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PubMed1995

mtDNA-depleted U937 cells are sensitive to TNF and Fas-mediated cytotoxicity.

It has been proposed that TNF cytotoxicity is mediated by reactive oxygen intermediates generated by uncoupling of mitochondrial respiration. We have compared sensitive U937 cells and derived cell lines depleted of mtDNA for their ability to undergo TNF- and Fas-induced apoptosis. Cells lacking around 98% of mtDNA were still sensitive to TNF-induced apoptosis. U937 cells devoid of mtDNA (U937-rho degree) were resistant to TNF, but this was due to the loss of its 55 kDa receptor. U937-rho degree cells were also resistant to docosahexaenoic acid, which causes U937 cell death by lipid peroxidation. These cells were sensitive to anti-Fas toxicity. The results indicate that TNF and Fas-induced toxicity occurs by a mechanism mostly independent of mitochondrial free radical generation.

Amobarbital↗
PubMed1996

Did de novo MELAS common mitochondrial DNA point mutation (mtDNA 3243, A-->G transition) occur in the mother of a proband of a Japanese MELAS pedigree?

MELAS is a major maternally inherited mitochondrial (mt) encephalomyopathy of which 80% of cases are associated with mtDNA point mutation (mtDNA 3243, A-->G transition) which exists under heteroplasmic conditions with wild-type mtDNA. The origin of this mutation remains obscure in the reported pedigrees. I analyzed this mutation in a Japanese MELAS pedigree by PCR. The proband had typical MELAS features. The proband's mother was oligosymptomatic (fatigability, nerve deafness and diabetes mellitus). The proband's maternal grandmother was diagnosed as having senile dementia of the Alzheimer type clinically. The brother of the proband's mother was healthy. The ratios of this mutation in muscle and leukocytes of the proband and his mother were 89%, 36%, 79% and 10%, respectively. There were no mutations in muscle and leukocytes of the proband's maternal grandmother and his mother's brother. These results showed the possibility that this mutation occurred in the proband's mother.

Adenine↗
PubMed1984

Identification of a promoter for transcription of the heavy strand of human mtDNA: in vitro transcription and deletion mutagenesis.

Plasmids containing the origin region of human mtDNA are specifically transcribed by the partially purified homologous mtRNA polymerase in vitro. Transcription of both the light and heavy strands initiates at the same sites previously identified as in vivo transcription start sites. The sequences responsible for initiation of heavy strand transcription are investigated in detail, since this transcript includes the rRNA cistrons and the majority of tRNA genes and potential mRNAs. Deletion mutagenesis is employed to delimit the sequences responsible for heavy strand transcription to a region of less than 35 bp surrounding the transcription start site. This region contains a repetitive sequence, AAACCCC, and shows homology to other regions of the human mtDNA that have been implicated as transcription initiation sites or that show unusual homology to other mammalian mtDNA genomes.

Base Sequence↗
PubMed1995

Mitochondrial DNA (mtDNA) diseases: correlation of genotype to phenotype.

This study examines the relationship of genotype to phenotype in 14 unselected patients who were found to harbour the A3243G transition in the mitochondrial transfer RNALeu(UUR) gene commonly associated with the syndrome of mitochondrial encephalopathy, lactic acidosis and strokes (MELAS). Only 6 of the 14 cases (43%) had seizures and recurrent strokes, the core clinical features of the MELAS phenotype. Of the remaining cases, four had an encephalomyopathy with deafness, ataxia and dementia, two had syndromes with progressive external ophthalmoplegia and two had limb weakness alone. Even within the MELAS subgroup, the majority of patients had one or more clinical manifestations considered to be atypical of the MELAS syndrome. They included developmental delay, ophthalmoparesis, pigmentary retinopathy and intestinal pseudo-obstruction. The proportion of mutant mitochondrial DNA (mtDNA) in muscle was generally higher in patients with recurrent strokes than in those without strokes, the highest levels being observed in MELAS cases with early onset disease. Studies of isolated muscle mitochondria identified a range of respiratory chain abnormalities mostly involving Complex I; immunoblots of Complex I in 3 of 10 cases showed selective loss of specific subunits encoded by nuclear genes. In the group as a whole, however, no clear correlations were observed between the severity or extent of the respiratory chain abnormality and clinical phenotype or the proportion of mutant mtDNA in biopsied skeletal muscle. These discrepancies suggest that, in patients harbouring the common MELAS3243 mutation, differences in heteroplasmy and the proportions of mutant mtDNA may not be the sole determinants of disease expression and that additional genetic mechanisms are involved in defining the range of clinical and biochemical phenotypes associated with this aberrant mitochondrial genome.

Adolescent↗
PubMed1995

mtDNA mutations in Leber's hereditary optic neuropathy.

At least five mtDNA point mutations appear sufficient in themselves to cause Leber's hereditary optic neuropathy (LHON), while several other base substitutions act synergistically by increasing the risk for optic atrophy. The three most common mutations associated with LHON are ND4/11778, ND1/3460 and ND6/14484 covering 50, 30 and 10% of the families, respectively. mtDNA heteroplasmy is seen most often in sporadic cases reflecting a recent mutational event. The etiology of LHON is still enigmatic. In addition to mtDNA mutations, nuclear gene interaction and environmental factors may contribute to the expression of optic atrophy.

Blindness↗
PubMed2006

Tumoral cell mtDNA approximately 8.9 kb deletion is more common than other deletions in gastric cancer.

BACKGROUND: The aim of the study was to clarify the role of deletion of mitochondrial DNA (mtDNA) in gastric carcinogenesis and to determine prevalence of mitochondrial deletions in different regions of tumoral tissue in comparison with adjacent non-tumoral tissue in gastric cancer. METHODS: In order to investigate whether a high incidence of mutations exists in mtDNA of gastric cancer tissues, we screened five regions of the mitochondrial genome by PCR amplification, Southern blot and DNA sequence analysis. RESULTS: Of 71 cancer patients, the approximately 8.9 kb deletion was detected among different deletions in 9 cases (12.67%) of the tumoral tissues and 1 case (1.40%) in non-tumoral tissues that were adjacent to the tumors. Level of the 8.9 kb deletion has been found to be more than other deletions in tumoral tissues. CONCLUSIONS: The approximately 8.9 kb deletion has an obvious correlation with age and histological type. These data suggest that the approximately 8.9 kb deletion in mtDNA may play an important role in gastric carcinogenesis.

Adult↗
PubMed2004

Bioenergetics of mitochondrial diseases associated with mtDNA mutations.

This mini-review summarizes our present view of the biochemical alterations associated with mitochondrial DNA (mtDNA) point mutations. Mitochondrial cytopathies caused by mutations of mtDNA are well-known genetic and clinical entities, but the biochemical pathogenic mechanisms are often obscure. Leber's hereditary optic neuropathy (LHON) is due to three main mutations in genes for complex I subunits. Even if the catalytic activity of complex I is maintained except in cells carrying the 3460/ND1 mutation, in all cases there is a change in sensitivity to complex I inhibitors and an impairment of mitochondrial respiration, eliciting the possibility of generation of reactive oxygen species (ROS) by the complex. Neurogenic muscle weakness, Ataxia and Retinitis Pigmentosa (NARP), is due to a mutation in the ATPase-6 gene. In NARP patients ATP synthesis is strongly depressed to an extent proportional to the mutation load; nevertheless, ATP hydrolysis and ATP-driven proton translocation are not affected. It is suggested that the NARP mutation affects the ability of the enzyme to couple proton transport to ATP synthesis. A point mutation in subunit III of cytochrome c oxidase is accompanied by a syndrome resembling MELAS: however, no major biochemical defect is found, if we except an enhanced production of ROS. The mechanism of such enhancement is at present unknown. In this review, we draw attention to a few examples in which the overproduction of ROS might represent a common step in the induction of clinical phenotypes and/or in the progression of several human pathologies associated with mtDNA point mutations.

Adenosine Triphosphatases↗
PubMed2003

The impact of mtDNA analysis between positions nt8306 and nt9021 for forensic casework.

Identification in forensic casework by mtDNA sequencing is predominantly done by sequencing the non-coding control region (HVI and HVII). In an attempt to further increase the discriminatory power of mtDNA analysis, we sequenced a coding region between nt8306 and nt9021 to identify additional polymorphisms in a group of 61 unrelated German individuals who had mtDNA profiles that occurred more than two times each, as well as a control group of 119 unrelated Germans whose profiles occurred one or two times each. Within these 180 individuals, 38 different polymorphisms in this region were observed; 64.4% of these individuals displayed the Cambridge reference sequence profile plus A8860G. For 28 individuals with the two most common profiles, A263G-315.1insC (N = 18) and A263G-309.1insC-315.1insC (N = 10), additional polymorphisms in this coding region permitted further discrimination of 56 and 40% of the individuals, respectively.

Journal Article↗
PubMed2006

RepeatAround: a software tool for finding and visualizing repeats in circular genomes and its application to a human mtDNA database.

RepeatAround is a Windows based software tool designed to find "direct repeats", "inverted repeats", "mirror repeats" and "complementary repeats", from 3 to 64 bp length, in circular genomes. It processes input files directly extracted from GenBank database, providing visualisation of the repeats location in the genomic structure, so that for instance, in most mtDNAs the user can check if the repeats are located in coding or non-coding region (and in the first case in which gene), and how far apart the repeat pair(s) are. Besides the visual tool, it provides other outputs in a spreadsheet containing information on the number and location of the repeats, facilitating graphic analyses. Several genomes can be inputed simultaneously, for phylogenetic comparison purposes. Other capabilities of the software are the generation of random circular genomes, for statistical evaluation of comparison between observed repeats distributions with their shuffled counterparts, as well as the search for specific motifs, allowing an easy confirmation of repeats flanking a newly detected rearrangement. As an example of the programme's applications we analysed the Direct Repeats distribution in a large human mtDNA database. Results showed that Direct Repeats, even the larger ones, are evenly distributed among the human mtDNA haplogroups, enabling us to state that, based only on the repetitive motifs, no haplogroup is particularly more or less prone to mtDNA macrodeletions.

Computational Biology↗
PubMed2005

Rapidly progressive neurodegeneration in a case with the 7472insC mutation and the A7472C polymorphism in the mtDNA tRNA ser(UCN) gene.

The authors report the clinical, neuroimaging, muscle biopsy and mtDNA findings in a patient affected by bilateral hearing loss and mental retardation since infancy, presenting at age 31 years with a rapid deterioration of mental status and ataxia leading to vegetative condition and death at the age of 32 years. Clinical and genetic studies have been also performed in the mother, affected by neurosensorial hearing loss. Muscle biopsy showed severe mitochondrial alterations in the propositus and evidence of mitochondrial alterations in his mother. Direct mtDNA sequencing in all family members revealed the known 7472insC mutation and the recently described A7472C sequence variation in the tRNA(Ser(UCN))gene. RFLP-PCR confirmed the heteroplasmic nature of the two mutations and failed to find the second transversion in 200 controls. The percentage of mutant genomes harbouring 7472insC ranged from 3 to 7% in asymptomatic family members to 70% in the proband and his mother, whereas the percentage of A7472C mutant genomes was about 90% in all maternal relatives except the proband (56%) and his sister (5%). In conclusion, this is the first report of a rapidly progressive encephalopathy in association with the 7472insC mutation in mtDNA, combined with an A>C variation at the same nucleotide with a possible suppression effect on the pathogenic mutation.

Adult↗
PubMed2006

Harvesting the fruit of the human mtDNA tree.

Human mitochondrial DNA (mtDNA) studies have entered a new phase since the blossoming of complete genome analyses. Sequencing complete mtDNAs is more expensive and more labour intensive than restriction analysis or simply sequencing the control region of the molecule. But the efforts are paying off, as the phylogenetic resolution of the mtDNA tree has been greatly improved, and, in turn, phylogeographic interpretations can be given correspondingly greater precision in terms of the timing and direction of human dispersals. Therefore, despite mtDNA being only a fraction of our total genome, the deciphering of its evolution is profoundly changing our perception about how modern humans spread across our planet. Here we illustrate the phylogeographic approach with two case studies: the initial dispersal out of Africa, and the colonization of Europe.

Africa↗
PubMed2005

Evolutionary history of the greater white-toothed shrew (Crocidura russula) inferred from analysis of mtDNA, Y, and X chromosome markers.

We investigate the evolutionary history of the greater white-toothed shrew across its distribution in northern Africa and mainland Europe using sex-specific (mtDNA and Y chromosome) and biparental (X chromosome) markers. All three loci confirm a large divergence between eastern (Tunisia and Sardinia) and western (Morocco and mainland Europe) lineages, and application of a molecular clock to mtDNA divergence estimates indicates a more ancient separation (2.25 M yr ago) than described by some previous studies, supporting claims for taxonomic revision. Moroccan ancestry for the mainland European population is inconclusive from phylogenetic trees, but is supported by greater nucleotide diversity and a more ancient population expansion in Morocco than in Europe. Signatures of rapid population expansion in mtDNA, combined with low X and Y chromosome diversity, suggest a single colonization of mainland Europe by a small number of Moroccan shrews >38 K yr ago. This study illustrates that multilocus genetic analyses can facilitate the interpretation of species' evolutionary history but that phylogeographic inference using X and Y chromosomes is restricted by low levels of observed polymorphism.

Africa, Northern↗
PubMed2000

Autosomal, mtDNA, and Y-chromosome diversity in Amerinds: pre- and post-Columbian patterns of gene flow in South America.

To evaluate sex-specific differences in gene flow between Native American populations from South America and between those populations and recent immigrants to the New World, we examined the genetic diversity at uni- and biparental genetic markers of five Native American populations from Colombia and in published surveys from native South Americans. The Colombian populations were typed for five polymorphisms in mtDNA, five restriction sites in the beta-globin gene cluster, the DQA1 gene, and nine autosomal microsatellites. Elsewhere, we published results for seven Y-chromosome microsatellites in the same populations. Autosomal polymorphisms showed a mean G(ST) of 6.8%, in agreement with extensive classical marker studies of South American populations. MtDNA and Y-chromosome markers resulted in G(ST) values of 0.18 and 0.165, respectively. When only Y chromosomes of confirmed Amerind origin were used in the calculations (as defined by the presence of allele T at locus DYS199), G(ST) increased to 0.22. G(ST) values calculated from published data for other South American natives were 0.3 and 0.29 for mtDNA and Amerind Y chromosomes, respectively. The concordance of these estimates does not support an important difference in migration rates between the sexes throughout the history of South Amerinds. Admixture analysis of the Colombian populations suggests an asymmetric pattern of mating involving mostly immigrant men and native women.

Africa↗
PubMed2002

External ophthalmoplegia with severe progressive multiorgan involvement associated with the mtDNA A3243G mutation.

BACKGROUND: Chronic progressive external ophthalmoplegia (CPEO) may be related to primary nuclear DNA or mitochondrial (mt)DNA mutations. The A3243G mtDNA point mutation most frequently causes mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, but also has been associated with other phenotypes including CPEO, migraine, seizure, diabetes, and sensorineural hearing loss. CASE DESCRIPTION: We report a 38-year-old white man with seizures and progressive difficulties of infantile origin including CPEO, sensorineural hearing loss, cataracts, migraines, multiple endocrinopathy, myopathy, and cardiomyopathy. Moderate hearing loss in association with CPEO, diabetes mellitus, or migraines were noted in the proband's maternal grandmother, great aunt, mother, and three sisters, suggesting either an autosomal dominant or maternal inheritance. Detailed histological and biochemical analysis of the proband's biopsied muscle specimen revealed severe abnormalities compatible with a mitochondrial disease. MtDNA analysis excluded large-scale deletions, but revealed a heteroplasmic A to G transition at nt3243 in 56.4% and 27.4% of molecules in muscle and white blood cells, respectively. CONCLUSION: We discuss possible causes of this intrafamilial heterogeneity of phenotypes associated with the A3243G mtDNA mutation.

Adult↗
PubMed2000

Longitudinal analysis of the segregation of mtDNA mutations in heteroplasmic individuals.

The mutation load of the pathogenic LHON (Leber hereditary optic neuropathy) mtDNA mutation at nucleotide 3460 has been followed over time in the WBC/platelet fraction from members of a matrilineal pedigree. Longitudinal analysis over a sampling period of five to six years indicates that, in all five heteroplasmic family members, the mutation load decreases at a mean overall rate of approximately 1% per year. There was no change in mutation load in homoplasmic wildtype or in homoplasmic mutant individuals. For the purposes of comparison, a longitudinal analysis of a silent mtDNA polymorphism at nucleotide 14560 was also carried out for members of a second matrilineal pedigree. In contrast to the results for the pathogenic mtDNA mutation, there was no change in the proportion of the silent polymorphism in the WBC/platelet fraction of four family members over a period of seven years. These results indicate that the pathogenic 3460 LHON mutation segregates under negative selection in these cell populations. One possible mechanism through which selection may operate is that, in heteroplasmic individuals, the hematopoietic stem cells are generally homoplasmic, either for the wildtype or for the mutant allele. The homoplasmic mutant stem cells, because of their mitochondrial respiratory chain defect, produce fewer mature WBCs and platelets over time than do the wildtype stem cells. Alternatively, the stem cells may be heteroplasmic and selection may act to favor proliferation of mitochondria with lower levels of the pathogenic mutation in the WBC/platelet cell populations.

DNA Mutational Analysis↗
PubMed2001

Natural selection and the evolution of mtDNA-encoded peptides: evidence for intergenomic co-adaptation.

Mitochondrial DNA (mtDNA) variation is an important tool for the investigation of the population genetics of animal species. Recently, recognition of the role of mtDNA mutations in human disease has spurred increasing interest in the function and evolution of mtDNA and the 13 polypeptides it encodes. These proteins interact with a large number of peptides encoded in the nucleus to form the mitochondrial electron transport system (ETS). As the ETS is the primary energy generation system in aerobic metazoans, natural selection would be expected to favor mutations that enhance ETS function. Such mutations could occur in either the mitochondrial or nuclear genes encoding ETS proteins and would lead to positive intergenomic interactions, or co-adaptation. Direct evidence for intergenomic co-adaptation comes from functional studies of systems where nuclear-mitochondrial DNA combinations vary naturally or can be manipulated experimentally.

Adaptation, Biological↗
PubMed2000

Efficiency of forensic mtDNA analysis. Case examples demonstrating the identification of traces.

The paper presents results of forensic mitochondrial DNA analyses which were aimed at typing the traces caused by touching or abrasion of skin cells. Five cases of strangulation tool investigation are summarised. Two cases of homicide could be cleared up by identifying the mtDNA of both the victim and the suspect on cables which had obviously been used as strangulation tools. In eight of 10 cases, weapons could be reliably assigned to their users. The mtDNA of the users could be even detected on cartridges after firing. In one case, evidence of a suicide could be provided by means of mtDNA sequencing of the wiping traces on a suicide note.

DNA Fingerprinting↗
PubMed2003

mt4216C variant in linkage with the mtDNA TJ cluster may confer a susceptibility to mitochondrial dysfunction resulting in an increased risk of Parkinson's disease in the Irish.

Polymorphism of the mtDNA genome has been implicated as playing a role in the development and pathogenesis of Parkinson's disease (PD). A PCR-RFLP methodology was employed to generate genetic haplotypes for a cohort of 90 PD sufferers. No association was observed between the various mtDNA haplotypes observed and PD in comparison to healthy aged controls. The longevity-associated European J haplogroup and T haplogroup were identified and were both found to be in tight linkage with the mt4216C polymorphism. The mt4216C variant was observed at a significantly increased frequency in the PD cases (28%) in comparison to the healthy aged controls (15%; p=0.014). However, when the frequency of the mt4216C variant was examined in a cohort of 200 young controls (18-45 years) a similar frequency to the PD cases (25%) was observed. The frequencies obtained for the two branches of the J haplogroup (J1 and J2) and the T haplogroup in the cohort of PD subjects also reflected those observed for the young controls used in the previous longevity study. These findings lead one to postulate that the mt4216C variant, in linkage with the mtDNA TJ cluster, may influence mitochondrial dysfunction, resulting in an increased risk of PD.

Adult↗