for Abf2p in mtDNA transactions. We find that in homozygous Δabf2 crosses, the pattern of sorting of mtDNA and mitochondrial matrix protein is altered, and mtDNA recombination is suppressed relative to homozygous ABF2 crosses. Although Abf 2p is known to be required for the maintenance of mtDNA in ρ+ cells growing on rich dextrose medium, we find that it is not required for the maintenance of mtDNA in ρ− cells grown on the same medium. The content of both ρ+ and ρ− mtDNAs is increased in cells by 50–150% by moderate (two- to threefold) increases in the ABF2 copy number, suggesting that Abf2p plays a role in mtDNA copy control. Overproduction of Abf 2p by ≥10-fold from an ABF2 gene placed under control of the GAL1 promoter, however, leads to a rapid loss of ρ+ mtDNA and a quantitative conversion of ρ+ cells to petites within two to four generations after a shift of the culture from glucose to galactose medium. Overexpression of Abf2p in ρ− cells also leads to a loss of mtDNA, but at a slower rate than was observed for ρ+ cells. The mtDNA instability phenotype is related to the DNA-binding properties of Abf 2p because a mutant Abf 2p that contains mutations in residues of both HMG box domains known to affect DNA binding in vitro, and that binds poorly to mtDNA in vivo, complements Δabf2 cells only weakly and greatly lessens the effect of overproduction on mtDNA instability. In vivo binding was assessed by colocalization to mtDNA of fusions between mutant or wild-type Abf 2p and green fluorescent protein. These findings are discussed in the context of a model relating mtDNA copy number control and stability to mtDNA recombination.

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Okamoto, Koji, Philip S. Perlman e Ronald A. Butow. "The Sorting of Mitochondrial DNA and Mitochondrial Proteins in Zygotes: Preferential Transmission of Mitochondrial DNA to the Medial Bud". Journal of Cell Biology 142, n. 3 (10 agosto 1998): 613–23. http://dx.doi.org/10.1083/jcb.142.3.613.

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Green fluorescent protein (GFP) was used to tag proteins of the mitochondrial matrix, inner, and outer membranes to examine their sorting patterns relative to mtDNA in zygotes of synchronously mated yeast cells in ρ+ × ρ0 crosses. When transiently expressed in one of the haploid parents, each of the marker proteins distributes throughout the fused mitochondrial reticulum of the zygote before equilibration of mtDNA, although the membrane markers equilibrate slower than the matrix marker. A GFP-tagged form of Abf2p, a mtDNA binding protein required for faithful transmission of ρ+ mtDNA in vegetatively growing cells, colocalizes with mtDNA in situ. In zygotes of a ρ+ × ρ+ cross, in which there is little mixing of parental mtDNAs, Abf2p–GFP prelabeled in one parent rapidly equilibrates to most or all of the mtDNA, showing that the mtDNA compartment is accessible to exchange of proteins. In ρ+ × ρ0 crosses, mtDNA is preferentially transmitted to the medial diploid bud, whereas mitochondrial GFP marker proteins distribute throughout the zygote and the bud. In zygotes lacking Abf2p, mtDNA sorting is delayed and preferential sorting is reduced. These findings argue for the existence of a segregation apparatus that directs mtDNA to the emerging bud.

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Meirelles, Flávio V., e Lawrence C. Smith. "Mitochondrial Genotype Segregation in a Mouse Heteroplasmic Lineage Produced by Embryonic Karyoplast Transplantation". Genetics 145, n. 2 (1 febbraio 1997): 445–51. http://dx.doi.org/10.1093/genetics/145.2.445.

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Mitochondrial genotypes have been shown to segregate both rapidly and slowly when transmitted to consecutive generations in mammals. Our objective was to develop an animal model to analyze the patterns of mammalian mitochondrial DNA (mtDNA) segregation and transmission in an intraspecific heteroplasmic maternal lineage to investigate the mechanisms controlling these phenomena. Heteroplasmic progeny were obtained from reconstructed blastocysts derived by transplantation of pronuclear-stage karyoplasts to enucleated zygotes with different mtDNA. Although the reconstructed zygotes contained on average 19% mtDNA of karyoplast origin, most progeny contained fewer mtDNA of karyoplast origin and produced exclusively homoplasmic first generation progeny. However, one founder heteroplasmic adult female had elevated tissue heteroplasmy levels, varying from 6% (lung) to 69% (heart), indicating that stringent replicative segregation had occurred during mitotic divisions. First generation progeny from the above female were all heteroplasmic, indicating that, despite a meiotic segregation, they were derived from heteroplasmic founder oocytes. Some second and third generation progeny contained exclusively New Zealand Black/BINJ mtDNA, suggesting, but not confirming, an origin from an homoplasmic oocyte. Moreover, several third to fifth generation individuals maintained mtDNA from both mouse strains, indicating a slow or persistent segregation pattern characterized by diminished tissue and litter variability beyond second generation progeny. Therefore, although some initial lineages appear to segregate rapidly to homoplasmy, within two generations other lineages transmit stable amounts of both mtDNA molecules, supporting a mechanism where mitochondria of different origin may fuse, leading to persistent intraorganellar heteroplasmy.

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Clark, A. G., e E. M. Lyckegaard. "Natural selection with nuclear and cytoplasmic transmission. III. Joint analysis of segregation and mtDNA in Drosophila melanogaster." Genetics 118, n. 3 (1 marzo 1988): 471–81. http://dx.doi.org/10.1093/genetics/118.3.471.

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Abstract Despite the widespread use of mitochondrial DNA by evolutionary geneticists, relatively little effort has been spent assessing the magnitude of forces maintaining mtDNA sequence diversity. In this study the influence of cytoplasmic variation on viability in Drosophila was examined by analysis of second chromosome segregation. A factorial experiment with balancer chromosomes permitted the effects of cytoplasma and reciprocal crosses to be individually distinguished. The first test used six lines of diverse geographic origin, testing the segregation of all six second chromosomes in all six cytoplasms. The second and third tests were also factorial designs, but used flies from one population in central Pennsylvania. The fourth test was a large chain cross, using 28 lines from the same Pennsylvania population. Only the first test detected a significant nuclear-cytoplasmic effect. Restriction site variation in the mtDNA of all of these lines was assayed by Southern blotting, and statistical tests were performed in an effort to detect an influence of mtDNA type on fitness components. Posterior linear contrasts revealed an effect of mtDNA on segregation only among lines of diverse geographic origin. Within a population, no such influence was detected, even though the experiment was sufficiently large to have revealed statistical significance of a 0.5% segregation difference with a 57% probability.

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Smith, Lawrence C., Jacob Thundathil e France Filion. "Role of the mitochondrial genome in preimplantation development and assisted reproductive technologies". Reproduction, Fertility and Development 17, n. 2 (2005): 15. http://dx.doi.org/10.1071/rd04084.

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Our fascination for mitochondria relates to their origin as symbiotic, semi-independent organisms on which we, as eukaryotic beings, rely nearly exclusively to produce energy for every cell function. Therefore, it is not surprising that these organelles play an essential role in many events during early development and in artificial reproductive technologies (ARTs) applied to humans and domestic animals. However, much needs to be learned about the interactions between the nucleus and the mitochondrial genome (mtDNA), particularly with respect to the control of transcription, replication and segregation during preimplantation. Nuclear-encoded factors that control transcription and replication are expressed during preimplantation development in mice and are followed by mtDNA transcription, but these result in no change in mtDNA copy number. However, in cattle, mtDNA copy number increases during blastocyst expansion and hatching. Nuclear genes influence the mtDNA segregation patterns in heteroplasmic animals. Because many ARTs markedly modify the mtDNA content in embryos, it is essential that their application is preceded by careful experimental scrutiny, using suitable animal models.

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Meeusen, Shelly, Quinton Tieu, Edith Wong, Eric Weiss, David Schieltz, John R. Yates e Jodi Nunnari. "Mgm101p Is a Novel Component of the Mitochondrial Nucleoid That Binds DNA and Is Required for the Repair of Oxidatively Damaged Mitochondrial DNA". Journal of Cell Biology 145, n. 2 (19 aprile 1999): 291–304. http://dx.doi.org/10.1083/jcb.145.2.291.

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Maintenance of mitochondrial DNA (mtDNA) during cell division is required for progeny to be respiratory competent. Maintenance involves the replication, repair, assembly, segregation, and partitioning of the mitochondrial nucleoid. MGM101 has been identified as a gene essential for mtDNA maintenance in S. cerevisiae, but its role is unknown. Using liquid chromatography coupled with tandem mass spectrometry, we identified Mgm101p as a component of highly enriched nucleoids, suggesting that it plays a nucleoid-specific role in maintenance. Subcellular fractionation, indirect immunofluorescence and GFP tagging show that Mgm101p is exclusively associated with the mitochondrial nucleoid structure in cells. Furthermore, DNA affinity chromatography of nucleoid extracts indicates that Mgm101p binds to DNA, suggesting that its nucleoid localization is in part due to this activity. Phenotypic analysis of cells containing a temperature sensitive mgm101 allele suggests that Mgm101p is not involved in mtDNA packaging, segregation, partitioning or required for ongoing mtDNA replication. We examined Mgm101p's role in mtDNA repair. As compared with wild-type cells, mgm101 cells were more sensitive to mtDNA damage induced by UV irradiation and were hypersensitive to mtDNA damage induced by gamma rays and H2O2 treatment. Thus, we propose that Mgm101p performs an essential function in the repair of oxidatively damaged mtDNA that is required for the maintenance of the mitochondrial genome.

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Ling, Feng, e Takehiko Shibata. "Mhr1p-dependent Concatemeric Mitochondrial DNA Formation for Generating Yeast Mitochondrial Homoplasmic Cells". Molecular Biology of the Cell 15, n. 1 (gennaio 2004): 310–22. http://dx.doi.org/10.1091/mbc.e03-07-0508.

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Mitochondria carry many copies of mitochondrial DNA (mtDNA), but mt-alleles quickly segregate during mitotic growth through unknown mechanisms. Consequently, all mtDNA copies are often genetically homogeneous within each individual (“homoplasmic”). Our previous study suggested that tandem multimers (“concatemers”) formed mainly by the Mhr1p (a yeast nuclear gene-encoded mtDNA-recombination protein)-dependent pathway are required for mtDNA partitioning into buds with concomitant monomerization. The transmission of a few randomly selected clones (as concatemers) of mtDNA into buds is a possible mechanism to establish homoplasmy. The current study provides evidence for this hypothesis as follows: the overexpression of MHR1 accelerates mt-allele-segregation in growing heteroplasmic zygotes, and mhr1-1 (recombination-deficient) causes its delay. The mt-allele-segregation rate correlates with the abundance of concatemers, which depends on Mhr1p. In G1-arrested cells, concatemeric mtDNA was labeled by [14C]thymidine at a much higher density than monomers, indicating concatemers as the immediate products of mtDNA replication, most likely in a rolling circle mode. After releasing the G1 arrest in the absence of [14C]thymidine, the monomers as the major species in growing buds of dividing cells bear a similar density of 14C as the concatemers in the mother cells, indicating that the concatemers in mother cells are the precursors of the monomers in buds.

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Goffart, Steffi, Anu Hangas e Jaakko L. O. Pohjoismäki. "Twist and Turn—Topoisomerase Functions in Mitochondrial DNA Maintenance". International Journal of Molecular Sciences 20, n. 8 (25 aprile 2019): 2041. http://dx.doi.org/10.3390/ijms20082041.

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Like any genome, mitochondrial DNA (mtDNA) also requires the action of topoisomerases to resolve topological problems in its maintenance, but for a long time, little was known about mitochondrial topoisomerases. The last years have brought a closer insight into the function of these fascinating enzymes in mtDNA topology regulation, replication, transcription, and segregation. Here, we summarize the current knowledge about mitochondrial topoisomerases, paying special attention to mammalian mitochondrial genome maintenance. We also discuss the open gaps in the existing knowledge of mtDNA topology control and the potential involvement of mitochondrial topoisomerases in human pathologies. While Top1mt, the only exclusively mitochondrial topoisomerase in mammals, has been studied intensively for nearly a decade, only recent studies have shed some light onto the mitochondrial function of Top2β and Top3α, enzymes that are shared between nucleus and mitochondria. Top3α mediates the segregation of freshly replicated mtDNA molecules, and its dysfunction leads to mtDNA aggregation and copy number depletion in patients. Top2β, in contrast, regulates mitochondrial DNA replication and transcription through the alteration of mtDNA topology, a fact that should be acknowledged due to the frequent use of Topoisomerase 2 inhibitors in medical therapy.

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Luo, Shiyu, C. Alexander Valencia, Jinglan Zhang, Ni-Chung Lee, Jesse Slone, Baoheng Gui, Xinjian Wang et al. "Biparental Inheritance of Mitochondrial DNA in Humans". Proceedings of the National Academy of Sciences 115, n. 51 (26 novembre 2018): 13039–44. http://dx.doi.org/10.1073/pnas.1810946115.

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Although there has been considerable debate about whether paternal mitochondrial DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is generally believed that mitochondria and mtDNA are exclusively maternally inherited in humans. Here, we identified three unrelated multigeneration families with a high level of mtDNA heteroplasmy (ranging from 24 to 76%) in a total of 17 individuals. Heteroplasmy of mtDNA was independently examined by high-depth whole mtDNA sequencing analysis in our research laboratory and in two Clinical Laboratory Improvement Amendments and College of American Pathologists-accredited laboratories using multiple approaches. A comprehensive exploration of mtDNA segregation in these families shows biparental mtDNA transmission with an autosomal dominantlike inheritance mode. Our results suggest that, although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring. Elucidating the molecular mechanism for this unusual mode of inheritance will provide new insights into how mtDNA is passed on from parent to offspring and may even lead to the development of new avenues for the therapeutic treatment for pathogenic mtDNA transmission.

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Cao, Liqin, Ellen Kenchington e Eleftherios Zouros. "Differential Segregation Patterns of Sperm Mitochondria in Embryos of the Blue Mussel (Mytilus edulis)". Genetics 166, n. 2 (1 febbraio 2004): 883–94. http://dx.doi.org/10.1093/genetics/166.2.883.

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Abstract In Mytilus, females carry predominantly maternal mitochondrial DNA (mtDNA) but males carry maternal mtDNA in their somatic tissues and paternal mtDNA in their gonads. This phenomenon, known as doubly uniparental inheritance (DUI) of mtDNA, presents a major departure from the uniparental transmission of organelle genomes. Eggs of Mytilus edulis from females that produce exclusively daughters and from females that produce mostly sons were fertilized with sperm stained with MitoTracker Green FM, allowing observation of sperm mitochondria in the embryo by epifluorescent and confocal microscopy. In embryos from females that produce only daughters, sperm mitochondria are randomly dispersed among blastomeres. In embryos from females that produce mostly sons, sperm mitochondria tend to aggregate and end up in one blastomere in the two- and four-cell stages. We postulate that the aggregate eventually ends up in the first germ cells, thus accounting for the presence of paternal mtDNA in the male gonad. This is the first evidence for different behaviors of sperm mitochondria in developing embryos that may explain the tight linkage between gender and inheritance of paternal mitochondrial DNA in species with DUI.

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Moreira, Jesse D., Deepa M. Gopal, Darrell N. Kotton e Jessica L. Fetterman. "Gaining Insight into Mitochondrial Genetic Variation and Downstream Pathophysiology: What Can i(PSCs) Do?" Genes 12, n. 11 (22 ottobre 2021): 1668. http://dx.doi.org/10.3390/genes12111668.

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Mitochondria are specialized organelles involved in energy production that have retained their own genome throughout evolutionary history. The mitochondrial genome (mtDNA) is maternally inherited and requires coordinated regulation with nuclear genes to produce functional enzyme complexes that drive energy production. Each mitochondrion contains 5–10 copies of mtDNA and consequently, each cell has several hundreds to thousands of mtDNAs. Due to the presence of multiple copies of mtDNA in a mitochondrion, mtDNAs with different variants may co-exist, a condition called heteroplasmy. Heteroplasmic variants can be clonally expanded, even in post-mitotic cells, as replication of mtDNA is not tied to the cell-division cycle. Heteroplasmic variants can also segregate during germ cell formation, underlying the inheritance of some mitochondrial mutations. Moreover, the uneven segregation of heteroplasmic variants is thought to underlie the heterogeneity of mitochondrial variation across adult tissues and resultant differences in the clinical presentation of mitochondrial disease. Until recently, however, the mechanisms mediating the relation between mitochondrial genetic variation and disease remained a mystery, largely due to difficulties in modeling human mitochondrial genetic variation and diseases. The advent of induced pluripotent stem cells (iPSCs) and targeted gene editing of the nuclear, and more recently mitochondrial, genomes now provides the ability to dissect how genetic variation in mitochondrial genes alter cellular function across a variety of human tissue types. This review will examine the origins of mitochondrial heteroplasmic variation and propagation, and the tools used to model mitochondrial genetic diseases. Additionally, we discuss how iPSC technologies represent an opportunity to advance our understanding of human mitochondrial genetics in disease.

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Chomyn, A., G. Meola, N. Bresolin, S. T. Lai, G. Scarlato e G. Attardi. "In vitro genetic transfer of protein synthesis and respiration defects to mitochondrial DNA-less cells with myopathy-patient mitochondria". Molecular and Cellular Biology 11, n. 4 (aprile 1991): 2236–44. http://dx.doi.org/10.1128/mcb.11.4.2236-2244.1991.

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A severe mitochondrial protein synthesis defect in myoblasts from a patient with mitochondrial myopathy was transferred with myoblast mitochondria into two genetically unrelated mitochondrial DNA (mtDNA)-less human cell lines, pointing to an mtDNA alteration as being responsible and sufficient for causing the disease. The transfer of the defect correlated with marked deficiencies in respiration and cytochrome c oxidase activity of the transformants and the presence in their mitochondria of mtDNA carrying a tRNA(Lys) mutation. Furthermore, apparently complete segregation of the defective genotype and phenotype was observed in the transformants derived from the heterogeneous proband myoblast population, suggesting that the mtDNA heteroplasmy in this population was to a large extent intercellular. The present work thus establishes a direct link between mtDNA alteration and a biochemical defect.

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Chomyn, A., G. Meola, N. Bresolin, S. T. Lai, G. Scarlato e G. Attardi. "In vitro genetic transfer of protein synthesis and respiration defects to mitochondrial DNA-less cells with myopathy-patient mitochondria." Molecular and Cellular Biology 11, n. 4 (aprile 1991): 2236–44. http://dx.doi.org/10.1128/mcb.11.4.2236.

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A severe mitochondrial protein synthesis defect in myoblasts from a patient with mitochondrial myopathy was transferred with myoblast mitochondria into two genetically unrelated mitochondrial DNA (mtDNA)-less human cell lines, pointing to an mtDNA alteration as being responsible and sufficient for causing the disease. The transfer of the defect correlated with marked deficiencies in respiration and cytochrome c oxidase activity of the transformants and the presence in their mitochondria of mtDNA carrying a tRNA(Lys) mutation. Furthermore, apparently complete segregation of the defective genotype and phenotype was observed in the transformants derived from the heterogeneous proband myoblast population, suggesting that the mtDNA heteroplasmy in this population was to a large extent intercellular. The present work thus establishes a direct link between mtDNA alteration and a biochemical defect.

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Vachin, Pauline, Elodie Adda-Herzog, Gihad Chalouhi, Caroline Elie, Marlène Rio, Sophie Rondeau, Nadine Gigarel et al. "Segregation of mitochondrial DNA mutations in the human placenta: implication for prenatal diagnosis of mtDNA disorders". Journal of Medical Genetics 55, n. 2 (28 luglio 2017): 131–36. http://dx.doi.org/10.1136/jmedgenet-2017-104615.

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BackgroundMitochondrial DNA (mtDNA) disorders have a high clinical variability, mainly explained by variation of the mutant load across tissues. The high recurrence risk of these serious diseases commonly results in requests from at-risk couples for prenatal diagnosis (PND), based on determination of the mutant load on a chorionic villous sample (CVS). Such procedures are hampered by the lack of data regarding mtDNA segregation in the placenta.The objectives of this report were to determine whether mutant loads (1) are homogeneously distributed across the whole placentas, (2) correlate with those in amniocytes and cord blood cells and (3) correlate with the mtDNA copy number.MethodsWe collected 11 whole placentas carrying various mtDNA mutations (m.3243A>G, m.8344A>G, m.8993T>G, m.9185T>C and m.10197G>A) and, when possible, corresponding amniotic fluid samples (AFSs) and cord blood samples. We measured mutant loads in multiple samples from each placenta (n= 6–37), amniocytes and cord blood cells, as well as total mtDNA content in placenta samples.ResultsLoad distribution was homogeneous at the sample level when average mutant load was low (<20%) or high (>80%) at the whole placenta level. By contrast, a marked heterogeneity was observed (up to 43%) in the intermediate range (20%–80%), the closer it was to 40%–50% the mutant load, the wider the distribution. Mutant loads were found to be similar in amniocytes and cord blood cells, at variance with placenta samples. mtDNA content correlated to mutant load in m.3243A>G placentas only.ConclusionThese data indicate that (1) mutant load determined from CVS has to be interpreted with caution for PND of some mtDNA disorders and should be associated with/substituted by a mutant load measurement on amniocytes; (2) the m.3243A>G mutation behaves differently from other mtDNA mutations with respect to the impact on mtDNA copy number, as previously shown in human preimplantation embryogenesis.

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Shitara, Hiroshi, Jun-Ichi Hayashi, Sumiyo Takahama, Hideki Kaneda e Hiromichi Yonekawa. "Maternal Inheritance of Mouse mtDNA in Interspecific Hybrids: Segregation of the Leaked Paternal mtDNA Followed by the Prevention of Subsequent Paternal Leakage". Genetics 148, n. 2 (1 febbraio 1998): 851–57. http://dx.doi.org/10.1093/genetics/148.2.851.

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Abstract The transmission profiles of sperm mtDNA introduced into fertilized eggs were examined in detail in F1 hybrids of mouse interspecific crosses by addressing three aspects. The first is whether the leaked paternal mtDNA in fertilized eggs produced by interspecific crosses was distributed stably to all tissues after the eggs' development to adults. The second is whether the leaked paternal mtDNA was transmitted to the subsequent generations. The third is whether paternal mtDNA continuously leaks in subsequent backcrosses. For identification of the leaked paternal mtDNA, we prepared total DNA samples directly from tissues or embryos and used PCR techniques that can detect a few molecules of paternal mtDNA even in the presence of 108-fold excess of maternal mtDNA. The results showed that the leaked paternal mtDNA was not distributed to all tissues in the F1 hybrids or transmitted to the following generations through the female germ line. Moreover, the paternal mtDNA leakage was limited to the first generation of an interspecific cross and did not occur in progeny from subsequent backcrosses. These observations suggest that species-specific exclusion of sperm mtDNA in mammalian fertilized eggs is extremely stringent, ensuring strictly maternal inheritance of mtDNA.

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Yamada, Mitsutoshi, Kazuhiro Akashi, Reina Ooka, Kenji Miyado e Hidenori Akutsu. "Mitochondrial Genetic Drift after Nuclear Transfer in Oocytes". International Journal of Molecular Sciences 21, n. 16 (16 agosto 2020): 5880. http://dx.doi.org/10.3390/ijms21165880.

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Abstract (sommario):

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.

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22

Cupini, L. M., R. Massa, R. Floris, G. Manenti, B. Martini, A. Tessa, G. Nappi, G. Bernardi e F. M. Santorelli. "Migraine-like disorder segregating with mtDNA 14484 Leber hereditary optic neuropathy mutation". Neurology 60, n. 4 (25 febbraio 2003): 717–19. http://dx.doi.org/10.1212/01.wnl.0000048662.77572.fb.

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Abstract (sommario):

The authors report neurologic features in a large family harboring the mitochondrial DNA (mtDNA) mutation T14484C associated with Leber hereditary optic neuropathy (LHON). In the maternal line the mtDNA mutation was associated with optic neuropathy or migraine with aura or without aura and transient neurologic/visual disturbances. The segregation of familiar cases of migraine and LHON mutation broadens the clinical phenotype associated with a primary LHON mutation.

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23

Pickrell, Alicia M., e Richard J. Youle. "Mitochondrial Disease: mtDNA and Protein Segregation Mysteries in iPSCs". Current Biology 23, n. 23 (dicembre 2013): R1052—R1054. http://dx.doi.org/10.1016/j.cub.2013.10.048.

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24

Boldogh, Istvan R., Dan W. Nowakowski, Hyeong-Cheol Yang, Haesung Chung, Sharon Karmon, Patrina Royes e Liza A. Pon. "A Protein Complex Containing Mdm10p, Mdm12p, and Mmm1p Links Mitochondrial Membranes and DNA to the Cytoskeleton-based Segregation Machinery". Molecular Biology of the Cell 14, n. 11 (novembre 2003): 4618–27. http://dx.doi.org/10.1091/mbc.e03-04-0225.

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Abstract (sommario):

Previous studies indicate that two proteins, Mmm1p and Mdm10p, are required to link mitochondria to the actin cytoskeleton of yeast and for actin-based control of mitochondrial movement, inheritance and morphology. Both proteins are integral mitochondrial outer membrane proteins. Mmm1p localizes to punctate structures in close proximity to mitochondrial DNA (mtDNA) nucleoids. We found that Mmm1p and Mdm10p exist in a complex with Mdm12p, another integral mitochondrial outer membrane protein required for mitochondrial morphology and inheritance. This interpretation is based on observations that 1) Mdm10p and Mdm12p showed the same localization as Mmm1p; 2) Mdm12p, like Mdm10p and Mmm1p, was required for mitochondrial motility; and 3) all three proteins coimmunoprecipitated with each other. Moreover, Mdm10p localized to mitochondria in the absence of the other subunits. In contrast, deletion of MMM1 resulted in mislocalization of Mdm12p, and deletion of MDM12 caused mislocalization of Mmm1p. Finally, we observed a reciprocal relationship between the Mdm10p/Mdm12p/Mmm1p complex and mtDNA. Deletion of any one of the subunits resulted in loss of mtDNA or defects in mtDNA nucleoid maintenance. Conversely, deletion of mtDNA affected mitochondrial motility: mitochondria in cells without mtDNA move 2–3 times faster than mitochondria in cells with mtDNA. These observations support a model in which the Mdm10p/Mdm12p/Mmm1p complex links the minimum heritable unit of mitochondria (mtDNA and mitochondrial outer and inner membranes) to the cytoskeletal system that drives transfer of that unit from mother to daughter cells.

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25

Bastiaans, E., D. K. Aanen, A. J. M. Debets, R. F. Hoekstra, B. Lestrade e M. F. P. M. Maas. "Regular bottlenecks and restrictions to somatic fusion prevent the accumulation of mitochondrial defects in Neurospora". Philosophical Transactions of the Royal Society B: Biological Sciences 369, n. 1646 (5 luglio 2014): 20130448. http://dx.doi.org/10.1098/rstb.2013.0448.

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Abstract (sommario):

The replication and segregation of multi-copy mitochondrial DNA (mtDNA) are not under strict control of the nuclear DNA. Within-cell selection may thus favour variants with an intracellular selective advantage but a detrimental effect on cell fitness. High relatedness among the mtDNA variants of an individual is predicted to disfavour such deleterious selfish genetic elements, but experimental evidence for this hypothesis is scarce. We studied the effect of mtDNA relatedness on the opportunities for suppressive mtDNA variants in the fungus Neurospora carrying the mitochondrial mutator plasmid pKALILO. During growth, this plasmid integrates into the mitochondrial genome, generating suppressive mtDNA variants. These mtDNA variants gradually replace the wild-type mtDNA, ultimately culminating in growth arrest and death. We show that regular sequestration of mtDNA variation is required for effective selection against suppressive mtDNA variants. First, bottlenecks in the number of mtDNA copies from which a ‘ Kalilo ’ culture started significantly increased the maximum lifespan and variation in lifespan among cultures. Second, restrictions to somatic fusion among fungal individuals, either by using anastomosis-deficient mutants or by generating allotype diversity, prevented the accumulation of suppressive mtDNA variants. We discuss the implications of these results for the somatic accumulation of mitochondrial defects during ageing.

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Lehtinen, Sanna K., Nicole Hance, Abdellatif El Meziane, M. Katariina Juhola, K. Martti I. Juhola, Ritva Karhu, Johannes N. Spelbrink, Ian J. Holt e Howard T. Jacobs. "Genotypic Stability, Segregation and Selection in Heteroplasmic Human Cell Lines Containing np 3243 Mutant mtDNA". Genetics 154, n. 1 (1 gennaio 2000): 363–80. http://dx.doi.org/10.1093/genetics/154.1.363.

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Abstract (sommario):

Abstract The mitochondrial genotype of heteroplasmic human cell lines containing the pathological np 3243 mtDNA mutation, plus or minus its suppressor at np 12300, has been followed over long periods in culture. Cell lines containing various different proportions of mutant mtDNA remained generally at a consistent, average heteroplasmy value over at least 30 wk of culture in nonselective media and exhibited minimal mitotic segregation, with a segregation number comparable with mtDNA copy number (≥1000). Growth in selective medium of cells at 99% np 3243 mutant mtDNA did, however, allow the isolation of clones with lower levels of the mutation, against a background of massive cell death. As a rare event, cell lines exhibited a sudden and dramatic diversification of heteroplasmy levels, accompanied by a shift in the average heteroplasmy level over a short period (<8 wk), indicating selection. One such episode was associated with a gain of chromosome 9. Analysis of respiratory phenotype and mitochondrial genotype of cell clones from such cultures revealed that stable heteroplasmy values were generally reestablished within a few weeks, in a reproducible but clone-specific fashion. This occurred independently of any straightforward phenotypic selection at the individual cell-clone level. Our findings are consistent with several alternate views of mtDNA organization in mammalian cells. One model that is supported by our data is that mtDNA is found in nucleoids containing many copies of the genome, which can themselves be heteroplasmic, and which are faithfully replicated. We interpret diversification and shifts of heteroplasmy level as resulting from a reorganization of such nucleoids, under nuclear genetic control. Abrupt remodeling of nucleoids in vivo would have major implications for understanding the developmental consequences of heteroplasmy, including mitochondrial disease phenotype and progression.

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Vozáriková, Veronika, Nina Kunová, Jacob A. Bauer, Ján Frankovský, Veronika Kotrasová, Katarína Procházková, Vladimíra Džugasová et al. "Mitochondrial HMG-Box Containing Proteins: From Biochemical Properties to the Roles in Human Diseases". Biomolecules 10, n. 8 (16 agosto 2020): 1193. http://dx.doi.org/10.3390/biom10081193.

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Abstract (sommario):

Mitochondrial DNA (mtDNA) molecules are packaged into compact nucleo-protein structures called mitochondrial nucleoids (mt-nucleoids). Their compaction is mediated in part by high-mobility group (HMG)-box containing proteins (mtHMG proteins), whose additional roles include the protection of mtDNA against damage, the regulation of gene expression and the segregation of mtDNA into daughter organelles. The molecular mechanisms underlying these functions have been identified through extensive biochemical, genetic, and structural studies, particularly on yeast (Abf2) and mammalian mitochondrial transcription factor A (TFAM) mtHMG proteins. The aim of this paper is to provide a comprehensive overview of the biochemical properties of mtHMG proteins, the structural basis of their interaction with DNA, their roles in various mtDNA transactions, and the evolutionary trajectories leading to their rapid diversification. We also describe how defects in the maintenance of mtDNA in cells with dysfunctional mtHMG proteins lead to different pathologies at the cellular and organismal level.

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Ling, Feng, Akiko Hori e Takehiko Shibata. "DNA Recombination-Initiation Plays a Role in the Extremely Biased Inheritance of Yeast [rho−] Mitochondrial DNA That Contains the Replication Origin ori5". Molecular and Cellular Biology 27, n. 3 (20 novembre 2006): 1133–45. http://dx.doi.org/10.1128/mcb.00770-06.

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Abstract (sommario):

ABSTRACT Hypersuppressiveness, as observed in Saccharomyces cerevisiae, is an extremely biased inheritance of a small mitochondrial DNA (mtDNA) fragment that contains a replication origin (HS [rho −] mtDNA). Our previous studies showed that concatemers (linear head-to-tail multimers) are obligatory intermediates for mtDNA partitioning and are primarily formed by rolling-circle replication mediated by Mhr1, a protein required for homologous mtDNA recombination. In this study, we found that Mhr1 is required for the hypersuppressiveness of HS [ori5] [rho −] mtDNA harboring ori5, one of the replication origins of normal ([rho +]) mtDNA. In addition, we detected an Ntg1-stimulated double-strand break at the ori5 locus. Purified Ntg1, a base excision repair enzyme, introduced a double-stranded break by itself into HS [ori5] [rho −] mtDNA at ori5 isolated from yeast cells. Both hypersuppressiveness and concatemer formation of HS [ori5] [rho −] mtDNA are simultaneously suppressed by the ntg1 null mutation. These results support a model in which, like homologous recombination, rolling-circle HS [ori5] [rho −] mtDNA replication is initiated by double-stranded breakage in ori5, followed by Mhr1-mediated homologous pairing of the processed nascent DNA ends with circular mtDNA. The hypersuppressiveness of HS [ori5] [rho −] mtDNA depends on a replication advantage furnished by the higher density of ori5 sequences and on a segregation advantage furnished by the higher genome copy number on transmitted concatemers.

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Satta, Yoko, Nobue Toyohara, Chiaki Ohtaka, Yumi Tatsuno, Takao K. Watanabe, Etsuko T. Matsuura, Sadao I. Chigusa e Naoyuki Takahata. "Dubious maternal inheritance of mitochondrial DNA in D. simulans and evolution of D. mauritiana". Genetical Research 52, n. 1 (agosto 1988): 1–6. http://dx.doi.org/10.1017/s0016672300027245.

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Abstract (sommario):

SummaryWithin-line heterogeneity has been found in the mitochondrial DNA (mtDNA) in two isofemale lines of D. simulans. The co-existing types, S and M, were typical of the mtDNA in D. simulans and in D. mauritiana, respectively, their nucleotide divergence per site being ca. 2·1%. Segregation analysis confirmed that some individuals in these lines were heteroplasmic and suggested incomplete maternal inheritance of mtDNA in Drosophila. Examination of other lines of D. simulans revealed that the M type of D. mauritiana occurs at 71% in Réunion, 38% in Madagascar and 0% in Kenya. This finding and interspecific sequence comparisons of both M types indicate that D. mauritiana diverged from D. simulans probably less than 240000 years ago.

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30

Kauppila, Timo E. S., Ana Bratic, Martin Borch Jensen, Francesca Baggio, Linda Partridge, Heinrich Jasper, Sebastian Grönke e Nils-Göran Larsson. "Mutations of mitochondrial DNA are not major contributors to aging of fruit flies". Proceedings of the National Academy of Sciences 115, n. 41 (24 settembre 2018): E9620—E9629. http://dx.doi.org/10.1073/pnas.1721683115.

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Abstract (sommario):

Mammals develop age-associated clonal expansion of somatic mtDNA mutations resulting in severe respiratory chain deficiency in a subset of cells in a variety of tissues. Both mathematical modeling based on descriptive data from humans and experimental data from mtDNA mutator mice suggest that the somatic mutations are formed early in life and then undergo mitotic segregation during adult life to reach very high levels in certain cells. To address whether mtDNA mutations have a universal effect on aging metazoans, we investigated their role in physiology and aging of fruit flies. To this end, we utilized genetically engineered flies expressing mutant versions of the catalytic subunit of mitochondrial DNA polymerase (DmPOLγA) as a means to introduce mtDNA mutations. We report here that lifespan and health in fruit flies are remarkably tolerant to mtDNA mutations. Our results show that the short lifespan and wide genetic bottleneck of fruit flies are limiting the extent of clonal expansion of mtDNA mutations both in individuals and between generations. However, an increase of mtDNA mutations to very high levels caused sensitivity to mechanical and starvation stress, intestinal stem cell dysfunction, and reduced lifespan under standard conditions. In addition, the effects of dietary restriction, widely considered beneficial for organismal health, were attenuated in flies with very high levels of mtDNA mutations.

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Kaufman, Brett A., Nela Durisic, Jeffrey M. Mativetsky, Santiago Costantino, Mark A. Hancock, Peter Grutter e Eric A. Shoubridge. "The Mitochondrial Transcription Factor TFAM Coordinates the Assembly of Multiple DNA Molecules into Nucleoid-like Structures". Molecular Biology of the Cell 18, n. 9 (settembre 2007): 3225–36. http://dx.doi.org/10.1091/mbc.e07-05-0404.

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Abstract (sommario):

Packaging DNA into condensed structures is integral to the transmission of genomes. The mammalian mitochondrial genome (mtDNA) is a high copy, maternally inherited genome in which mutations cause a variety of multisystem disorders. In all eukaryotic cells, multiple mtDNAs are packaged with protein into spheroid bodies called nucleoids, which are the fundamental units of mtDNA segregation. The mechanism of nucleoid formation, however, remains unknown. Here, we show that the mitochondrial transcription factor TFAM, an abundant and highly conserved High Mobility Group box protein, binds DNA cooperatively with nanomolar affinity as a homodimer and that it is capable of coordinating and fully compacting several DNA molecules together to form spheroid structures. We use noncontact atomic force microscopy, which achieves near cryo-electron microscope resolution, to reveal the structural details of protein–DNA compaction intermediates. The formation of these complexes involves the bending of the DNA backbone, and DNA loop formation, followed by the filling in of proximal available DNA sites until the DNA is compacted. These results indicate that TFAM alone is sufficient to organize mitochondrial chromatin and provide a mechanism for nucleoid formation.

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Viramontes, F., F. Filion e L. C. Smith. "5 NEUTRAL SEGREGATION OF DONOR CELL MITOCHONDRIA IN FETAL AND ADULT TISSUES OF SOMATIC CELL CLONES IN CATTLE". Reproduction, Fertility and Development 17, n. 2 (2005): 153. http://dx.doi.org/10.1071/rdv17n2ab5.

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Abstract (sommario):

Until now, animal cloning has been extremely inefficient: only 1–2% of nuclear transfer (NT) clones survive to birth. Some of these anomalies may be related to an incompatibility between nuclear and mitochondrial genes (Cummins JM 2001 Hum. Reprod. Update 7, 217–228). Controversy exists as to the levels of donor cell mitochondrial DNA (mtDNA) inheritance in somatic clones (heteroplasmy). Whereas some researchers found very low quantities (0.1–4%) (Steinborn R et al. 2000 Nat. Genet. 25, 255–257), others found levels of heteroplasmy ranging from 6 to 40% (Takeda et al. Mol. Reprod. Dev. 64, 429–437). Since it remains unclear whether mtDNA segregation is neutral or selective, the purpose of this study was to analyze the transmission of the mtDNA from donor somatic cells in fetal and adult clones using a particular mtDNA marker (mtDNA Bos taurus with one mutation in the D-loop of 40 base pairs plus than the wild type). Fibroblasts from a fetus of 60 days were used as donor cells. The fetus was produced by artificial insemination of a Holstein (Bos taurus) heifer carrying an mtDNA mutation with semen from a Zebu (Bos indicus) bull. Oocytes derived from slaughterhouse ovaries of Holstein cows carrying wild-type mtDNA were used as recipient cells. The presence of the mutated mtDNA from the donor cell (heteroplasmy) was analyzed in a male cloned fetus of 60 days and in three adult male clones at 18 months of age. Heteroplasmy was detected in 7 tissues in the foetus: muscle, skin, stomach, testicle, thymus, tongue, and umbilical cord. Three tissues were analyzed from the adult clones: semen, skin, and white blood cells. Heteroplasmy was detected in all the tissues by nested PCR amplification of the D-loop and analyzed by ANOVA and Tukey-Kramer multiple comparison test. The mean (%) of the mutated mtDNA of the donor cell in the seven tissues of the60-day-old fetus was 1.14 ± 0.34 (SEM). There was no differences in the means of heteroplasmy (%) between the tissues of the fetus (P > 0.05). The mean level of heteroplasmy in the three adult clones analyzed (clones A, B, and C) was 1.41 ± 0.18 (SEM). Analysis of heteroplasmy between the tissues of each clone showed no differences (P > 0.05) with the exception of clone B, where semen was different (P < 0.05) from white blood cells. There were significant differences (P < 0.05) between some clones (taking together all the results of all tissues of each clone). The heteroplasmy in clone B (%) (2.59 ± 0.18 SEM) was different (P < 0.05) from that of both clone A (1.04 ± 0.18) and clone C (1.46 ± 0.18). There was no difference between the heteroplasmy (%) of clone A and that of clone C (P > 0.05). These results show that the tissues of the fetus and the adult clones were heteroplasmic at similar levels, suggesting neutral segregation of the donor cell mtDNA during development and tissue differentiation.

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Battersby, Brendan J., e Eric A. Shoubridge. "Reactive oxygen species and the segregation of mtDNA sequence variants". Nature Genetics 39, n. 5 (maggio 2007): 571–72. http://dx.doi.org/10.1038/ng0507-571.

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34

Kurtz, Andreas, Maria Lueth, Lan Kluwe, Tingguo Zhang, Rosemary Foster, Victor-Felix Mautner, Melanie Hartmann et al. "Somatic Mitochondrial DNA Mutations in Neurofibromatosis Type 1-Associated Tumors". Molecular Cancer Research 2, n. 8 (1 agosto 2004): 433–41. http://dx.doi.org/10.1158/1541-7786.433.2.8.

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Abstract (sommario):

Abstract Neurofibromatosis type 1 is an autosomal dominantly inherited disease predisposing to a multitude of tumors, most characteristically benign plexiform neurofibromas and diffuse cutaneous neurofibromas. We investigated the presence and distribution of somatic mitochondrial DNA (mtDNA) mutations in neurofibromas and in nontumor tissue of neurofibromatosis type 1 patients. MtDNA alterations in the entire mitochondrial genome were analyzed by temporal temperature gradient gel electrophoresis followed by DNA sequencing. Somatic mtDNA mutations in tumors were found in 7 of 19 individuals with cutaneous neurofibromas and in 9 of 18 patients with plexiform neurofibromas. A total of 34 somatic mtDNA mutations were found. All mutations were located in the displacement loop region of the mitochondrial genome. Several plexiform neurofibromas from individual patients had multiple homoplasmic mtDNA mutations. In cutaneous neurofibromas, the same mtDNA mutations were always present in tumors from different locations of the same individual. An increase in the proportion of the mutant mtDNA was always found in the neurofibromas when compared with nontumor tissues. The somatic mtDNA mutations were present in the Schwann cells of the analyzed multiple cutaneous neurofibromas of the same individual. The observed dominance of a single mtDNA mutation in multiple cutaneous neurofibromas of individual patients indicates a common tumor cell ancestry and suggests a replicative advantage rather than random segregation for cells carrying these mutated mitochondria.

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Cieslak, Jakub, Lukasz Wodas, Alicja Borowska, Ernest G. Cothran, Anas M. Khanshour e Mariusz Mackowski. "Characterization of the Polish Primitive Horse (Konik) maternal lines using mitochondrial D-loop sequence variation". PeerJ 5 (24 agosto 2017): e3714. http://dx.doi.org/10.7717/peerj.3714.

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Abstract (sommario):

The Polish Primitive Horse (PPH, Konik) is a Polish native horse breed managed through a conservation program mainly due to its characteristic phenotype of a primitive horse. One of the most important goals of PPH breeding strategy is the preservation and equal development of all existing maternal lines. However, until now there was no investigation into the real genetic diversity of 16 recognized PPH dam lines using mtDNA sequence variation. Herein, we describe the phylogenetic relationships between the PPH maternal lines based upon partial mtDNA D-loop sequencing of 173 individuals. Altogether, 19 mtDNA haplotypes were detected in the PPH population. Five haplotypes were putatively novel while the remaining 14 showed the 100% homology with sequences deposited in the GenBank database, represented by both modern and primitive horse breeds. Generally, comparisons found the haplotypes conformed to 10 different recognized mtDNA haplogroups (A, B, E, G, J, M, N, P, Q and R). A multi-breed analysis has indicated the phylogenetic similarity of PPH and other indigenous horse breeds derived from various geographical regions (e.g., Iberian Peninsula, Eastern Europe and Siberia) which may support the hypothesis that within the PPH breed numerous ancestral haplotypes (found all over the world) are still present. Only in the case of five maternal lines (Bona, Dzina I, Geneza, Popielica and Zaza) was the segregation of one specific mtDNA haplotype observed. The 11 remaining lines showed a higher degree of mtDNA haplotype variability (2–5 haplotypes segregating in each line). This study has revealed relatively high maternal genetic diversity in the small, indigenous PPH breed (19 haplotypes, overall HapD = 0.92). However, only some traditionally distinguished maternal lines can be treated as genetically pure. The rest show evidence of numerous mistakes recorded in the official PPH pedigrees. This study has proved the importance of maternal genetic diversity monitoring based upon the application of molecular mtDNA markers and can be useful for proper management of the PPH conservation program in the future.

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DiMauro, Salvatore. "A Brief History of Mitochondrial Pathologies". International Journal of Molecular Sciences 20, n. 22 (12 novembre 2019): 5643. http://dx.doi.org/10.3390/ijms20225643.

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Abstract (sommario):

The history of “mitochondrial pathologies”, namely genetic pathologies affecting mitochondrial metabolism because of mutations in nuclear DNA-encoded genes for proteins active inside mitochondria or mutations in mitochondrial DNA-encoded genes, began in 1988. In that year, two different groups of researchers discovered, respectively, large-scale single deletions of mitochondrial DNA (mtDNA) in muscle biopsies from patients with “mitochondrial myopathies” and a point mutation in the mtDNA gene for subunit 4 of NADH dehydrogenase (MTND4), associated with maternally inherited Leber’s hereditary optic neuropathy (LHON). Henceforth, a novel conceptual “mitochondrial genetics”, separate from mendelian genetics, arose, based on three features of mtDNA: (1) polyplasmy; (2) maternal inheritance; and (3) mitotic segregation. Diagnosis of mtDNA-related diseases became possible through genetic analysis and experimental approaches involving histochemical staining of muscle or brain sections, single-fiber polymerase chain reaction (PCR) of mtDNA, and the creation of patient-derived “cybrid” (cytoplasmic hybrid) immortal fibroblast cell lines. The availability of the above-mentioned techniques along with the novel sensitivity of clinicians to such disorders led to the characterization of a constantly growing number of pathologies. Here is traced a brief historical perspective on the discovery of autonomous pathogenic mtDNA mutations and on the related mendelian pathology altering mtDNA integrity.

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Adel Hussein, Marwa, Ruaa Hameed Abdulridha, Ibtisam Jasim Sodan, Mais Adnan Al-Ward, May Ridha Jaafar, Hala Khalid Ibrahim Al-Sammarrie, Shahad Emad Neamah, Asmaa A. Jawad e Nadhum Hussen Safir. "Mitochondrial DNA and Disease: A review". Al-Nahrain Journal of Science 27, n. 2 (1 giugno 2024): 81–90. http://dx.doi.org/10.22401/anjs.27.2.08.

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Abstract (sommario):

Mitochondria are organelles responsible for converting energy into a usable form for cellular metabolic activities. These organelles have their own DNA. Mutations in mitochondrial DNA (mtDNA) are frequent despite Its limited number of genes. Molecular genetics diagnostics enables the examination of DNA in manyfields,like infectiology, cancer, andgenetics of people. It is essential to identify abnormalities in mitochondrial DNA in patients since these mutations directly affect mitochondrial metabolism and may contribute to various illnesses. The mtDNA found in every human cell is a limited and significant source of harmful mutations and rearrangements. This review provides a concise overview of the unique principles of mitochondrial genetics, including maternal inheritance, mitotic segregation, heteroplasmy, and the threshold effect. It emphasizes the relatively common occurrence of medical conditions associated with mitochondrial DNA (mtDNA) and discusses recent discoveries of pathogenic mutations, with a particular focus on mutations that impact protein-coding genes. Next, we go into more contentious topics, such as the functional or pathological significance of mtDNA haplotypes, the disease-causing potential of homoplasmic mutations, and the mostly unknown mechanisms behind mtDNA mutations.

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Poulton, J. "Segregation of mitochondrial DNA (mtDNA) in human oocytes and in animal models of mtDNA disease: clinical implications". Reproduction 123, n. 6 (1 giugno 2002): 751–55. http://dx.doi.org/10.1530/reprod/123.6.751.

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Yin, Tao, Jikun Wang, Hai Xiang, Carl A. Pinkert, Qiuyan Li e Xingbo Zhao. "Dynamic characteristics of the mitochondrial genome in SCNT pigs". Biological Chemistry 400, n. 5 (27 maggio 2019): 613–23. http://dx.doi.org/10.1515/hsz-2018-0273.

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Abstract (sommario):

Abstract Most animals generated by somatic cell nuclear transfer (SCNT) are heteroplasmic; inheriting mitochondrial genetics from both donor cells and recipient oocytes. However, the mitochondrial genome and functional mitochondrial gene expression in SCNT animals are rarely studied. Here, we report the production of SCNT pigs to study introduction, segregation, persistence and heritability of mitochondrial DNA transfer during the SCNT process. Porcine embryonic fibroblast cells from male and female Xiang pigs were transferred into enucleated oocytes from Yorkshire or Landrace pigs. Ear biopsies and blood samples from SCNT-derived pigs were analyzed to characterize the mitochondrial genome haplotypes and the degree of mtDNA heteroplasmy. Presence of nuclear donor mtDNA was less than 5% or undetectable in ear biopsies and blood samples in the majority of SCNT-derived pigs. Yet, nuclear donor mtDNA abundance in 14 tissues in F0 boars was as high as 95%. Additionally, mtDNA haplotypes influenced mitochondrial respiration capacity in F0 fibroblast cells. Our results indicate that the haplotypes of recipient oocyte mtDNA can influence mitochondrial function. This leads us to hypothesize that subtle developmental influences from SCNT-derived heteroplasmy can be targeted when using donor and recipient mitochondrial populations from breeds of swine with limited evolutionary divergence.

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Nunnari, J., W. F. Marshall, A. Straight, A. Murray, J. W. Sedat e P. Walter. "Mitochondrial transmission during mating in Saccharomyces cerevisiae is determined by mitochondrial fusion and fission and the intramitochondrial segregation of mitochondrial DNA." Molecular Biology of the Cell 8, n. 7 (luglio 1997): 1233–42. http://dx.doi.org/10.1091/mbc.8.7.1233.

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Abstract (sommario):

To gain insight into the process of mitochondrial transmission in yeast, we directly labeled mitochondrial proteins and mitochondrial DNA (mtDNA) and observed their fate after the fusion of two cells. To this end, mitochondrial proteins in haploid cells of opposite mating type were labeled with different fluorescent dyes and observed by fluorescence microscopy after mating of the cells. Parental mitochondrial protein markers rapidly redistributed and colocalized throughout zygotes, indicating that during mating, parental mitochondria fuse and their protein contents intermix, consistent with results previously obtained with a single parentally derived protein marker. Analysis of the three-dimensional structure and dynamics of mitochondria in living cells with wide-field fluorescence microscopy indicated that mitochondria form a single dynamic network, whose continuity is maintained by a balanced frequency of fission and fusion events. Thus, the complete mixing of mitochondrial proteins can be explained by the formation of one continuous mitochondrial compartment after mating. In marked contrast to the mixing of parental mitochondrial proteins after fusion, mtDNA (labeled with the thymidine analogue 5-bromodeoxyuridine) remained distinctly localized to one half of the zygotic cell. This observation provides a direct explanation for the genetically observed nonrandom patterns of mtDNA transmission. We propose that anchoring of mtDNA within the organelle is linked to an active segregation mechanism that ensures accurate inheritance of mtDNA along with the organelle.

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Saavedra, Carlos, Donald T. Stewart, Rebecca R. Stanwood e Eleftherios Zouros. "Species-Specific Segregation of Gender-Associated Mitochondrial DNA Types in an Area Where Two Mussel Species (Mytilus edulis and M. trossulus) Hybridize". Genetics 143, n. 3 (1 luglio 1996): 1359–67. http://dx.doi.org/10.1093/genetics/143.3.1359.

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Abstract (sommario):

Abstract In each of the mussel species Mytilus edulis and M. trossulus there exist two types of mtDNA, the F type transmitted through females and the M type transmitted through males. Because the two species produce fertile hybrids in nature, F and M types of one may introgress into the other. We present the results from a survey of a population in which extensive hybridization occurs between these two species. Among specimens classified as “pure” M. edulis or “pure” M. trossulus on the basis of allozyme analysis, we observed no animal that carried the F or the M mitotype of the other species. In most animals of mixed nuclear background, an individual's mtDNA came from the species that contributed the majority of the individual's nuclear genes. Most importantly, the two mtDNA types in post-F1 male hybrids were of the same species origin. We interpret this to mean that there are intrinsic barriers to the exchange of mtDNA between these two species. Because such barriers were not noted in other hybridizing species pairs (many being even less interfertile than M. edulis and M. trossulus), their presence in Mytilus could be another feature of the unusual mtDNA system in this genus.

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Nicholls, Thomas J., Cristina A. Nadalutti, Elisa Motori, Ewen W. Sommerville, Gráinne S. Gorman, Swaraj Basu, Emily Hoberg et al. "Topoisomerase 3α Is Required for Decatenation and Segregation of Human mtDNA". Molecular Cell 69, n. 1 (gennaio 2018): 9–23. http://dx.doi.org/10.1016/j.molcel.2017.11.033.

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43

Jokinen⁎, Riikka, Paula Marttinen, Katarin Sandell, Tuula Manninen, Heli Teerenhovi, Timothy Wai, Daniella Teoli, J. C. Loredo-Osti, Eric A. Shoubridge e Brendan J. Battersby. "Cloning a novel mitochondrial protein which regulates tissue-specific mtDNA segregation". Mitochondrion 11, n. 4 (luglio 2011): 641–42. http://dx.doi.org/10.1016/j.mito.2011.03.023.

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44

Howell, Neil, Soumitra S. Ghosh, Eoin Fahy e Laurence A. Bindoff. "Longitudinal analysis of the segregation of mtDNA mutations in heteroplasmic individuals". Journal of the Neurological Sciences 172, n. 1 (gennaio 2000): 1–6. http://dx.doi.org/10.1016/s0022-510x(99)00207-5.

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45

Tesarova, M., H. Hansikova, J. Kytnarova, H. Houstkova, M. Bohm, L. Cerna, J. Zeman e J. Houstek. "Clinical Heterogeneity, Tissue Distribution, and Intergenerational Segregation of mtDNA Mutation A3243G". Toxicology Mechanisms and Methods 14, n. 1-2 (gennaio 2004): 79–84. http://dx.doi.org/10.1080/15376520490257527.

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46

Aretz, Ina, Christopher Jakubke e Christof Osman. "Power to the daughters – mitochondrial and mtDNA transmission during cell division". Biological Chemistry 401, n. 5 (28 aprile 2020): 533–46. http://dx.doi.org/10.1515/hsz-2019-0337.

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Abstract (sommario):

AbstractMitochondria supply virtually all eukaryotic cells with energy through ATP production by oxidative phosphoryplation (OXPHOS). Accordingly, maintenance of mitochondrial function is fundamentally important to sustain cellular health and various diseases have been linked to mitochondrial dysfunction. Biogenesis of OXPHOS complexes crucially depends on mitochondrial DNA (mtDNA) that encodes essential subunits of the respiratory chain and is distributed in multiple copies throughout the mitochondrial network. During cell division, mitochondria, including mtDNA, need to be accurately apportioned to daughter cells. This process requires an intimate and coordinated interplay between the cell cycle, mitochondrial dynamics and the replication and distribution of mtDNA. Recent years have seen exciting advances in the elucidation of the mechanisms that facilitate these processes and essential key players have been identified. Moreover, segregation of qualitatively distinct mitochondria during asymmetric cell division is emerging as an important quality control step, which secures the maintenance of a healthy cell population.

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Kustova, Maria E., Vasilina A. Sokolova, Oksana V. Kidgotko, Mikhail G. Bass, Faina M. Zakharova e Vadim B. Vasilyev. "Distribution of introduced human mitochondrial DNA in early stage mouse embryos". Medical academic journal 20, n. 2 (2 settembre 2020): 69–78. http://dx.doi.org/10.17816/maj34657.

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Objective. The aim of study was the analysis of human mitochondrial DNA (mtDNA) distribution among murine blastomeres in the embryos developing after an injection of human mitochondria suspension at the stage of one or two cells is presented. Material and methods. Mice CBA/C57Black from Rappolovo aged three weeks were used. Zygotes were obtained upon hormonal stimulation of animals and mated with males. 310 pL of mitochondrial suspension from HepG2 cells was injected into a zygote or one blastomere of a two-cell embryo. Zygotes or two-cell embryos cultured in M3 medium drops covered with mineral oil in Petri dishes. Upon reaching the two-, four- or eight-cell stage the cultured embryos were separated into blastomeres. The latter were lysed and the total DNA was isolated. Human mtDNA was detected by PCR using species-specific primers. Results. The development of 2848 mouse embryos was monitored. In 520 embryos that achieved the stage of 2, 4, 8 in proper time the presence of human mtDNA was assayed in each blastomere. Along with murine mtDNA all embryos contained human mitochondrial genome, which is an evidence of artificially modelled heteroplasmy. Not every blastomere of transmitochondrial embryos contained foreign (human) mtDNA. Mathematical elaboration evidenced an uneven distribution of human mtDNA in cytoplasm within the time elapsed between the injection of human mitochondria and the subsequent splitting of the embryo. Conclusion. The results obtained confirm our previous notion of the presence of 1011 segregation units of human mtDNA in the total amount of mitochondria (about 5 ∙ 102) injected into an embryo.

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Blok, Rozanne B., Debra A. Gook, David R. Thorburn e Hans-Henrik M. Dahl. "Skewed Segregation of the mtDNA nt 8993 (TrG) Mutation in Human Oocytes". American Journal of Human Genetics 60, n. 6 (giugno 1997): 1495–501. http://dx.doi.org/10.1086/515453.

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Cavelier, Lucia, Elena Jazin, Paula Jalonen e Ulf Gyllensten. "MtDNA substitution rate and segregation of heteroplasmy in coding and noncoding regions". Human Genetics 107, n. 1 (luglio 2000): 45–50. http://dx.doi.org/10.1007/s004390000305.

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50

Cavelier, Lucia, Elena Jazin, Paula Jalonen e Ulf Gyllensten. "MtDNA substitution rate and segregation of heteroplasmy in coding and noncoding regions". Human Genetics 107, n. 1 (28 luglio 2000): 45–50. http://dx.doi.org/10.1007/s004390050009.

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