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PubMed1992

A novel mitochondrial genome organization for the blue mussel, Mytilus edulis.

The sequence of 13.9 kilobases (kb) of the 17.1-kb mitochondrial genome of Mytilus edulis has been determined, and the arrangement of all genes has been deduced. Mytilus mitochondrial DNA (mtDNA) contains 37 genes, all of which are transcribed from the same DNA strand. The gene content of Mytilus is typically metazoan in that it includes genes for large and small ribosomal RNAs, for a complete set of transfer RNAs and for 12 proteins. The protein genes encode the cytochrome b apoenzyme, cytochrome c oxidase (CO) subunits I-III, NADH dehydrogenase (ND) subunits 1-6 and 4L, and ATP synthetase (ATPase) subunit 6. No gene for ATPase subunit 8 could be found. The reading frames for the ND1, COI, and COIII genes contain long extensions relative to those genes in other metazoan mtDNAs. There are 23 tRNA genes, one more than previously found in any metazoan mtDNA. The additional tRNA appears to specify methionine, making Mytilus mtDNA unique in having two tRNA(Met) genes. Five lengthy unassigned intergenic sequences are present, four of which vary in length from 79 to 119 nucleotides and the largest of which is 1.2 kb. The base compositions of these are unremarkable and do not differ significantly from that of the remainder of the mtDNA. The arrangement of genes in Mytilus mtDNA is remarkably unlike that found in any other known metazoan mtDNA.

Adenosine Triphosphatases↗
PubMed2002

Arrangement and structural conservation of the mitochondrial control region of two species of Plecoptera: utility of tandem repeat-containing regions in studies of population genetics and evolutionary history.

Low levels of primary sequence similarity across insect taxa have led to the suggestion of conserved structural elements in the insect mitochondrial control region. Our aim was to determine whether previously described motifs and secondary structures exist in stoneflies (Plecoptera). Several motifs and structural elements previously described in Orthoptera and Diptera were found, including a conserved 'hairpin' structure that may play a role in the initiation of mtDNA replication. The repeat region had the highest percentage similarity, lowest A-T content and highest transition to transversion ratio, suggesting a unique evolutionary pattern for the repeats. Finally, we discuss the usefulness of the control region in population genetic and evolutionary studies.

Animals↗
PubMed2005

MITOMAP: a human mitochondrial genome database--2004 update.

MITOMAP (http://www.MITOMAP.org), a database for the human mitochondrial genome, has grown rapidly in data content over the past several years as interest in the role of mitochondrial DNA (mtDNA) variation in human origins, forensics, degenerative diseases, cancer and aging has increased dramatically. To accommodate this information explosion, MITOMAP has implemented a new relational database and an improved search engine, and all programs have been rewritten. System administrative changes have been made to improve security and efficiency, and to make MITOMAP compatible with a new automatic mtDNA sequence analyzer known as Mitomaster.

DNA, Mitochondrial↗
PubMed1994

Iron ion induces mitochondrial DNA damage in HTC rat hepatoma cell culture--role of antioxidants in mitochondrial DNA protection from oxidative stresses.

The mitochondrial DNA (mtDNA) is exposed to the reactive oxygen species generated in the mitochondrial electron transfer system. While mitochondrial superoxide dismutase (Mn-SOD) scavenges superoxide anions to prevent damage of mtDNA, excess amount of reactive oxygen generated by quinone compounds impairs the mtDNA, in which involvement of iron ion-catalyzed reactions is suggested. In this communication, we report that the mtDNA in HTC rat hepatoma cells was markedly damaged in the presence of either ferrous (Fe2+) or ferric (Fe3+) iron in the culture medium. The mtDNA of HTC cells was damaged in the presence of 100 microM of iron ions in the culture medium within 3 h. There was no significant difference in the potency of Fe2+ and Fe3+. Deferoxamine, a Fe(3+)-specific chelating reagent, blocked the iron ion-induced mtDNA damage completely. The mtDNA in rat hepatocyte primary culture was, on the other hand, not damaged by either Fe2+ or Fe3+. To understand the difference between iron ion-induced damage of mtDNA in HTC cells and in the primary hepatocytes, the Mn-SOD activity and lipid-soluble antioxidant contents were compared. The Mn-SOD activity in HTC cells was markedly lower (< 0.02 U/mg cell protein) than that in rat hepatocyte primary cell cultures (1.5 U/mg cell protein). Immunoreactive Mn-SOD content in HTC cells was also lower (21 ng/mg cell protein) than in the primary cultures (99 ng/mg cell protein). HTC cells contain much smaller amounts (3-11% of that of normal rat hepatocytes) of alpha-tocopherol and coenzyme Q homologs (CoQn). These results suggest that reactive oxygen species produced by iron ion impaired mtDNA of HTC cells, in which antioxidant activity was markedly decreased.

Animals↗
PubMed2001

Mitochondrial DNA content affects the fertilizability of human oocytes.

Mitochondrial DNA content varies considerably in oocytes, even when collected from the same patient. In the present study, real-time quantitative polymerase chain reaction analysis of 113 unfertilized oocytes obtained from 43 patients revealed an average of 193,000 (range: 20,000 to 598,000) mitochondrial genomes per cell. We compared several groups of oocytes to investigate the relationship between mitochondrial DNA content and fertilizability. The average mitochondrial DNA copy number was significantly lower in cohorts suffering from fertilization failure compared to cohorts with a normal rate of fertilization. In addition, the mitochondrial copy number of oocytes from patients with fertilization failure due to unknown causes was significantly lower than that of oocytes from patients in which IVF failure was due mainly to a severe sperm defect. The lower mtDNA copy number could be due to defective cytoplasmic maturation of oocytes. We conclude that low mitochondrial DNA content, due to inadequate mitochondrial biogenesis or cytoplasmic maturation, may adversely affect oocyte fertilizability.

Adult↗
PubMed1997

Chronically ultraviolet-exposed human skin shows a higher mutation frequency of mitochondrial DNA as compared to unexposed skin and the hematopoietic system.

Normal ageing processes are associated with an accumulation of mutations within the mitochondrial (mt) DNA. The most frequent mutation is a 4977 base pair (bp) deletion known as common deletion. In order to test the hypothesis that chronically sun-exposed skin is characterized by an increased mutation frequency of mtDNA, the mutation frequency of the common deletion between skin and another replicating tissue (the hematopoietic system) and chronically sun-exposed versus sun-protected skin was compared in the same individuals. This was done by comparing the amount of mutated mtDNA molecules with the whole mitochondrial genome in the same specimen with a semiquantitative polymerase chain reaction method, thus allowing direct comparison of different tissues. In all skin specimens the common deletion could be observed. In contrast only 3 of 10 blood samples revealed detectable amounts of the common deletion. Comparison of sun-exposed versus sun-protected skin exhibited a higher content of the common deletion in sun-exposed skin in 7 of 10 individuals. Additionally, a hitherto undescribed mtDNA mutation was detected exclusively in human skin. These studies indicate that exposure of human skin to solar radiation leads to an accumulation of mtDNA mutations, possibly via oxidative damage, which may play an important role in photoageing.

Adult↗
PubMed2006

Mitochondrial genome anatomy and species-specific lifespan.

Several lines of evidence implicate mtDNA in the mechanisms of aging and longevity. The authors examined possible links between mtDNA composition and maximum lifespan of multicellular eukaryotes, including 102 mammals. MLS correlates positively with cytosine and negatively with adenine or thymine content, whereas guanine has no apparent effect. This is especially noted for primates. It appears that an increase in MLS of mammals is associated with thymine-to-cytosine substitution. The results suggest that the MLS may be associated with stability and/or mutability of mtDNA and call for further investigation of the mitochondrial genome as a potential target for lifespan-extending interventions.

Aging↗
PubMed2005

Decline in skeletal muscle mitochondrial function with aging in humans.

Cumulative mtDNA damage occurs in aging animals, and mtDNA mutations are reported to accelerate aging in mice. We determined whether aging results in increased DNA oxidative damage and reduced mtDNA abundance and mitochondrial function in skeletal muscle of human subjects. Studies performed in 146 healthy men and women aged 18-89 yr demonstrated that mtDNA and mRNA abundance and mitochondrial ATP production all declined with advancing age. Abundance of mtDNA was positively related to mitochondrial ATP production rate, which in turn, was closely associated with aerobic capacity and glucose tolerance. The content of several mitochondrial proteins was reduced in older muscles, whereas the level of the oxidative DNA lesion, 8-oxo-deoxyguanosine, was increased, supporting the oxidative damage theory of aging. These results demonstrate that age-related muscle mitochondrial dysfunction is related to reduced mtDNA and muscle functional changes that are common in the elderly.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2005

Mitochondrial biogenesis in mtDNA-depleted cells involves a Ca2+-dependent pathway and a reduced mitochondrial protein import.

Alterations in mitochondrial activity resulting from defects in mitochondrial DNA (mtDNA) can modulate the biogenesis of mitochondria by mechanisms that are still poorly understood. In order to study mitochondrial biogenesis in cells with impaired mitochondrial activity, we used rho-L929 and rho(0)143 B cells (partially and totally depleted of mtDNA, respectively), that maintain and even up-regulate mitochondrial population, to characterize the activity of major transcriptional regulators (Sp1, YY1, MEF2, PPARgamma, NRF-1, NRF-2, CREB and PGC-1alpha) known to control the expression of numerous nuclear genes encoding mitochondrial proteins. Among these regulators, cyclic AMP-responsive element binding protein (CREB) activity was the only one to be increased in mtDNA-depleted cells. CREB activation mediated by a calcium-dependent pathway in these cells also regulates the expression of cytochrome c and the abundance of mitochondrial population as both are decreased in mtDNA-depleted cells that over-express CREB dominant negative mutants. Mitochondrial biogenesis in mtDNA-depleted cells is also dependent on intracellular calcium as its chelation reduces mitochondrial mass. Despite a slight increase in mitochondrial mass in mtDNA-depleted cells, the mitochondrial protein import activity was reduced as shown by a decrease in the import of radiolabeled matrix-targeted recombinant proteins into isolated mitochondria and by the reduced mitochondrial localization of ectopically expressed HA-apoaequorin targeted to the mitochondria. Decrease in ATP content, in mitochondrial membrane potential as well as reduction in mitochondrial Tim44 abundance could explain the lower mitochondrial protein import in mtDNA-depleted cells. Taken together, these results suggest that mitochondrial biogenesis is stimulated in mtDNA-depleted cells and involves a calcium-CREB signalling pathway but is associated with a reduced mitochondrial import for matrix proteins.

Adenosine Triphosphate↗
PubMedDate not supplied

[Isolation and characteristics of DNA fragments bound to mitochondrial membrane proteins].

Fragments of rat liver mitochondrial DNA were isolated. In vivo these fragments were able to form the complexes with the proteins of inner mitochondrial membrane. The fragments represent unique DNA regions with the secondary structure, their A-T content being equal to 82%. With the aid of phosphomonoesterase, polynucleotidkinase and gamma-(32P)-ATP mtDNA fragments were labeled and analyzed for oligopyrimidine composition. It was shown that they were enriched in di- and tri-oligo-pyrimidine blocks. The fragments are shown to form in vitro a complex with the membrane proteins. A single protein m. wt. 40,000) was reisolated from the complex.

Animals↗
PubMed1999

The complete sequence of the mitochondrial genome of Daphnia pulex (Cladocera: Crustacea).

The sequence of the mitochondrial DNA (mtDNA) of the branchiopod crustacean Daphnia pulex has been completed. It is 15333bp with an A+T content of 62.3%, and contains the typical complement of 13 protein-coding, 22 transfer RNA (tRNA) and two ribosomal RNA (rRNA) genes. Comparison of this sequence with the sequences of the other eight completely sequenced arthropod mtDNAs showed that gene order and orientation are identical to that of Drosophila but different from Artemia due to the rearrangement of two tRNA genes. Nucleotide composition, codon usage, and amino acid composition are very similar in the crustaceans, but divergent from insects and chelicerates which show a much higher bias towards A+T. However, with few exceptions, the mitochondrial proteins of Daphnia are more similar to those of the dipteran insects (Drosophila and Anopheles) than to those of Artemia, at both the nucleotide and amino acid levels, suggesting that Artemia mtDNA is evolving at an accelerated rate. These results also show that sequence evolution and the evolution of nucleotide composition can be decoupled. Analysis of nucleotide substitution patterns in COII showed that there has been an unbiased acceleration of the overall substitution rate in Artemia. In contrast, the accelerated substitution rate in Apis is due partly to extreme A+T mutation pressure. Secondary structures are proposed for the Daphnia tRNAs and rRNAs. The tRNAs are similar to those of other arthropods but tend to have TPsiC arms that are only 4bp long. The rRNA secondary structures are similar to those proposed for insects except for the absence of a small number of helices in Daphnia. Phylogenetic analysis of second codon positions grouped Daphnia with Artemia, as expected, despite the latter's accelerated divergence rate. In contrast, the unusual pattern of mtDNA divergence in Apis led to a topology in which the holometabolous insects (Anopheles, Drosophila, Apis) appeared to be paraphyletic with respect to the hemimetabolous insect, Locusta, due to the early branching of Apis.

Animals↗
PubMed2002

Mitochondrial DNA mutations and oxidative damage in skeletal muscle of patients with chronic uremia.

Abundant evidence has been gathered to suggest that mitochondrial DNA (mtDNA) sustains many more mutations and greater oxidative damage than does nuclear DNA in human tissues. Uremic patients are subject to a state of enhanced oxidative stress due to excess production of oxidants and a defective antioxidant defense system. This study was conducted to investigate mtDNA mutations and oxidative damage in skeletal muscle of patients with chronic uremia. Results showed that large-scale deletions between nucleotide position (np) 7,900 and 16,300 of mtDNA occurred at a high frequency in muscle of uremic patients. Among them, the 4,977-bp deletion (mtDNA(4977)) was the most frequent and most abundant large-scale mtDNA deletion in uremic skeletal muscle. The proportion of mtDNA(4977) was found to correlate positively with the level of 8-hydroxy 2'-deoxyguanosine (8-OHdG) in the total DNA of skeletal muscle (r = 0.62, p < 0.05). Using long-range PCR and DNA sequencing, we identified and characterized multiple deletions of mtDNA in skeletal muscle of 16 of 19 uremic patients examined. The 8,041-bp deletion, which occurred between np 8035 and 16,075, was flanked by a 5-bp direct repeat of 5'-CCCAT-3'. Some of the deletions were found in more than 1 patient. On the other hand, we found that the mean 8-OHdG/10(5 )dG ratio in the total cellular DNA of muscle of uremic patients was significantly higher than that of the controls (182.7 +/- 63.6 vs. 50.9 +/- 21.5, p = 0.05). In addition, the mean 8-OHdG/10(5 )dG ratio in muscle mtDNA of uremic patients was significantly higher than that in nuclear DNA (344.0 +/- 56.9 vs. 146.3 +/- 95.8, p = 0.001). Moreover, we found that the average content of lipid peroxides in mitochondrial membranes of skeletal muscle of uremic patients was significantly higher than that of age-matched healthy subjects (23.76 +/- 6.06 vs. 7.67 +/- 0.95 nmol/mg protein; p < 0.05). The average content of protein carbonyls in the mitochondrial membranes prepared from uremic skeletal muscles was significantly higher than that in normal controls (24.90 +/- 4.00 vs. 14.48 +/- 1.13 nmol/mg protein; p < 0.05). Taken together, these findings suggest that chronic uremia leads to mtDNA mutations together with enhanced oxidative damage to DNA, lipids, and proteins of mitochondria in skeletal muscle, which may contribute to the impairment of mitochondrial bioenergetic function and to skeletal myopathy commonly seen in uremic patients.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1997

Mitochondrial ATP synthase subunit 9 is not required for viability of the petite-negative yeast Kluyveromyces lactis.

Specific mutations in nuclear MGI genes encoding the alpha, beta and gamma subunits of the mitochondrial inner membrane F1-ATPase complex allow mitochondrial DNA (mtDNA) to be lost from K. lactis. In the absence of a mutation in any of these three nuclear genes, loss of mtDNA is lethal. These results imply that mtDNA encodes a gene that is essential. Likely candidates for such an essential role are the ATP6, 8 and 9 genes coding for proteins of the ATP synthase-F0 component. The present study removes ATP9 from contention as a vital mitochondrial gene because in a respiratory deficient mutant, Gly- 3. 9, lacking a nuclear mgi mutation, we have found that a rearrangement in mtDNA has deleted 22 amino acids from the carboxy terminus of the 75 amino-acid subunit-9 protein. Rearrangement in mtDNA has occurred by recombination at a 23-bp repeated sequence in the introns of the ATP9 and large ribosomal RNA (LSU) subunit genes. These two introns, of 394 (ATP9) and 410 (LSU) nucleotides, both belong to group 1.

Amino Acid Sequence↗
PubMed1995

Early-onset cerebellar ataxia, myoclonus and hypogonadism in a case of mitochondrial complex III deficiency treated with vitamins K3 and C.

A 16-year-old girl presented with early-onset cerebellar ataxia, myoclonus, elevated lactic acidosis and hypogonadotropic hypogonadism. Muscle biopsy specimens revealed fibres with a "ragged" appearance with increased mitochondria and lipid droplets. Biochemical investigation revealed a deficiency of complex bc1 (complex III) of the mitochondrial respiratory chain. Genetic analysis did not show either deletions or known mutations of mitochondrial DNA (mtDNA). Phosphorus magnetic resonance spectroscopy (31P-MRS) showed defective energy metabolism in brain and gastrocnemius muscle. A decreased phosphocreatine (PCr) content was found in the occipital lobes accompanied by normal inorganic phosphate (Pi) and cytosolic pH. These findings represented evidence of a high cytosolic adenosine diphosphate concentration and a relatively high rate of metabolism accompanied by a low phosphorylation potential. Muscle 31P-MRS showed a high Pi content at rest, abnormal exercise transfer pattern and a low rate of PCr post-exercise recovery. These findings suggested a deficit of mitochondrial function. Therapy with vitamins K3 and C normalized brain 31P-MRS indices, whereas it did not affect muscle bioenergetic metabolism. In this patient, the endocrinological disorder is putatively due to a mitochondrial cytopathy. Although an unknown mtDNA mutation cannot be ruled out, the genetic defect may lie in the nuclear genome.

Adolescent↗
PubMed2000

Transcription and replication of mitochondrial DNA.

The physical isolation of mammalian mitochondrial DNA (mtDNA) over 30 years ago marked the beginning of studies of its structure, replication and the expression of its genetic content. Such analyses have revealed a number of surprises: novel DNA structural features of the circular genome such as the displacement loop (D-loop); multiple sized and deleted forms of the circular genome; a minimal set of mitochondrially encoded rRNAs and tRNAs needed for translation; a bacteriophage-like, nuclear-encoded mitochondrial RNA polymerase for transcription; and a direct linkage between transcription and the commitment to replication of the leading mtDNA strand that centres on the nuclear encoded mitochondrial transcription factor A. One of the more recent revelations is the existence, near the D-loop, of an atypical, stable RNA-DNA hybrid (or R-loop) at the origin of mammalian leading-strand DNA replication, composed of the parent DNA strands and an RNA transcript. In mammalian mitochondrial systems, all of the proteins known to be involved in DNA replication are encoded in the nucleus. Thus alterations and deficiencies in mtDNA replication must arise from mutations in mtDNA regulatory sequences and nuclear gene defects. Further studies of the relationships between nuclear-encoded proteins and their mtDNA target sequences could result in strategies to manipulate genotypes within cellular mtDNA populations.

Animals↗
PubMed1998

Reduced mitochondrial DNA transcription in senescent rat heart.

We studied the effect of senescence on mitochondrial DNA (mtDNA) transcription with an in organello system using intact isolated rat heart mitochondria. A comparison of the electrophoretic patterns of mtDNA transcription products in young, adult and senescent rats showed an age-related reduction in newly-synthesized mitochondrial RNAs that reflects a decrease in the synthesis rate. These results correlate with the enzyme activities of the oxidative phosphorylation complexes I and IV, that are partially encoded by the mitochondrial genome. In addition, an age-related increase in the protein carbonyl content of the mitochondrial membranes was observed in senescent mitochondria suggesting an accumulation of mitochondrial oxidative damage. This reduction in the mtDNA transcriptional rate in the heart of senescent animals suggests that this could be one of the molecular bases underlying senescence of the myocardium.

Aging↗
PubMed2003

Mitochondrial portraits of the Madeira and Açores archipelagos witness different genetic pools of its settlers.

We have studied the matrilineal genetic composition of the Madeira and Açores north Atlantic archipelagos, which were settled by the Portuguese in the 15th century. Both archipelagos, and particularly Madeira, were involved in a complex commercial network established by the Portuguese, which included the trading of slaves across the Atlantic. One hundred and fifty-five mtDNAs sampled from the Madeira and 179 from the Açores archipelagos were analysed for the hypervariable segment I (HVS-I), and for haplogroup-diagnostic coding-region RFLPs. The different settlement histories of both groups of islands are well reflected in their present day mtDNA pool. Although both archipelagos show identical diversity values, they are clearly different in their haplogroup content. Madeira displays a stronger sub-Saharan imprint, with haplogroups L1-L3 constituting about 13% of the lineages. Also, the relative frequencies of L sub-clusters in Madeira and mainland Portugal suggests that, at least in part, African presence in Madeira can be attributed to a direct gene flow from West Africa and not via Portugal. A comparison of the genetic composition of these two archipelagos with the Canary Islands, specially taking into account that their European source population was essentially from the Iberian Peninsula, testifies the stronger impact of the North African U6 cluster in the Canaries. This group is present in Madeira at a moderate frequency, but very reduced in the Açores. Nevertheless the recorded introduction of Canary native Guanches, who are characterized by the presence of particular sub-clade U6b1, has left no detectable imprints in the present day population of Madeira.

DNA↗
PubMed2005

Mitochondrial genomes of two demosponges provide insights into an early stage of animal evolution.

Mitochondrial DNA (mtDNA) of multicellular animals (Metazoa) is typically a small ( approximately 16 kbp), circular-mapping molecule that encodes 37 tightly packed genes. The structures of mtDNA-encoded transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs) are usually highly unorthodox, and proteins are translated with multiple deviations from the standard genetic code. In contrast, mtDNA of the choanoflagellate Monosiga brevicollis, the closest unicellular relative of animals, is four times larger, contains 1.5 times as many genes, and lacks mentioned peculiarities of animal mtDNA. To investigate the evolutionary transition that led to the specific organization of metazoan mtDNA, we determined complete mitochondrial sequences from the demosponges Geodia neptuni and Tethya actinia, two representatives of the most basal animal phylum, the Porifera. We found that poriferan mtDNAs resemble those of other animals in their compact organization, lack of introns, and a well-conserved animal-like gene order. Yet, they contain several extra genes, encode bacterial-like rRNAs and tRNAs, and use a minimally derived genetic code. Our findings suggest that the evolution of the typical metazoan mtDNA has been a multistep process in which the compact genome organization and the reduced gene content were established prior to the reduction of tRNA and rRNA structures and the introduction of multiple changes of the translation code.

Amino Acid Sequence↗