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PubMed1988

Drosophila melanogaster mitochondrial DNA: gene organization and evolutionary considerations.

The sequence of a 8351-nucleotide mitochondrial DNA (mtDNA) fragment has been obtained extending the knowledge of the Drosophila melanogaster mitochondrial genome to 90% of its coding region. The sequence encodes seven polypeptides, 12 tRNAs and the 3' end of the 16S rRNA and CO III genes. The gene organization is strictly conserved with respect to the Drosophila yakuba mitochondrial genome, and different from that found in mammals and Xenopus. The high A + T content of D. melanogaster mitochondrial DNA is reflected in a reiterative codon usage, with more than 90% of the codons ending in T or A, G + C rich codons being practically absent. The average level of homology between the D. melanogaster and D. yakuba sequences is very high (roughly 94%), although insertion and deletions have been detected in protein, tRNA and large ribosomal genes. The analysis of nucleotide changes reveals a similar frequency for transitions and transversions, and reflects a strong bias against G + C on both strands. The predominant type of transition is strand specific.

Amino Acid Sequence↗
PubMed2004

Complete nucleotide sequence and gene rearrangement of the mitochondrial genome of the bell-ring frog, Buergeria buergeri (family Rhacophoridae).

In this study we determined the complete nucleotide sequence (19,959 bp) of the mitochondrial DNA of the rhacophorid frog Buergeria buergeri. The gene content, nucleotide composition, and codon usage of B. buergeri conformed to those of typical vertebrate patterns. However, due to an accumulation of lengthy repetitive sequences in the D-loop region, this species possesses the largest mitochondrial genome among all the vertebrates examined so far. Comparison of the gene organizations among amphibian species (Rana, Xenopus, salamanders and caecilians) revealed that the positioning of four tRNA genes and the ND5 gene in the mtDNA of B. buergeri diverged from the common vertebrate gene arrangement shared by Xenopus, salamanders and caecilians. The unique positions of the tRNA genes in B. buergeri are shared by ranid frogs, indicating that the rearrangements of the tRNA genes occurred in a common ancestral lineage of ranids and rhacophorids. On the other hand, the novel position of the ND5 gene seems to have arisen in a lineage leading to rhacophorids (and other closely related taxa) after ranid divergence. Phylogenetic analysis based on nucleotide sequence data of all mitochondrial genes also supported the gene rearrangement pathway.

Animals↗
PubMed2003

Complete mtDNA sequence of the North American freshwater mussel, Lampsilis ornata (Unionidae): an examination of the evolution and phylogenetic utility of mitochondrial genome organization in Bivalvia (Mollusca).

Molluscs in general, and bivalves in particular, exhibit an extraordinary degree of mitochondrial gene order variation when compared with other metazoans. Two factors inhibiting our understanding the evolution of gene rearrangement in bivalves are inadequate taxonomic sampling and failure to examine gene order in a phylogenetic framework. Here, we report the first complete nucleotide sequence (16,060 bp) of the mitochondrial (mt) genome of a North American freshwater bivalve, Lampsilis ornata (Mollusca: Paleoheterodonta: Unionidae). Gene order and mt genome content is examined in a comparative phylogenetic framework for Lampsilis and five other bivalves, representing five families. Mitochondrial genome content is shown to vary by gene duplication and loss among taxa and between male and female mitotypes within a species. Although mt gene arrangement is highly variable among bivalves, when optimized on an independently derived phylogenetic hypothesis, it allows for the reconstruction of ancestral gene order states and indicates the potential phylogenetic utility of the data. However, the interpretation of reconstructed ancestral gene order states must take in to account both the accuracy of the phylogenetic estimation and the probability of character state change across the topology, such as the presence/absence of atp8 in bivalve lineages. We discuss what role, if any, doubly uniparental inheritance (DUI) and recombination between sexual mitotypes may play in influencing gene rearrangement of the mt genome in some bivalve lineages.

Animals↗
PubMed2000

The mitochondrial DNA of Dictyostelium discoideum: complete sequence, gene content and genome organization.

We present an overview of the gene content and organization of the mitochondrial genome of Dictyostelium discoideum. The mitochondria genome consists of 55,564 bp with an A + T content of 72.6%. The identified genes include those for two ribosomal RNAs (rn1 and rns), 18 tRNAs, ten subunits of the NADH dehydrogenase complex (nad1, 2, 3, 4, 4L, 5, 6, 7, 9 and 11), apocytochrome b (cytb), three subunits of the cytochrome oxidase (cox1/2 and 3), four subunits of the ATP synthase complex (atp1, 6, 8 and 9), 15 ribosomal proteins, and five other ORFs, excluding intronic ORFs. Notable features of D. discoideum mtDNA include the following. (1) All genes are encoded on the same strand of the DNA and a universal genetic code is used. (2) The cox1 gene has no termination codon and is fused to the downstream cox2 gene. The 13 genes for ribosomal proteins and four ORF genes form a cluster 15.4 kb long with several gene overlaps. (3) The number of tRNAs encoded in the genome is not sufficient to support the synthesis of mitochondrial protein. (4) In total, five group I introns reside in rnl and cox1/2, and three of those in cox1/2 contain four free-standing ORFs. We compare the genome to other sequenced mitochondrial genomes, particularly that of Acanthamoeba castellanii.

Animals↗
PubMed1998

A late-onset mitochondrial myopathy is associated with a novel mitochondrial DNA (mtDNA) point mutation in the tRNA(Trp) gene.

We detected a novel pathogenic mutation, a G-->A transition at position 5521 of mitochondrial tRNA(Trp) gene, in association with familial late-onset mitochondrial myopathy. The mutation was detected in muscle but not in leukocytes from the family's proband. Morphological and biochemical studies documented a severe defect of muscle cytochrome c oxidase (COX) activity. RFLP analysis of single muscle fibers demonstrated segregation of higher percentages of mutated genomes in COX-negative ragged red fibres compared with normal fibers. A predominant impairment in synthesis of subunits I and III of complex IV due to their highest relative content of tryptophane might explain the greater susceptibility of complex IV to the pathogenic effect of this mutation. A progressive accumulation of mutated genomes in muscle can account for the late onset of symptoms observed in affected members.

Aged↗
PubMed1998

Mutation and selection at silent and replacement sites in the evolution of animal mitochondrial DNA.

Two patterns are presented that illustrate the interaction of mutation and selection in the evolution of animal mtDNA: 1) variation among taxa in the ratio of polymorphism to divergence (rpd) at silent and replacement sites in protein-coding genes, and 2) strand-differences in polymorphism and divergence at 'silent' sites that suggest a mutation-selection balance in the evolution of codon usage. Cytochrome b data from GenBank show that about half of the species pairs tested have a significant excess of amino acid polymorphism, relative to divergence. The remaining half of species pairs do not depart from neutrality, but generally do show an excess of amino acid polymorphism. Sequences from Drosophila pseudoobscura displaying a signature of an expanding population show a slight, but non-significant, deficiency of amino acid polymorphism suggestive of recently intensified selection on mildly deleterious mutations. Genes whose reading frames lie on the major coding strand of Drosophila mtDNA show a preponderance of T- > C substitutions, while genes encoded on the minor strand experience more A- > G than T- > C substitutions between species at both silent and replacement sites. However, silent mutations at third codon positions are introduced into the population in proportions opposite to those observed as fixed differences between species (e.g., an excess of T- > C polymorphisms are found at the ND5 gene on the minor coding strand). The high A + T content of insect mtDNAs imposes strong codon usage bias favoring A-ending and T-ending codons resulting in a distinct mutation-selection balance for genes encoded on opposites strands. Thus, at both replacement and silent sites, mutations that appear to be constrained in terms of divergence between species are in excess within species. The data suggest that mildly deleterious mutations are common in mitochondrial genes. A test of this, and a competing, hypothesis is proposed that requires additional sequence surveys of polymorphism and divergence. An important challenge is to tease apart the impact of mutation and selection on levels of polymorphism versus divergence in a genome that does not generally recombine.

Animals↗
PubMed1995

Complete sequence of the mitochondrial DNA of the rhodophyte Chondrus crispus (Gigartinales). Gene content and genome organization.

The complete nucleotide sequence of the circular mitochondrial (mt) DNA from the red alga Chondrus crispus was determined (25,836 nucleotides, A+T content 72.1%). Fifty one genes were identified. They include genes encoding three subunits of the cytochrome oxidase (cox1 to 3), apocytochrome b (cob), seven subunits of the NADH dehydrogenase complex (nad1 to 6, nad4L), two ATPase subunits (atp6 and atp9), three ribosomal RNAs (rrn5, srn and lrn), 23 tRNAs and four ribosomal proteins (rps3, rps11, rps12 and rpl16). Two subunits of the succinate dehydrogenase complex (sdhB and sdhC), usually found on nuclear genomes, are also located on the mtDNA of C. crispus. One group IIb intron is inserted in the tRNAIle gene. Six potentially functional open reading frames were identified, four of them having counterparts among green plant mtDNAs. The use of a modified genetic code and the absence of RNA editing, previously reported for the cox3 gene, appears as a general characteristic of this molecule. Mitochondrial genes are encoded on both DNA strands, in two opposite major transcriptional directions, suggesting the existence of two main transcriptional units. Two long and stable stem-loops were identified in intergenic regions, which are believed to be involved with transcription and replication. The main structural features of this genome are compared with the overall organization of mtDNAs and are discussed in view of the evolution of mitochondria.

Amino Acid Sequence↗
PubMed1999

Phylogeny and evolution of the Drosophila nasuta subgroup based on mitochondrial ND4 and ND4L gene sequences.

The sequences of the mitochondrial ND4 gene (1339 bp) and the ND4L gene (290 bp) were determined for all the 14 extant taxa of the Drosophila nasuta subgroup. The average A + T content of ND4 genes is 76.5% and that of ND4L genes is 83.5%. A total of 114 variable sites were scored. The ND4 gene sequence divergence ranged from 0 to 5.4% within the subgroup. The substitution rate of the ND4 gene is about 1.25% per million years. The base substitution of the genes is strongly transition biased. Neighbor-joining and parsimony were used to construct a phylogeny based on the resultant sequence data set. According to these trees, five distinct mtDNA clades can be identified. D. niveifrons represents the most diverged lineage. D. sulfurigaster bilimbata and D. kepulauana form two independent lineages. The other two clades are the kohkoa complex and the albomicans complex. The kohkoa complex consists of D. sulfurigaster sulfurigaster, D. pulaua, D. kohkoa, and Taxon-F. The albomicans complex can be divided into two groups: D. nasuta, D. sulfurigaster neonasuta, D. sulfurigaster albostrigata, and D. albomicans from Chiangmai form one group; and D. pallidifrons, Taxon-I, Taxon-J, and D. albomicans from China form the other group. High genetic differentiation was found among D. albomicans populations. Based on our phylogenetic results, we hypothesize that D. niveifrons diverged first from the D. nasuta subgroup in Papua New Guinea about 3.5 Mya. The ancestral population spread to the north and when it reached Borneo, it diversified sequentially into the kohkoa complex, D. s. bilimbata, and D. kepulauana. About 1 Mya, another radiation occurred when the ancestral populations reached the Indo-China Peninsula, forming the albomicans complex. Discrepancy between morphological groupings and phylogenetic results suggests that the male morphological traits may not be orthologous.

Animals↗
PubMed1976

Complex mitochondrial DNA in animal thyroids. A comparative study.

1. The frequency of circular dimers and catenanes was determined in thyroid mitochondrial DNA (mtDNA) from rabbits, mice, pigs, sheep and cattle. 2. The mtDNA from freshly removed thyroids was isolated by buoyant density centrifugation in ethidium bromide/CsCl gradients after DNAase treatment of the mitochondrial pellet. Typically, more than 90% of the recovered mtDNA was found in the lower band, indicating a low rate of nicking during isolation. A sample of the total mtDNA (upper and lower bands) was examined by electron microscopy after preparation by the aqueous protein film technique. 3. The frequency of circular dimers generally ranged from 0.1 to 0.3%. However, in an mtDNA sample from cow thyroid, the frequency of circular dimers was 0.6% (0.9% if circular dimers occuring in catenanes are included(, differing significantly from the frequency of these forms in bull thyroid, 0.1%. A small but significant variability also occurred in the frequency of catenanes ranging from 2 to 8% in the different groups; this variation is within the limits usually observed in normal tissues. 4. These observations indicate that thyroids, like other normal tissues examined so far, have a low content of circular dimers. A high frequency of these forms seems to be the trademark of some genetically and physiologically abnormal cells such as certain established cell lines, virus-transformed cells and malignant or otherwise pathological tissues.

Animals↗
PubMed1995

Altered properties of mitochondrial ATP-synthase in patients with a T-->G mutation in the ATPase 6 (subunit a) gene at position 8993 of mtDNA.

A family is described with a T-->G mutation at position 8993 of mtDNA. This mutation is located in the ATPase 6 gene of mtDNA which encodes subunit a of the ATP-synthase complex (FlFo-ATPase). Clinically, the patients showed severe infantile lactate acidosis and encephalomyopathy in a form that was different from the classical Leigh syndrome. In 3 affected boys, ranging in age from 3 months to 8 years, the mutation was found in 95-99% of the mtDNA population. The clinical symptoms correlated with the mtDNA heteroplasmy and in the healthy mother 50% of the mtDNA was mutated. The rate of mitochondrial ATP production by cultured skin fibroblasts containing 99% of mutated mtDNA was about 2-fold lower than that in normal fibroblasts. Native electrophoresis of the mitochondrial enzyme complexes revealed instability of the FlFo-ATPase in all the tissues of the patient that were investigated (heart, muscle, kidney, liver). Only a small portion of the ATP-synthase complex was present in the complete, intact form (620 kDa). Incomplete forms of the enzyme were present as subcomplexes with approx. molecular weights of 460, 390 and 150 kDa, respectively, which differed in the content of F1 and Fo subunits. Immunochemical analysis of the subunits of the FlFo-ATPase further revealed a markedly decreased content of the Fo subunit b in mitochondria from muscle and heart, and an increased content of the Fo subunit c in muscle mitochondria, respectively. These results indicate that in this family the T-->G point mutation at position 8993 in the mitochondrial ATPase 6 gene is accompanied by structural instability and altered assembly of the enzyme complex, that are both most likely due to changes in the properties of subunit a of the membrane sector part of the ATP-synthase.

Acidosis, Lactic↗
PubMed2006

Mitigation of age-dependent oxidative damage to DNA in rat heart by carnitine and lipoic acid.

Endogenous damage to mtDNA by free radicals is believed to be a major contributory factor to aging. Mitochondrial DNA exists in a highly genotoxic environment created by exposure to reactive oxygen species and thus are more vulnerable to free radical attack. In the present study we have focused on the age associated alterations to DNA during aging and in parallel investigated the efficacy of carnitine (300 mg/kg bw) and lipoic acid (100 mg/kg bw) for 28 days in altering these changes. We observed a decline in the content of both mitochondrial and nuclear DNA during aging with an exponential increase in the 8-OHdG levels. We also observed an age-dependent increase in DNA protein crosslinks and double strand and single strand breaks. Supplementation of carnitine and lipoic acid during aging process decreased the incidence of these DNA damage, therefore suggesting that this feeding regimen inhibits the accumulation of age-associated oxidative DNA damage.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2003

New insights into the bioenergetics of mitochondrial disorders using intracellular ATP reporters.

Mutations in mitochondrial DNA (mtDNA) cause impairment of ATP synthesis. It was hypothesized that high-energy compounds, such as ATP, are compartmentalized within cells and that different cell functions are sustained by different pools of ATP, some deriving from mitochondrial oxidative phosphorylation (OXPHOS) and others from glycolysis. Therefore, an OXPHOS dysfunction may affect different cell compartments to different extents. To address this issue, we have used recombinant forms of the ATP reporter luciferase localized in different cell compartments- the cytosol, the subplasma membrane region, the mitochondrial matrix, and the nucleus- of cells containing either wild-type or mutant mtDNA. We found that with glycolytic substrates, both wild-type and mutant cells were able to maintain adequate ATP supplies in all compartments. Conversely, with the OXPHOS substrate pyruvate ATP levels collapsed in all cell compartments of mutant cells. In wild-type cells normal levels of ATP were maintained with pyruvate in the cytosol and in the subplasma membrane region, but, surprisingly, they were reduced in the mitochondria and, to a greater extent, in the nucleus. The severe decrease in nuclear ATP content under "OXPHOS-only" conditions implies that depletion of nuclear ATP plays an important, and hitherto unappreciated, role in patients with mitochondrial dysfunction.

Adenosine Triphosphate↗
PubMed1990

An improved procedure for quantitating mitochondrial DNA in cultured mammalian cells.

A new improved method that reproducibly measures small perturbations of mitochondrial DNA in populations of cells has been developed. It is based on first obtaining a cell count and then analyzing three aliquots of cells: one for total DNA per cell by fluorometry, one for total protein per cell and one for the amount of mitochondrial DNA per microgram of total cell DNA. To quantitate mitochondrial DNA, 0, 1, 2, and 3 nanograms of mouse mtDNA purified from a plasmid are added as internal standard DNA to four 1.0-microgram samples of purified total cell DNA containing an unknown amount of mitochondrial DNA (a sample set). Three sample sets are electrophoresed in an agarose gel devoid of ethidium bromide. Following Southern transfer to nitrocellulose and hybridization to purified 32P-labeled mouse mitochondrial DNA, an autoradiogram is prepared for use as a template to locate the mitochondrial DNA bands. These bands are cut out of the nitrocellulose filters, and their 32P-content is determined using a liquid scintillation counter. For each sample set, the counts per minute is plotted against the amount of mitochondrial DNA added. The plot is linear and the negative average of the values for the three intercepts on the x-axis yields the amount of nanograms of mitochondrial DNA per microgram of total cell DNA. The method is highly reproducible with a standard deviation of approximately 9 percent. The advantages of using this method over others that have been reported are discussed.

Animals↗
PubMed1994

Cloning and characterization of the platypus mitochondrial genome.

The vertebrate mitochondrial genome is highly conserved in size and gene content. Among the chordates there appears to be one basic gene arrangement, but rearrangements in the mitochondrial gene order of the avian lineages have indicated that the mitochondrial genome may be more variable than once thought. Different gene orders in marsupials and eutherian mammals leave the ancestral mammalian order in some doubt. We have investigated the mitochondrial gene order in the platypus (Ornithorhynchus anatinus), a representative of the third major group of mammals, to determine which mitochondrial gene arrangement is ancestral in mammals. We have found that the platypus mtDNA conforms to the basic chordate gene arrangement, common to fish, amphibians, and eutherian mammals, indicating that this arrangement was the original mammalian arrangement, and that the unusual rearrangements observed in the avians and marsupials are probably lineage-specific.

Animals↗
PubMed1992

The cytochrome b and ATPase genes of honeybee mitochondrial DNA.

The gene sequences for honeybee cytochrome b, ATPase 6, and ATPase 8 are presented, along with the inferred amino acid sequences of the proteins. These mitochondrial genes are in the same relative positions as are their counterparts in Drosophila mitochondrial mtDNA and have evolved at a significantly greater overall rate than have those of Drosophila. Comparisons using both amino acid identity and the proportion of conservative replacements between the inferred Apis and vertebrate cytochrome b sequences shows the two highly conserved sections reported by Howell, but his recognition of five conserved regions is not well supported. A very high AT bias is reflected in very high codon biases. The best predictors of the number of occurrences of an amino acid in honeybee cytochrome b are the T and G contents of its codon family--unlike the case for vertebrate cytochrome b, in which the codon family size and AT bias are the strongest predictors; protein function, at least as judged by hydrophilicity characteristics, appears to be unaffected by these differing influences on amino acid composition.

Adenosine Triphosphatases↗
PubMed1998

Pyruvate dehydrogenase complex deficiency and altered respiratory chain function in a patient with Kearns-Sayre/MELAS overlap syndrome and A3243G mtDNA mutation.

Combined alteration of the pyruvate dehydrogenase complex and respiratory chain function is described in a 21 year-old male patient with overlapping MELAS (mitochondrial encephalomyopathy, lactic acidosis, and 'stroke-like' episodes) and Kearns-Sayre syndrome. Progressive external ophthalmoplegia, pigmentary retinopathy and right bundle branch block were present when he experienced the first 'stroke-like' episode at 18 years old. The A>G tRNALeu(UUR) point mutation at nucleotide 3243 of the mitochondrial DNA was predominant in muscle tissue (79%) and present, but at lower levels in fibroblasts (49%) and blood cells (37%). Biochemical analysis revealed diminished activities of pyruvate dehydrogenase (23%) and respiratory chain complexes I and IV (57%, respectively) in muscle, but normal activities in the fibroblasts. Immunochemical studies of the muscular pyruvate dehydrogenase components showed normal content of E1alpha, E1beta and E2 protein. Molecular screening of the E1alpha gene did not indicate a nuclear mutation. These observations suggest that mitochondrial DNA defects may be associated with altered nuclear encoded enzymes which are actively imported into mitochondria and constitute components of the mitochondrial matrix. Biochemical workup of mitochondrial disorders should not be restricted to the respiratory chain even if mitochondrial DNA mutations are present.

Adult↗
PubMed2006

[What is the future of our genome?].

Where do we go and what will happen with our genomes? Viewed as a reflection of what we know about our origin as Homo sapiens, history and forecast. Archeogenetics tries to find our sourcing place and to explain how humans occupied the globe. One of the first theories based on mtDNA polymorphisms@ studies stressed on our African origin followed by stepwise dispersal all over the world which took approximately 80,000 years. But not all findings agreed with this assumption if based on nuclear loci and supported multifocal origin of humans. The process of establishing a new species--Homo sapiens, is still not fully understood and many questions remained unanswered. From the point of view of population genetics we can assume that: 1. Mutability (natural or from internal causes) does not change though we cannot neglect suspicion that environment could influence its increase. The content of harming mutations in our genome, due to the protective effect of health care, which blocks natural selection, is increasing and moreover changes of our life style opened the door for manifestation of week deleterious alleles accumulated during foregoing period of evolution. Also prolongation of our life span is accompanied with effects of genotypes positively selected because of their positive effect on our reproductive period but which could be harmful during postreproductive stage--antagonistic pleiotropy. 2. According traditional assumption on the quality of new mutations is that they are either neutral or harming. Changes which are drift-dependent are becoming reduced. 3. Effective population size (steady state could be supposed or some increase due to more intensive local migration). 4. Migration (In spite of absence of corresponding demographic data) seems to be nowadays more intensive than it was in the past.

Forecasting↗
PubMed2006

How to prevent 'half-bastard' progeny? or An alternative for three-parent babies: two-parent babies through transplantation of sperm mitochondria.

Body development and activity depend on the level of internal energy generation. Therefore, unaffected, optimally active mitochondria are indispensable in a healthy and vital body. A mutation in the DNA of the semi-autonomous mitochondria (mtDNA) may cause an inheritable insufficiency that is due to decreased energy generation needed for adequate development. Sperm mitochondria will not enter the egg cell during fusion of male and female gametocytes. Since women with mutated mtDNA will increasingly know and realize the effect of such mutation in their own body, they will more often ask for treatment to stop the effect of such inconvenient mutation in their progeny. Thus far, solutions for this problem were thought to be: (i) nucleus transplantation just after fertilization into a nucleus-free egg cell of a second healthy woman and later (ii) transplantation of healthy mitochondria from a second woman into the egg cell before fertilization. Although both transplantations create babies with three, instead of two-parents that have contributed to the genetic content, in case of the newer mitochondria transplantation technique the part of the second woman is somewhat more reduced, but still clearly present. Thus, assisted-reproduction techniques that mix egg cell mitochondria from two women may create not only 'three-parents' babies, but also fears for 'three-parents' babies, since this handling may create non-scientific problems, especially regarding emotional, ethical, religious and juridical aspects of life. Transplantation of healthy sperm mitochondria of the partner into the egg cell with insufficient mitochondria is thought to be the best solution for this problem, since it may create a 'two-parents' instead of a 'three-parents' baby. This only implies that at the moment of (successful) transplantation the biological dogma is broken that mitochondria are maternally inherited: the mitochondria of the maternal line of the woman will have been substituted by the mitochondria of the maternal line of the man.

Female↗