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PubMed2000

No sex please, we're mitochondria: a hypothesis on the somatic unit of inheritance of mammalian mtDNA.

In this article we develop a model for the organization and maintenance of mitochondrial DNA (mtDNA) in mammalian somatic cells, based on the idea that the unit of genetic function comprises a group of mtDNA molecules that are semi-permanently associated as a mitochondrial nucleoid. Different mtDNA molecules within a nucleoid need not be genetically identical. We propose that nucleoids replicate faithfully via a kind of mitochondrial mitosis, generating daughter nucleoids that are identical copies of each other, but which can themselves segregate freely. This model can account for the very slow rates of mitotic segregation observed in cultured, heteroplasmic cell-lines, and also for the apparently poor complementation observed between different mutant mtDNAs co-introduced into rho(0) cells (cells that lack endogenous mtDNA). It also provides a potential system for maintaining the mitochondrial genetic fitness of stem cells in the face of a presumed high somatic mutation rate of mtDNA and many rounds of cell division in the absence of phenotypic selection. BioEssays 22:564-572, 2000.

Animals↗
PubMed2005

Microevolution in prehistoric Andean populations: chronologic mtDNA variation in the desert valleys of northern Chile.

Archeological evidence suggests that the iconographic and technological developments that took place in the highlands around Lake Titicaca in the Central Andean region had an influence on the cultural elaborations of the human groups in the valleys and the Pacific coast of northern Chile. In a previous communication, we were able to show, by means of a distance analysis, that a craniofacial differentiation accompanied the process of cultural evolution in the valleys (Rothhammer and Santoro [2001] Lat. Am. Antiq. 12:59-66). Recently, numerous South Amerindian mtDNA studies were published, and more accurate molecular techniques to study ancient mtDNA are available. In view of these recent developments, we decided 1) to study chronological changes of ancient mtDNA haplogroup frequencies in the nearby Lluta, Azapa, and Camarones Valleys, 2) to identify microevolutionary forces responsible for such changes, and 3) to compare ancient mtDNA haplogroup frequencies with previous data in order to validate craniometrical results and to reconstruct the biological history of the prehistoric valley groups in the context of their interaction with culturally more developed highland populations. From a total of 97 samples from 83 individuals, 68 samples (61 individuals) yielded amplifications for the fragments that harbor classical mtDNA markers. The haplogroup distribution among the total sample was as follows: 26.2%, haplogroup A; 34.4%, haplogroup B; 14.8%, haplogroup C; 3.3%, haplogroup D; and 21.3%, other haplogroups. Haplogroup B tended to increase, and haplogroup A to decrease during a 3,900-year time interval. The sequence data are congruent with the haplogroup analysis. In fact, the sequencing of hypervariable region I of 30 prehistoric individuals revealed 43 polymorphic sites. Sequence alignment and subsequent phylogenetic tree construction showed two major clusters associated with the most common restriction haplogroups. Individuals belonging to haplogroups C and D tended to cluster together with nonclassical lineages.

Base Sequence↗
PubMed1995

Whole mitochondrial genome amplification reveals basal level multiple deletions in mtDNA of patients with dilated cardiomyopathy.

Basal level multiple deletions in the heart mitochondrial (mt) DNA of patients with dilated cardiomyopathy were analyzed with the recently developed long PCR technique. The amplification of the whole mitochondrial genome and the length dependent preferential amplification ensure that all existing deletions are detected simultaneously. Primer shift long PCR proved the specificity of our method in the detection of deletions. We used primers that were 15644 bp and 13765 bp apart, which comprised almost the entire mitochondrial genome, detected a total of 14 kinds of deletions in 18 out of the 40 endomyocardial biopsy samples from patients with dilated cardiomyopathy. These deletions ranged in size from 3.3 kb to 12.6 kb. The proportion of the deleted to wild-type mtDNA was calculated to be less than 9% for any of these deletions. Aged patients had a comparatively higher proportion. Deletions were rarely found in mtDNA of leukocytes from the same group of patients and of 38 additional patients, as well as in myocardia of 25 normal controls (P < 0.01). No deletion was found in leukocytic mtDNA of the 21 control subjects. It is therefore concluded that cardiomyopathic heart has a high frequency of mtDNA deletions. With regard to the low quantity and the cumulative nature of these deletions by aging, they could have only little pathogenic effect on the development of dilated cardiomyopathy, but rather be a sign of increasing stress of the heart promoting the damage of mtDNA.

Base Sequence↗
PubMed1999

Characterization of cybrid cell lines containing mtDNA from Huntington's disease patients.

Electron transport chain (ETC) dysfunction may arise from mitochondrial genetic, nuclear genetic, or toxic etiologies. Cytoplasmic hybrid (cybrid) systems can help distinguish between these possibilities by facilitating expression of suspect mitochondrial DNA (mtDNA) within a nuclear and environmentally controlled context. Perpetuation of ETC dysfunction in cybrids is consistent with an mtDNA pathogenesis while defect correction is not. We previously used cybrids to screen sporadic Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis patients for mtDNA mutation with positive results. To further address the fidelity of these experiments, we created and characterized cybrids expressing mtDNA from persons with Huntington's disease (HD), an autosomal dominant, nuclear DNA-determined disorder in which mitochondrial ETC functioning is abnormal. On ETC, oxidative stress, and calcium homeostasis assays HD cybrid lines were indistinguishable from control cybrid lines. These data support the use of the cybrid technique for mtDNA mutation screening in candidate diseases.

Adult↗
PubMed2000

Mitochondrial GPx1 decreases induced but not basal oxidative damage to mtDNA in T47D cells.

The production of oxyradicals by mitochondria (mt) is a source of oxidative damage to mtDNA such as 8-oxo-dG lesions that may lead to mutations and mitochondrial dysfunction. The potential protection of mtDNA by glutathione peroxidase-1 (GPx1) was investigated in GPx1-proficient (GPx-2) and GPx1-deficient (Hygro-3) human breast T47D cell transfectants. GPx activity and GPx1-like antigen concentration in mitochondria were respectively at least 100-fold and 20- to 25-fold higher in GPx2 than Hygro-3 cells. In spite of this large difference in peroxide-scavenging capacity, the basal 8-oxo-dG frequency in mtDNA, assessed by carefully controlled postlabeling assay, was strikingly similar in both cell lines. In contrast, in response to menadione-mediated oxidative stress, induction of 8-oxo-dG and DNA strand breaks was much lower in the GPx1-proficient mitochondria (e.g., +14% 8-oxo-dG versus +54% in Hygro-3 after 1-h exposure to 25 microM menadione, P < 0.05). Our data indicate that the mitochondrial glutathione/GPx1 system protected mtDNA against damage induced by oxidative stress, but did not prevent basal oxidative damage to mtDNA, which, surprisingly, appeared independent of GPx1 status in the T47D model.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1996

Complete nucleotide sequences of the domestic cat (Felis catus) mitochondrial genome and a transposed mtDNA tandem repeat (Numt) in the nuclear genome.

The complete 17,009-bp mitochondrial genome of the domestic cat, Felis catus, has been sequenced and conforms largely to the typical organization of previously characterized mammalian mtDNAs. Codon usage and base composition also followed canonical vertebrate patterns, except for an unusual ATC (non-AUG) codon initiating the NADH dehydrogenase subunit 2 (ND2) gene. Two distinct repetitive motifs at opposite ends of the control region contribute to the relatively large size (1559 bp) of this carnivore mtDNA. Alignment of the feline mtDNA genome to a homologous 7946-bp nuclear mtDNA tandem repeat DNA sequence in the cat, Numt, indicates simple repeat motifs associated with insertion/deletion mutations. Overall DNA sequence divergence between Numt and cytoplasmic mtDNA sequence was only 5.1%. Substitutions predominate at the third codon position of homologous feline protein genes. Phylogenetic analysis of mitochondrial gene sequences confirms the recent transfer of the cytoplasmic mtDNA sequences to the domestic cat nucleus and recapitulates evolutionary relationships between mammal species.

Amino Acid Sequence↗
PubMed1994

Novel features of metazoan mtDNA revealed from sequence analysis of three mitochondrial DNA segments of the land snail Albinaria turrita (Gastropoda: Clausiliidae).

The mitochondrial DNA (mtDNA) size of the terrestrial gastropod Albinaria turrita was determined by restriction enzyme mapping and found to be approximately 14.5 kb. Its partial gene content and organization were examined by sequencing three cloned segments representing about one-fourth of the mtDNA molecule. Complete sequences of cytochrome c oxidase subunit II (COII), and ATPase subunit 8 (ATPase8), as well as partial sequences of cytochrome c oxidase subunit I (COI), NADH dehydrogenase subunit 6 (ND6), and the large ribosomal RNA (lrRNA) genes were determined. Nine putative tRNA genes were also identified by their ability to conform to typical mitochondrial tRNA secondary structures. An 82-nt sequence resembles a noncoding region of the bivalve Mytilus edulis, even though it might contain a tenth tRNA gene with an unusual 5-nt overlap with another tRNA gene. The genetic code of Albinaria turrita appears to be the same as that of Drosophila and Mytilus edulis. The structures of COI and COII are conservative, but those of ATPase8 and ND6 are diversified. The sequenced portion of the lrRNA gene (1,079 nt) is characterized by conspicuous deletions in the 5' and 3' ends; this gene represents the smallest coelomate lrRNA gene so far known. Sequence comparisons of the identified genes indicate that there is greater difference between Albinaria and Mytilus than between Albinaria and Drosophila. An evolutionary analysis, based on COII sequences, suggests a possible nonmonophyletic origin of molluskan mtDNA. This is supported also by the absence of the ATPase8 gene in the mtDNA of Mytilus and nematodes, while this gene is present in the mtDNA of Albinaria and Cepaea nemoralis and in all other known coelomate metazoan mtDNAs.

Amino Acid Sequence↗
PubMed2000

Forensic evaluation of mtDNA in a population from south west Switzerland.

The polymorphism of the two hypervariable segments (HVI and HVII) of the control region of mtDNA was analyzed in a population of 154 unrelated individuals from south west Switzerland using a fluorescent based capillary electrophoresis sequencing method. In our population data of 154 random individuals, 137 mtDNA types were observed. Of these, 124 sequences were observed only in one individual whereas 10 sequences were observed in 2 individuals, 2 sequences in 3 individuals and 1 sequence in 4 individuals. The probability of two unrelated individuals having the same sequence was 0.84%. The results were compared with four other Caucasian populations. Furthermore, the usefulness of the mtDNA sequencing was tested, for exclusion and inclusion, in 18 forensic cases including 69 evidence samples and 44 reference samples. Despite the fact that 55% of the evidence samples yielded a negative result for the nuclear DNA with the human dot quantitation system, the success rate of the mtDNA sequencing was 71.0%. This validation study proves the great usefulness and sensitivity of the mtDNA sequencing technique using nested PCR and fluorescent capillary electrophoresis.

DNA, Mitochondrial↗
PubMed2005

Mitochondrial DNA control region sequences in Koreans: identification of useful variable sites and phylogenetic analysis for mtDNA data quality control.

We have established a high-quality mtDNA control region sequence database for Koreans. To identify polymorphic sites and to determine their frequencies and haplotype frequencies, the complete mtDNA control region was sequenced in 593 Koreans, and major length variants of poly-cytosine tracts in HV2 and HV3 were determined in length heteroplasmic individuals by PCR analysis using fluorescence-labeled primers. Sequence comparison showed that 494 haplotypes defined by 285 variable sites were found when the major poly-cytosine tract genotypes were considered in distinguishing haplotypes, whereas 441 haplotypes were found when the poly-cytosine tracts were ignored. Statistical parameters indicated that analysis of partial mtDNA control region which encompasses the extended regions of HV1 and HV2, CA dinucleotide repeats in HV3 and nucleotide position 16497, 16519, 456, 489 and 499 (HV1ex+HV2ex+HV3CA+5SNPs) and the analysis of another partial mtDNA control region including extended regions of HV1 and HV2, HV3 region and nucleotide position 16497 and 16519 (HV1ex+HV2ex+HV3+2SNPs) can be used as efficient alternatives for the analysis of the entire mtDNA control region in Koreans. Also, we collated the basic informative SNPs, suggested the important mutation motifs for the assignment of East Asian haplogroups, and classified 592 Korean mtDNAs (99.8%) into various East Asian haplogroups or sub-haplogroups. Haplogroup-directed database comparisons confirmed the absence of any major systematic errors in our data, e.g., a mix-up of site designations, base shifts or mistypings.

Asian People↗
PubMed2001

MtDNA control region and RFLP data for Sicily and France.

The forensic application of mtDNA typing requires large databases which are regionally well defined. To further this aim, we have typed mtDNA in a sample of 111 French and 106 Sicilians. The French were typed for both hypervariable segments (HVR1 and HVR2) of the mtDNA control region, whereas the Sicilians were only typed for HVR1, but in addition for the coding region RFLP markers for mtDNA groups H, I, J, K, L, M, T, U, V and X. In both samples, the predominant sequence type by far was the Cambridge reference sequence. Comparing HVR1 sequences, we found that the French sample was twice as diverse as the Sicilian sample as measured by sequence matches. A further set of sequence match comparisons including the French, Sicilian, and the published British mtDNA samples, demonstrate that sequence matching probabilities within samples differ by less than a factor of 2 from the matching probabilities between samples.

Complementarity Determining Regions↗
PubMed1998

Population data for 101 Austrian Caucasian mitochondrial DNA d-loop sequences: application of mtDNA sequence analysis to a forensic case.

The sequence of the two hypervariable segments of the mitochondrial DNA (mtDNA) control region was generated for 101 random Austrian Caucasians. A total of 86 different mtDNA sequences was observed, where 11 sequences were shared by more than 1 individual, 7 sequences were shared by 2 individuals and 4 sequences were shared by 3 individuals. One of the four most common mtDNA sequences in Austrians is also the most common sequence in both U.S. and British Caucasians, found in approximately 3.0% of Austrians, 4.0% of British, and 3.9% of U.S. Caucasians. Of the remaining three common Austrian sequences, one was not observed in either U.S. or British Caucasians. However, three British Caucasians exhibited a similar sequence type. Therefore, this particular cluster of sequence polymorphisms may represent a common "European" mtDNA sequence type. In general, Austrian Caucasians show little deviation from other Caucasian databases of European descent. Finally, mtDNA sequence analysis was applied to a forensic case, where hairs found at a crime scene matched the control hairs from the suspect.

Austria↗
PubMed1999

Demonstration and semi-quantification of mtDNA from human dentine and its relation to age.

In order to study if mitochondrial DNA (mtDNA) could be retrieved from isolated human dentine, small pieces of dentine were cut out from the central part of the apical half of wisdom teeth from 21 individuals aged 15 to 85 years. The dental pulp was used as a control. After extraction, amplification and agarose gel electrophoresis the amount of mtDNA was semi-quantified from the intensity of the stained bands in the gel. Mitochondrial DNA was retrieved from all samples and the sequences were identical in pulp and dentine from each individual. There was a clear age-dependent decrease in the amount of amplified mtDNA. Since the odontoblastic processes in the apical dentine undergo degeneration with age and the dentinal tubules subsequently become occluded with calcium phosphate crystals, the conclusion was drawn that even after dissolution of the odontoblastic processes, at least remains of the mtDNA are trapped in the dentine. This well protected mtDNA could thus be regarded a good source of DNA in identification cases with severe degradation.

Adolescent↗
PubMed2001

An annotated mtDNA database.

We have compiled a database of mitochondrial DNA (mtDNA) control region, hypervariable regions 1 (HVR1) and 2 (HVR2) sequences of a total of 14,138 individuals compiled from 103 mtDNA publications before 1 January 2000, 13 data sets published in 2000 and 2001 and 2 unpublished data sets of Iraqi Kurds and Indians from Kerala. By contacting the authors and by other means, we have confirmed and corrected sequence errors, eliminated duplications and harmonised the sequence format. These changes affected all but 26 of the 116 publications. Furthermore, we have implemented a geographic information system ("mtradius") which searches for closest matches to a given mtDNA control region sequence and displays them on a geographic map. A potential application is to estimate a chance matching probability when a forensic stain and a suspect have an identical mtDNA sequence: we suggest that the geographic area with the highest frequency of closely related mtDNA sequence types may be used to define a reference population to give the suspect the maximum benefit of doubt in accordance with the ceiling principle.

DNA Fingerprinting↗
PubMed1998

Immunohistochemical detection of human mtDNA polymerase gamma and of human mitochondrial transcription factor A in cytochrome-c-oxidase-deficient oxyphil cells of hyperfunctional parathyroids.

Immunohistochemical studies were performed in 18 hyperfunctional parathyroids with oxyphil cell aggregates for the detection of cytochrome-c-oxidase (complex IV of the respiratory chain), mitochondrial DNA polymerase gamma and human mitochondrial transcription factor A (h-mtTFA). Seventy-three oxyphil areas exhibiting a defect of cytochrome-c-oxidase were found. The defect involved both the mitochondrially coded subunits II/III and the nuclear derived subunits Vab. There was no loss of mtDNA polymerase gamma or of h-mtTFA in these foci, corresponding to a high content of mtDNA revealed by in situ hybridization. Isolated defects of h-mtTFA were also not found. In contrast, isolated defects of mtDNA polymerase gamma were present in 22 oxyphil foci. These results show that defects of cytochrome-c-oxidase in oxyphil cells are not due to altered expression of h-mtTFA or DNA polymerase gamma, indicating that other nuclear factors involved in the generation of the respiratory chain may be impaired. The low incidence of defects of mtDNA polymerase gamma and the absence of alterations of h-mtTFA and cytochrome-c-oxidase in these foci suggest that defects of mtDNA polymerase gamma are of minor pathogenetic significance.

Cytochrome-c Oxidase Deficiency↗
PubMed2006

A reappraisal of complete mtDNA variation in East Asian families with hearing impairment.

In a number of recent studies, we summarized the obvious errors and shortcomings that can be spotted in many (if not most) mitochondrial DNA (mtDNA) data sets published in medical genetics. We have reanalyzed here the complete mtDNA genome data published in various recent reports of East Asian families with hearing impairment, using a phylogenetic approach, in order to demonstrate the persistence of lab-specific mistakes in mtDNA genome sequencing in cases where those caveats were (deliberately) neglected. A phylogenetic reappraisal of complete mtDNAs with mutation A1555G (or G11778A) indeed supports the suggested lack of association between haplogroup background and phenotypic presentation of these mutations in East Asians. In contrast, the claimed pathogenicity of mutation T1095C in Chinese families with hearing impairment seems unsupported, basically because this mutation is rather basal in the mtDNA phylogeny, being specific to haplogroup M11 in East Asia. The roles of other haplogroup specific or associated variants, such as A827G, T961C, T1005C, in East Asian subjects with aminoglycoside-induced and non-syndromic hearing loss are also unclear in view of the known mtDNA phylogeny.

DNA, Mitochondrial↗
PubMed2001

Novel mtDNA mutations and oxidative phosphorylation dysfunction in Russian LHON families.

Leber's hereditary optic neuropathy (LHON) is characterized by maternally transmitted, bilateral, central vision loss in young adults. It is caused by mutations in the mitochondrial DNA (mtDNA) encoded genes that contribute polypeptides to NADH dehydrogenase or complex I. Four mtDNA variants, the nucleotide pair (np) 3460A, 11778A, 14484C, and 14459A mutations, are known as "primary" LHON mutations and are found in most, but not all, of the LHON families reported to date. Here, we report the extensive genetic and biochemical analysis of five Russian families from the Novosibirsk region of Siberia manifesting maternally transmitted optic atrophy consistent with LHON. Three of the five families harbor known LHON primary mutations. Complete sequence analysis of proband mtDNA in the other two families has revealed novel complex I mutations at nps 3635A and 4640C, respectively. These mutations are homoplasmic and have not been reported in the literature. Biochemical analysis of complex I in patient lymphoblasts and transmitochondrial cybrids demonstrated a respiration defect with complex-I-linked substrates, although the specific activity of complex I was not reduced. Overall, our data suggests that the spectrum of mtDNA mutations associated with LHON in Russia is similar to that in Europe and North America and that the np 3635A and 4640C mutations may be additional mtDNA complex I mutations contributing to LHON expression.

Adolescent↗
PubMed1992

Multiple short direct repeats associated with single mtDNA deletions.

We have sequenced the breakpoints of deleted mtDNA in muscle from four children with mitochondrial myopathy and multisystem mitochondrial disorders. The deletions were 4884, 6067, 7663 and 7150 base pairs (bp) in size and affected several protein and transfer RNA genes. The sequences needed for transcription and replication of mtDNA were not affected in any case. The deletions were flanked by direct short repeats in all cases. Multiple repeats were found in case 1 and 4. Imperfect repeats were found in case 3 and 4 and this made it possible to distinguish the repeats 5' and 3' to the deletion. In both cases the 3' repeat was retained. The deletion of 7663 bp in case 3 has been reported in two other cases and may represent a second hotspot for mtDNA deletions in addition to the common deletion of 4977 bp found in one third of cases. A comparison of the breakpoint sequence of case 3 with the two other reported cases revealed that when a deletion is formed between the same repeats in different patients either the 5' or 3' repeat can be retained. This study shows that both single and multiple repeats can be associated with single mtDNA deletions and that both 5' and 3' repeated sequences can be retained. These findings are consistent with the slip-replication model for the generation of mtDNA deletions.

Base Sequence↗
PubMed2004

Abnormal cardiac energetics in patients carrying the A3243G mtDNA mutation measured in vivo using phosphorus MR spectroscopy.

Cardiomyopathy is a frequent cause of morbidity and mortality in patients carrying the A3243G transition in the mitochondrial DNA (mtDNA) tRNALeu(UUR) gene, the most common heteroplasmic single mtDNA defect. We used phosphorus magnetic resonance spectroscopy (31P-MRS) to look for evidence of an in vivo bioenergetics defect in patients carrying the A3243G mtDNA mutation with and without echocardiographic signs of left ventricle hypertrophy (LVH). Eight patients, three with LVH, carrying the A3243G mtDNA mutation and 10 healthy subjects underwent one-dimensional chemical shift imaging 31P-MRS. In the patients, mean cardiac phosphocreatine to adenosine triphosphate ratio (PCr/ATP) (1.55 +/- 0.58) was significantly reduced compared to the control group (2.34 +/- 0.14; P < 0.001). Cardiac PCr/ATP was within the normal range only in one case that showed normal echocardiography. Our results point to a central role of bioenergetics deficit in the development of cardiac hypertrophy in patients with the A3243G mtDNA mutation. Impaired cardiac energy metabolism in patients with normal echocardiography suggests that the enhancement of mitochondrial function may be beneficial not only to patients with cardiac hypertrophy but also to those patients carrying the mutation in the absence of signs of cardiac hypertrophy and/or dysfunction but with cardiac bioenergetics deficit.

Adult↗