Recombination in human mitochondrial DNA?

The possibility of recombination in human mitochondrial DNA (mtDNA) has been hotly debated over the last few years. In this study, a general model of recombination in circular molecules is developed and applied to a recently published African sample (n = 21) of complete mtDNA sequences. It is shown that the power of correlation measures to detect recombination in circular molecules can be vanishingly small and that the data are consistent with the given model and no recombination only if the overall heterogeneity in mutation rate is <0.09.     

Is mitochondrial DNA a strictly neutral marker?

Variation and change in mitochondrial DNA (mtDNA) is often assumed to conform to a constant mutation rate equilibrium neutral model of molecular evolution. Recent evidence, however, indicates that the assumptions underlying this model are frequently violated. The mitochondria) genome may be subject to the same suite of forces known to be acting in the nuclear genome, including hitchhiking and selection, as well as forces that do not affect nuclear variation. Wherever possible, evolutionary studies involving mtDNA should incorporate statistical tests to investigate the forces shaping sequence variation and evolution.     

The accessory subunit of mitochondrial DNA polymerase γ determines the DNA content of mitochondrial nucleoids in human cultured cells

The accessory subunit of mitochondrial DNA polymerase γ, POLGβ, functions as a processivity factor in vitro. Here we show POLGβ has additional roles in mitochondrial DNA metabolism. Mitochondrial DNA is arranged in nucleoprotein complexes, or nucleoids, which often contain multiple copies of the mitochondrial genome. Gene-silencing of POLGβ increased nucleoid numbers, whereas over-expression of POLGβ reduced the number and increased the size of mitochondrial nucleoids. Both increased and decreased expression of POLGβ altered nucleoid structure and precipitated a marked decrease in 7S DNA molecules, which form short displacement-loops on mitochondrial DNA. Recombinant POLGβ preferentially bound to plasmids with a short displacement-loop, in contrast to POLGα. These findings support the view that the mitochondrial D-loop acts as a protein recruitment centre, and suggest POLGβ is a key factor in the organization of mitochondrial DNA in multigenomic nucleoprotein complexes.     

Nuclear and mitochondrial DNA repair: similar pathways?

Mitochondrial DNA (mtDNA) alterations are implicated in a broad range of human diseases and alterations of the mitochondrial genome are assumed to be a result of its high susceptibility to oxidative damage and its limited DNA repair compared to nuclear DNA (nDNA). Characterization of DNA repair mechanisms has generally focused on these processes in nDNA but increasing interest and research effort have contributed to our knowledge of the mechanisms underlying DNA repair in mitochondria. In this review, we make comparisons between nDNA and mtDNA repair pathways and propose a model for how these pathways interact in mitochondria.     

What regulates mitochondrial DNA copy number in animal cells?

The study of the control of mitochondrial DNA copy number spans several decades and has identified many factors involved in the replication of the mitochondrial genome. However, the mechanisms involved in the regulation of this process are still obscure, particularly in animal cells. During the past decade, however, the identification of human diseases associated with drastically reduced levels of mtDNA caused renewed interest in this topic. Here, I will discuss recent work that sheds some light on how animal cells might maintain and control mtDNA levels.     

A mechanistic view of human mitochondrial DNA polymerase γ: Providing insight into drug toxicity and mitochondrial disease

Mitochondrial DNA polymerase gamma (Pol γ) is the sole polymerase responsible for replication of the mitochondrial genome. The study of human Pol γ is of key importance to clinically relevant issues such as nucleoside analog toxicity and mitochondrial disorders such as progressive external ophthalmoplegia. The development of a recombinant form of the human Pol γ holoenzyme provided an essential tool in understanding the mechanism of these clinically relevant phenomena using kinetic methodologies. This review will provide a brief history on the discovery and characterization of human mitochondrial DNA polymerase γ, focusing on kinetic analyses of the polymerase and mechanistic data illustrating structure–function relationships to explain drug toxicity and mitochondrial disease.     

Reviewing population studies for forensic purposes: Dog?mitochondrial DNA

The identification of dog hair through mtDNA analysis has become increasingly important in the last 15 years, as it can provide associative evidence connecting victims and suspects. The evidential value of an mtDNA match between dog hair and its potential donor is determined by the random match probability of the haplotype. This probability is based on the haplotype’s population frequency estimate. Consequently, implementing a population study representative of the population relevant to the forensic case is vital to the correct evaluation of the evidence. This paper reviews numerous published dog mtDNA studies and shows that many of these studies vary widely in sampling strategies and data quality. Therefore, several features influencing the representativeness of a population sample are discussed. Moreover, recommendations are provided on how to set up a dog mtDNA population study and how to decide whether or not to include published data. This review emphasizes the need for improved dog mtDNA population data for forensic purposes, including targeting the entire mitochondrial genome. In particular, the creation of a publicly available database of qualitative dog mtDNA population studies would improve the genetic analysis of dog traces in forensic casework.     

Transfer of chloramphenicol‐resistant mitochondrial DNA into the chimeric mouse

The mitochondrial DNA (mtDNA) chloramphenicol (CAP)resistance (CAP^R) mutation has been introduced into the tissues of adult mice via female embryonic stem (ES) cells. The endogenous CAPsensitive (CAP^S) mtDNAs were eliminated by treatment of the ES cells with the lipophilic dye Rhodamine6G (R6G). The ES cells were then fused to enucleated cell cytoplasts prepared from the CAP^R mouse cell line 5011. This procedure converted the ES cell mtDNA from 100% wildtype to 100% mutant. The CAP^R ES cells were then injected into blastocysts and viable chimeric mice were isolated. Molecular testing for the CAP^R mutant mtDNAs revealed that the percentage of mutant mtDNAs varied from zero to approximately 50% in the tissues analyzed. The highest percentage of mutant mtDNA was found in the kidney in three of the chimeric animals tested. These data suggest that, with improved efficiency, it may be possible to transmit exogenous mtDNA mutants through the mouse germline.     

Animal mitochondrial DNA polymorphism：a valuable tool for evolutionary studies

Since the mitochondrial DNA(mtDNA) was discovered[1],a great amount of information have been accumulated about its sturcutres and functions[2],The complete nucleotide sequence of the mitochondrial genome has been determined for one individual in each of the following species:mouse(Mus musculus)[3],human(HOmo sapiens)[4],cow(Bos taurus)[5],Xenopus laevis[6],fruit fly(Drosophila yacuba)[7],sea urchin (Strongylocentrotus purpuratus)[8].rat(rattus novegicus)[9],fin whale(Balaenoptera physalus)[10],and harbor seal(Phoca vitulina)[11],More than 300 species of animals have been studied on mtDNA^3.In the past 10 years.mtDNA has been a useful and powerful tool in the field of evolutionary biology and taxonomy.     

Animal mitochondrial DNA polymorphism: a valuable tool for evolutionary studies~1

Since the mitochondrial DNA (mtDNA) was discovered, a great amount of information have been accumulated about its strucutres and functions. The complete nucleotide sequence of the mitochondrial genome has been determined for one individual in each of the following species: mouse (Mus musculus), human (Homo sapiens), cow (Bos taurus), Xenopus laevis, fruit fly (Drosophila yacuba),     

Polymorphism of mitochondrial DNA ‘S’ regions among normal cytoplasms of maize

Genomic variation in S1 and S2 homologous sequences, defined as the S regions, were examined in mitochondrial DNAs of 12 normal cytoplasm maize lines collected in the United States. Three genomic variants were detected among the 12 cytoplasms, eight of which were identical to the Wf9 model structure. Hybridization data with S1 and S2 DNAs and with two cosmids spanning these regions were consistent with the concept that S1 and S2 sequences are found in each normal cytoplasm. Three variations of the S1 region were established; the Wf9 structure, a second group consisting of F6, A188, and W182BN, and a third, Black Mexican. Genome structure was conserved through the S2 region in all lines examined. None of the cytoplasms included complete copies of S1; the 1400 bp repeat characteristic of S1 and S2 was absent in the S1 region of all lines. A 2.1 kb linear DNA was observed instead of a 2.3 kb DNA in F6, A188, and W182BN. Integrated copies of S1 and S2 sequences may be a constituitive characteristic of normal, male-fertile maize cytoplasms.     

Review: can diet influence the selective advantage of mitochondrial DNA haplotypes?

This review explores the potential for changes in dietary macronutrients to differentially influence mitochondrial bioenergetics and thereby the frequency of mtDNA haplotypes in natural populations. Such dietary modification may be seasonal or result from biogeographic or demographic shifts. Mechanistically, mtDNA haplotypes may influence the activity of the electron transport system (ETS), retrograde signalling to the nuclear genome and affect epigenetic modifications. Thus, differential provisioning by macronutrients may lead to selection through changes in the levels of ATP production, modulation of metabolites (including AMP, reactive oxygen species (ROS) and the NAD⁺/NADH ratio) and potentially complex epigenetic effects. The exquisite complexity of dietary influence on haplotype frequency is further illustrated by the fact that macronutrients may differentially influence the selective advantage of specific mutations in different life-history stages. In Drosophila, complex I mutations may affect larval growth because dietary nutrients are fed through this complex in immaturity. In contrast, the majority of electrons are provided to complex III in adult flies. We conclude the review with a case study that considers specific interactions between diet and complex I of the ETS. Complex I is the first enzyme of the mitochondrial ETS and co-ordinates in the oxidation of NADH and transfer of electrons to ubiquinone. Although the supposition that mtDNA variants may be selected upon by dietary macronutrients could be intuitively consistent to some and counter intuitive to others, it must face a multitude of scientific hurdles before it can be recognized.     

Does strong hypertrophic condition induce fast mitochondrial DNA mutation of rabbit heart?

Homo- and heteroplasmic mitochondrial DNA (mtDNA) mutations were observed and identified in an isoproterenol-induced rabbit model of cardiac hypertrophy. Genes encoding proteins essential for catalyzing mitochondrial electron transfer and for generating the proton motive force, such as NADH dehydrogenases (ND2, ND3, ND4, and ND6), cytochrome b, and ATPase 8, showed increased susceptibility for mutation. Specifically, five mutations caused amino acid changes and were located in Complex I and Complex V gene clusters. To our knowledge, this is the first demonstration of a relationship between cardiac hypertrophy induced by a strong sympathetic load and rapid mtDNA mutations.     

Incorporation of β-sitosterol into mitochondrial membrane enhances mitochondrial function by promoting inner mitochondrial membrane fluidity

Recent findings suggest that mitochondrial membrane fluidity could influence mitochondrial energy metabolism. β-sitosterol (BS) is a common plant sterol that is prevalent in plant oils, nuts, cereals and plant food products. Its chemical structure is very similar to that of cholesterol. As a cholesterol analog, BS is highly lipid soluble and largely resides in the membranes of cells or organelles where it may have an influence on the membrane fluidity. The present study reports that, with the cholesterol chelator 2-hydroxypropyl-β-cyclodextrin (HPβCD) as its carrier, BS is able to increase the fluidity of the inner mitochondrial membrane (IMM) without affecting the fluidity of the outer mitochondrial membrane (OMM), and consequently to increase the mitochondrial membrane potential (?Ψm) and mitochondrial ATP content. It has been previously proposed that a therapeutical boost in adenosine triphosphate (ATP) levels in mitochondria may be beneficial for neurodegenerative diseases such as Alzheimer’s disease (AD). Given that dietary administration of plant sterols could increase brain BS concentrations, these results may provide a better understanding of the beneficial effects of plant sterol-enriched nutrients on neurodegenerative diseases such as AD.