Electron microscopy reveals mitochondrial DNA in discrete foci. Bars: 200 nm. (A) Cytoplasmic section after immunogold labelling with anti-DNA; gold particles marking mtDNA are found near the mitochondrial membrane. (B) Whole mount view of cytoplasm after extraction with CSK buffer and immunogold labelling with anti-DNA; mtDNA (marked by gold particles) resists extraction. From Iborra et al., 2004.
[1]
Mitochondrial DNA (mtDNA or mDNA[2]) is the DNA located in organelles called mitochondria, structures within eukaryotic cells that convert the chemical energy from food into a form that cells can use, adenosine triphosphate (ATP). Most other DNA present in eukaryotic organisms is found in the cell nucleus.
Mitochondrial DNA can be regarded as the smallest chromosome coding for only 37 genes and containing only 16,569 base pairs. Human mitochondrial DNA was the first significant part of the human genome to be sequenced. In most species, including humans, mtDNA is inherited solely from the mother.[3]
The DNA sequence of mtDNA has been determined from a large number of organisms and individuals (including some organisms that are extinct), and the comparison of those DNA sequences represents a mainstay of phylogenetics, in that it allows biologists to elucidate the evolutionary relationships among species. It also permits an examination of the relatedness of populations, and so has become important in anthropology and field biology.
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Contents
- 1 Origin
- 2 Mitochondrial inheritance
- 2.1 Female inheritance
- 2.2 Male inheritance
- 3 Structure
- 4 Replication
- 5 Mutations
- 5.1 Susceptibility
- 5.2 Genetic illness
- 5.3 Use in disease diagnosis
- 5.4 Effects on aging
- 6 Use in identification
- 7 History
- 8 See also
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Origin
Nuclear and mitochondrial DNA are thought to be of separate evolutionary origin, with the mtDNA being derived from the circular genomes of the bacteria that were engulfed by the early ancestors of today's eukaryotic cells. This theory is called the endosymbiotic theory. Each mitochondrion is estimated to contain 2-10 mtDNA copies.[4] In the cells of extant organisms, the vast majority of the proteins present in the mitochondria (numbering approximately 1500 different types in mammals) are coded for by nuclear DNA, but the genes for some of them, if not most, are thought to have originally been of bacterial origin, having since been transferred to the eukaryotic nucleus during evolution.
Mitochondrial inheritance
In most multicellular organisms, mtDNA is inherited from the mother (maternally inherited). Mechanisms for this include simple dilution (an egg contains 100,000 to 1,000,000 mtDNA molecules, whereas a sperm contains only 100 to 1000), degradation of sperm mtDNA in the fertilized egg, and, at least in a few organisms, failure of sperm mtDNA to enter the egg. Whatever the mechanism, this single parent (uniparental) pattern of mtDNA inheritance is found in most animals, most plants and in fungi as well.
Female inheritance
In sexual reproduction, mitochondria are normally inherited exclusively from the mother. The mitochondria in mammalian sperm are usually destroyed by the egg cell after fertilization. Also, most mitochondria are present at the base of the sperm's tail, which is used for propelling the sperm cells. Sometimes the tail is lost during fertilization. In 1999 it was reported that paternal sperm mitochondria (containing mtDNA) are marked with ubiquitin to select them for later destruction inside the embryo.[5] Some in vitro fertilization techniques, particularly injecting a sperm into an oocyte, may interfere with this.
The fact that mitochondrial DNA is maternally inherited enables researchers to trace maternal lineage far back in time. (Y-chromosomal DNA, paternally inherited, is used in an analogous way to trace the agnate lineage.) This is accomplished on human mitochondrial DNA by sequencing one or more of the hypervariable control regions (HVR1 or HVR2) of the mitochondrial DNA, as with a genealogical DNA test. HVR1 consists of about 440 base pairs. These 440 base pairs are then compared to the control regions of other individuals (either specific people or subjects in a database) to determine maternal lineage. Most often, the comparison is made to the revised Cambridge Reference Sequence. Vilà et al. have published studies tracing the matrilineal descent of domestic dogs to wolves.[6] The concept of the Mitochondrial Eve is based on the same type of analysis, attempting to discover the origin of humanity by tracking the lineage back in time.
Because mtDNA is not highly conserved and has a rapid mutation rate, it is useful for studying the evolutionary relationships - phylogeny - of organisms. Biologists can determine and then compare mtDNA sequences among different species and use the comparisons to build an evolutionary tree for the species examined.
Because mtDNA is transmitted from mother to child (both male and female), it can be a useful tool in genealogical research into a person's maternal line.
Male inheritance
Main article: Paternal mtDNA transmission
It has been reported that mitochondria can occasionally be inherited from the father in some species such as mussels.[7][8] Paternally inherited mitochondria have additionally been reported in some insects such as fruit flies,[9] honeybees,[10] and periodical cicadas.[11]
Evidence supports rare instances of male mitochondrial inheritance in some mammals as well. Specifically, documented occurrences exist for mice,[12][13] where the male-inherited mitochondria was subsequently rejected. It has also been found in sheep,[14] and in cloned cattle.[15] It has been found in a single case in a human male.[16]
While many of these cases involve cloned embryos or subsequent rejection of the paternal mitochondria, others document in vivo inheritance and persistence under lab conditions.
Structure
In most multicellular organisms, the mtDNA is organized as a circular, covalently closed, double-stranded DNA. But in many unicellular (e.g. the ciliate Tetrahymena or the green alga Chlamydomonas reinhardtii) and in rare cases also in multicellular organisms (e.g. in some species of Cnidaria) the mtDNA is found as linearly organized DNA. Most of these linear mtDNAs possess telomerase independent telomeres (i.e. the ends of the linear DNA) with different modes of replication, which have made them interesting objects of research, as many of these unicellular organisms with linear mtDNA are known pathogens.[17]
For human mitochondrial DNA (and probably for that of metazoans in general), 100-10,000 separate copies of mtDNA are usually present per cell (egg and sperm cells are exceptions). In mammals, each double-stranded circular mtDNA molecule consists of 15,000-17,000[18] base pairs. The two strands of mtDNA are differentiated by their nucleotide content with the guanine rich strand referred to as the heavy strand, and the cytosine rich strand referred to as the light strand. The heavy strand encodes 28 genes, and the light strand encodes 9 genes for a total of 37 genes. Of the 37 genes, 13 are for proteins (polypeptides), 22 are for transfer RNA (tRNA) and two are for the small and large subunits of ribosomal RNA (rRNA). This pattern is also seen among most metazoans, although in some cases one or more of the 37 genes is absent and the mtDNA size range is greater. Even greater variation in mtDNA gene content and size exists among fungi and plants, although there appears to be a core subset of genes that are present in all eukaryotes (except for the few that have no mitochondria at all). Some plant species have enormous mtDNAs (as many as 2,500,000 base pairs per mtDNA molecule) but, surprisingly, even those huge mtDNAs contain the same number and kinds of genes as related plants with much smaller mtDNAs.[19]
The genome of the mitochondrion of the cucumber (Cucumis sativus) consists of three circular chromosomes (lengths 1556, 84 and 45 kilobases), which are entirely or largely autonomous with regard to their replication.[20]
Replication
mtDNA is replicated by the DNA polymerase gamma complex which is composed of a 140 kDa catalytic DNA polymerase encoded by the POLG gene and a 55 kDa accessory subunit encoded by the POLG2 gene. During embryogenesis, replication of mtDNA is strictly down-regulated from the fertilized oocyte through the preimplantation embryo.[21] At the blastocyst stage, the onset of mtDNA replication is specific to the cells of the trophectoderm.[21] In contrast, the cells of the inner cell mass restrict mtDNA replication until they receive the signals to differentiate to specific cell types.[21]
Mutations
The involvement of mitochondrial DNA in several human diseases.
Susceptibility
mtDNA is particularly susceptible to reactive oxygen species generated by the respiratory chain due to its proximity. Though mtDNA is packaged by proteins and harbors significant DNA repair capacity, these protective functions are less robust than those operating on nuclear DNA and are therefore thought to contribute to enhanced susceptibility of mtDNA to oxidative damage. The outcome of mutation in mtDNA may be alteration in the coding instructions for some proteins,[22] which may have an effect on organism metabolism and/or fitness.
Genetic illness
Further information: Mitochondrial disease
Mutations of mitochondrial DNA can lead to a number of illnesses including exercise intolerance and Kearns-Sayre syndrome (KSS), which causes a person to lose full function of heart, eye, and muscle movements. Some evidence suggests that they might be major contributors to the aging process and age-associated pathologies.[23]
Use in disease diagnosis
Recently a mutation in mtDNA has been used to help diagnose prostate cancer in patients with negative prostate biopsy.[24][25]
Effects on aging
A link between aging and Mitochondrial DNA has been proposed as a result from the findings of many scientific studies. The proposed theory is that the damage to Mitochondrial DNA caused by oxidative stress is a primary cause of aging within the body. As Mitochondrial DNA accumulates genetic damage from free radicals, the Mitochondria become less efficient at performing their physiological functions. As extensive scientific experiments have previously shown, the mitochondria are responsible for the majority of ATP production within the cell. As the efficiency of the Mitochondria decreases so does its inherent ability to create ATP and fuel the processes of the cell and, ultimately, the body. Extensive research is being conducted to further investigate this link and possible ways to combat the effects of aging. [26] [27]
Use in identification
For use in human identification, see Human mitochondrial DNA.
Unlike nuclear DNA, which is inherited from both parents and in which genes are rearranged in the process of recombination, there is usually no change in mtDNA from parent to offspring. Although mtDNA also recombines, it does so with copies of itself within the same mitochondrion. Because of this and because the mutation rate of animal mtDNA is higher than that of nuclear DNA,[28] mtDNA is a powerful tool for tracking ancestry through females (matrilineage) and has been used in this role to track the ancestry of many species back hundreds of generations.
The low effective population size and rapid mutation rate (in animals) makes mtDNA useful for assessing genetic relationships of individuals or groups within a species and also for identifying and quantifying the phylogeny (evolutionary relationships; see phylogenetics) among different species, provided they are not too distantly related. To do this, biologists determine and then compare the mtDNA sequences from different individuals or species. Data from the comparisons is used to construct a network of relationships among the sequences, which provides an estimate of the relationships among the individuals or species from which the mtDNAs were taken. This approach has limits that are imposed by the rate of mtDNA sequence change. In animals, the high mutation rate makes mtDNA most useful for comparisons of individuals within species and for comparisons of species that are closely or moderately-closely related, among which the number of sequence differences can be easily counted. As the species become more distantly related, the number of sequence differences becomes very large; changes begin to accumulate on changes until an accurate count becomes impossible.
History
Mitochondrial DNA was discovered in the 1960s by Margit M. K. Nass and Sylvan Nass by electron microscopy as DNase-sensitive thread inside mitochondria,[29] and by Ellen Haslbrunner, Hans Tuppy and Gottfried Schatz by biochemical assays on highly purified mitochondrial fractions.[30]
See also
- Archaeogenetics of the Near East
- CORR Hypothesis
- Haplogroup
- Heteroplasmy
- Human mitochondrial DNA haplogroup
- Human mitochondrial genetics
- Mitochondrial disease
- Mitochondrial DNA (journal)
- Mitochondrial Eve
- Mitochondrial rCRS
- Paternal mtDNA transmission
- Single origin theory
- Supercluster (genetic)
- TIM/TOM Complex
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- Genetic history of Africa
- Genetic history of Europe
- Genetic history of the British Isles
- Genetic history of the Iberian Peninsula
- Genetic history of indigenous peoples of the Americas
- Genetic history of Italy
- Genetic history of North Africa
- Genetics and archaeogenetics of South Asia
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Molecular Anthropology portal |
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Evolutionary biology portal |
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- ^ Iborra FJ, Kimura H, Cook PR (2004). "The functional organization of mitochondrial genomes in human cells". BMC Biol. 2: 9. doi:10.1186/1741-7007-2-9. PMC 425603. PMID 15157274. http://www.biomedcentral.com/1741-7007/2/9.
- ^ Sykes, B (10 September 2003). "Mitochondrial DNA and human history". The Human Genome. Wellcome Trust. http://genome.wellcome.ac.uk/doc_WTD020876.html. Retrieved 5 February 2012.
- ^ "Mitochondrial DNA: The Eve Gene". Bradshaw Foundation. Bradshaw Foundation. http://www.bradshawfoundation.com/journey/eve.html. Retrieved 5 November 2012.
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- ^ Sutovsky, P., et al. (Nov. 25, 1999). "Ubiquitin tag for sperm mitochondria". Nature 402 (6760): 371–372. doi:10.1038/46466. PMID 10586873. Discussed in [1].
- ^ Vilà C, Savolainen P, Maldonado JE, and Amorin IR (13 June 1997). "Multiple and Ancient Origins of the Domestic Dog". Science 276 (5319): 1687–1689. doi:10.1126/science.276.5319.1687. ISSN 0036-8075. PMID 9180076.
- ^ Hoeh WR, Blakley KH, Brown WM (1991). "Heteroplasmy suggests limited biparental inheritance of Mytilus mitochondrial DNA". Science 251 (5000): 1488–1490. doi:10.1126/science.1672472. PMID 1672472.
- ^ Penman, Danny (23 August 2002). "Mitochondria can be inherited from both parents". NewScientist.com. http://www.newscientist.com/article.ns?id=dn2716. Retrieved 2008-02-05.
- ^ Kondo R, Matsuura ET, Chigusa SI (1992). "Further observation of paternal transmission of Drosophila mitochondrial DNA by PCR selective amplification method,". Genet. Res. 59 (2): 81–4. doi:10.1017/S0016672300030287. PMID 1628820.
- ^ Meusel MS, Moritz RF (1993). "Transfer of paternal mitochondrial DNA during fertilization of honeybee (Apis mellifera L.) eggs". Curr. Genet. 24 (6): 539–43. doi:10.1007/BF00351719. PMID 8299176.
- ^ Fontaine, KM, Cooley, JR, Simon, C (2007). Crusio, Wim. ed. "Evidence for Paternal Leakage in Hybrid Periodical Cicadas (Hemiptera: Magicicada spp.)". PLoS One. 9 (9): e892. doi:10.1371/journal.pone.0000892. PMC 1963320. PMID 17849021. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1963320/.
- ^ Gyllensten U, Wharton D, Josefsson A, Wilson AC (1991). "Paternal inheritance of mitochondrial DNA in mice". Nature 352 (6332): 255–7. doi:10.1038/352255a0. PMID 1857422.
- ^ Shitara H, Hayashi JI, Takahama S, Kaneda H, Yonekawa H (1998). "Maternal inheritance of mouse mtDNA in interspecific hybrids: segregation of the leaked paternal mtDNA followed by the prevention of subsequent paternal leakage". Genetics 148 (2): 851–7. PMC 1459812. PMID 9504930. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1459812/.
- ^ Zhao X, Li N, Guo W, et al. (2004). "Further evidence for paternal inheritance of mitochondrial DNA in the sheep (Ovis aries)". Heredity 93 (4): 399–403. doi:10.1038/sj.hdy.6800516. PMID 15266295.
- ^ Steinborn R, Zakhartchenko V, Jelyazkov J, et al. (1998). "Composition of parental mitochondrial DNA in cloned bovine embryos". FEBS Lett. 426 (3): 352–6. doi:10.1016/S0014-5793(98)00350-0. PMID 9600265.
- ^ Schwartz M, Vissing J (2002). "Paternal inheritance of mitochondrial DNA". N. Engl. J. Med. 347 (8): 576–80. doi:10.1056/NEJMoa020350. PMID 12192017.
- ^ Nosek J, Tomáska L, Fukuhara H, Suyama Y, Kovác L (May 1998). "Linear mitochondrial genomes: 30 years down the line". Trends Genet. 14 (5): 184–8. doi:10.1016/S0168-9525(98)01443-7. PMID 9613202.
- ^ "Genetic Genealogy". Ramsdale.org. 2003-05-19. doi:10.1371/journal.pbio.1000285. http://www.ramsdale.org/genetic.htm. Retrieved 2012-07-14.
- ^ Ward BL, Anderson RS, Bendich AJ (September 1981). "The mitochondrial genome is large and variable in a family of plants (cucurbitaceae)". Cell 25 (3): 793–803. doi:10.1016/0092-8674(81)90187-2. PMID 6269758. http://linkinghub.elsevier.com/retrieve/pii/0092-8674(81)90187-2. Retrieved 2010-08-09.
- ^ Alverson AJ, Rice DW, Dickinson S, Barry K, Palmer JD (2011) Origins and Recombination of the Bacterial-Sized Multichromosomal Mitochondrial Genome of Cucumber. Plant Cell
- ^ a b c John JC, Facucho-Oliveira J, Jiang Y, Kelly R, Salah R (March 2010). "Mitochondrial DNA transmission, replication and inheritance: a journey from the gamete through the embryo and into offspring and embryonic stem cells". Hum Reprod Update 16 (5): 488–509. doi:10.1093/humupd/dmq002. PMID 20231166.
- ^ C.Michael Hogan. 2010. Mutation. ed. E.Monosson and C.J.Cleveland. Encyclopedia of Earth. National Council for Science and the Environment. Washington DC
- ^ Alexeyev, Mikhail F.; LeDoux, Susan P.; Wilson, Glenn L. (July 2004). "Mitochondrial DNA and aging". Clinical Science 107 (4): 355–364. doi:10.1042/CS20040148. PMID 15279618. http://www.clinsci.org/cs/107/0355/1070355.pdf.
- ^ Reguly B, Jakupciak JP, Parr RL. (2010). "3.4 kb mitochondrial genome deletion serves as a surrogate predictive biomarker for prostate cancer in histopathologically benign biopsy cores". Canadian Urological Association journal = Journal de l'Association des urologues du Canada 4 (5): E118–22. PMC 2950771. PMID 20944788. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2950771/.
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- ^ Oxidative Damage and Mitochondrial Decay in Aging Mark K. Shigenaga, Tory M. Hagen and Bruce N. Ames Proceedings of the National Academy of Sciences of the United States of America Vol. 91, No. 23 (Nov. 8, 1994), pp. 10771-10778 Published by: National Academy of Sciences Stable URL: http://www.jstor.org/stable/2365473
- ^ "Mitochondria and Aging." (ActionBioscience). N.p., n.d. Web. 12 Dec. 2012.
- ^ Brown WM, George M Jr., Wilson AC (1979). "Rapid evolution of animal mitochondrial DNA". Proc Natl Acad Sci USA 76 (4): 1967–1971. doi:10.1073/pnas.76.4.1967. PMC 383514. PMID 109836. //www.ncbi.nlm.nih.gov/pmc/articles/PMC383514/.
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Types of nucleic acids
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| Constituents |
- Nucleobases
- Nucleosides
- Nucleotides
- Deoxynucleotides
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Ribonucleic acids
(coding and non-coding) |
- translation: mRNA
- tRNA
- rRNA
- tmRNA
- regulatory: miRNA
- siRNA
- piRNA
- aRNA
- RNAi
- RNA processing: snRNA
- snoRNA
- other/ungrouped: gRNA
- shRNA
- stRNA
- ta-siRNA
- SgRNA
- Sutherland RNA
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| Deoxyribonucleic acids |
- cDNA
- cpDNA
- gDNA
- msDNA
- mtDNA
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| Nucleic acid analogues |
- GNA
- LNA
- PNA
- TNA
- morpholino
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| Cloning vectors |
- phagemid
- plasmid
- lambda phage
- cosmid
- fosmid
- PAC
- BAC
- YAC
- HAC
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- biochemical families: carbohydrates
- alcohols
- glycoproteins
- glycosides
- lipids
- eicosanoids
- fatty acids / intermediates
- phospholipids
- sphingolipids
- steroids
- nucleic acids
- constituents / intermediates
- proteins
- amino acids / intermediates
- tetrapyrroles / intermediates
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Mitochondrial proteins
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| Outer membrane |
fatty acid degradation (Carnitine palmitoyltransferase I, Long fatty acyl CoA synthetase)
tryptophan metabolism (Kynureninase)
monoamine neurotransmitter metabolism (Monoamine oxidase)
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| Intermembrane space |
Adenylate kinase - Creatine kinase
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| Inner membrane |
oxidative phosphorylation (Coenzyme Q - cytochrome c reductase, Cytochrome c, NADH dehydrogenase, Succinate dehydrogenase)
pyrimidine metabolism (Dihydroorotate dehydrogenase)
mitochondrial shuttle (Malate-aspartate shuttle, Glycerol phosphate shuttle)
other (Glutamate aspartate transporter, Glycerol-3-phosphate dehydrogenase, ATP synthase, Carnitine palmitoyltransferase II, Uncoupling protein)
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| Matrix |
citric acid cycle (Citrate synthase, Aconitase, Isocitrate dehydrogenase, Oxoglutarate dehydrogenase, Succinyl coenzyme A synthetase, Fumarase, Malate dehydrogenase)
anaplerotic reactions (Aspartate transaminase, Glutamate dehydrogenase, Pyruvate dehydrogenase complex)
urea cycle (Carbamoyl phosphate synthetase I, Ornithine transcarbamylase, N-Acetylglutamate synthase)
alcohol metabolism (ALDH2)
PMPCB
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| Other/to be sorted |
steroidogenesis (Cholesterol side-chain cleavage enzyme, Steroid 11-beta-hydroxylase, Aldosterone synthase), Frataxin
Mitochondrial membrane transport protein (Mitochondrial permeability transition pore, Mitochondrial carrier)
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| Mitochondrial DNA |
Complex I (MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L, MT-ND5, MT-ND6) - Complex III (MT-CYB) - Complex IV (MT-CO1, MT-CO2, MT-CO3)
ATP synthase (MT-ATP6, MT-ATP8)
tRNA (MT-TA, MT-TC, MT-TD, MT-TE, MT-TF, MT-TG, MT-TH, MT-TI, MT-TK, MT-TL1, MT-TL2, MT-TM, MT-TN, MT-TP, MT-TQ, MT-TR, MT-TS1, MT-TS2, MT-TT, MT-TV, MT-TW, MT-TY)
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see also mitochondrial diseases
B strc: edmb (perx), skel (ctrs), epit, cili, mito, nucl (chro)
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