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(Redirected from Mitochondrial)
In cell biology, a 'mitochondrion' (plural 'mitochondria') is a membrane-enclosed organelle that is found in most eukaryotic cells.[1] Mitochondria are sometimes described as "cellular power plants," because they generate most of the cell's supply of ATP, used as a source of chemical energy. The number of mitochondria in a cell varies widely by organism and tissue type. Many cells possess only a single mitochondrion, while others can contain several thousand mitochondria. Molecular Biology of the Cell, , Bruce, Alberts, Garland Publishing Inc., 1994, ISBN 0-815-33218-1 [2]
Although most of a cell's DNA is contained in the cell nucleus, mitochondria have their own independent genomes. This DNA shows similarity to bacterial genomes and according to the endosymbiotic theory, mitochondria are descended from free-living prokaryotes. The word mitochondrion comes from the Greek ''μίτος '' or ''mitos'', thread + ''χονδρίον'' or ''khondrion'', granule.
A mitochondrion contains inner and outer membranes composed of phospholipid bilayers and proteins. The two membranes, however, have different properties. Because of this double-membraned organization, there are 5 distinct compartments within mitochondria. There is the outer membrane, the intermembrane space (the space between the outer and inner membranes), the inner membrane, the cristae space (formed by infoldings of the inner membrane), and the matrix (space within the inner membrane). Mitochondria range from 1 to 10 micrometers (μm) in size.
Main articles: Outer mitochondrial membrane
The outer mitochondrial membrane, which encloses the entire organelle, has a protein-to-phospholipid ratio similar to the eukaryotic plasma membrane (about 1:1 by weight). It contains numerous integral proteins called ''porins''.
The intermembrane space is the space between the outer membrane and the inner membrane.
:''See also Inner mitochondrial membrane''
The inner mitochondrial membrane contains proteins with four types of functions:
# Those that carry out the oxidation reactions of the respiratory chain.
# ATP synthase, which makes ATP in the matrix.
# Specific transport proteins that regulate the passage of metabolites into and out of the matrix.
# Protein import machinery.
It contains more than 100 different polypeptides, and has a very high protein-to-phospholipid ratio (more than 3:1 by weight, which is about 1 protein for 15 phospholipids). Additionally the inner membrane is rich in an unusual phospholipid, cardiolipin. This phospholipid was originally discovered in beef hearts in 1942 and is usually characteristic of mitochondrial and bacterial plasma membranes. Cardiolipin and apoptosis, McMillin JB, Dowhan W, , , Biochim. et Biophys. Acta., Unlike the outer membrane, the inner membrane does not contain porins, and is highly impermeable; almost all ions and molecules require special membrane transporters to enter or exit the matrix. In addition, there is a membrane potential across the inner membrane.
The inner mitochondrial membrane is compartmentalized into numerous cristae, which expand the surface area of the inner mitochondrial membrane, enhancing its ability to generate ATP. In typical liver mitochondria, for example, the surface area, including cristae, is about five times that of the outer membrane. Mitochondria of cells which have greater demand for ATP, such as muscle cells, contain more cristae than typical liver mitochondria.
:''See also mitochondrial matrix''
The matrix is the space enclosed by the inner membrane. The matrix is important in the production of ATP with the aid of the ATP synthase contained in the inner membrane. The matrix contains a highly concentrated mixture of hundreds of enzymes, in addition to the special mitochondrial ribosomes, tRNA, and several copies of the mitochondrial DNA genome. Of the enzymes, the major functions include oxidation of pyruvate and fatty acids, and the citric acid cycle.
Mitochondria possess their own genetic material, and the machinery to manufacture their own RNAs and proteins. (''See: protein synthesis''). A published human mitochondrial DNA sequence revealed 16,569 base pairs encoding 37 total genes, 24 tRNA and rRNA genes and 13 peptide genes.[3] The 13 mitochondrial peptides in humans are integrated into the inner mitochondrial membrane, along with proteins encoded by genes that reside in the host cell's nucleus.
Although it is well known that the mitochondria convert organic materials into cellular energy in the form of ATP, mitochondria play an important role in many metabolic tasks, such as:
★ Apoptosis-programmed cell death
★ Glutamate-mediated excitotoxic neuronal injury
★ Cellular proliferation
★ Regulation of the cellular redox state
★ Heme synthesis
★ Steroid synthesis
Some mitochondrial functions are performed only in specific types of cells. For example, mitochondria in liver cells contain enzymes that allow them to detoxify ammonia, a waste product of protein metabolism. A mutation in the genes regulating any of these functions can result in mitochondrial diseases.
A dominant role for the mitochondria is the production of ATP as reflected by the large number of proteins in the inner membrane for this task. This is done by oxidizing the major products of glycolysis: pyruvate and NADH that are produced in the cytosol. This process of cellular respiration, also known as aerobic respiration, is dependent on the presence of oxygen. When oxygen is limited the glycolytic products will be metabolised by anaerobic respiration, a process that is independent of the mitochondria. The production of ATP from glucose has an approximately 15 fold higher yield during aerobic respiration compared to anaerobic respiration.
Main articles: pyruvate decarboxylation, citric acid cycle
Each pyruvate molecule produced by glycolysis is actively transported across the inner mitochondrial membrane, and into the matrix where it is oxidized and combined with coenzyme A to form CO2, acetyl-CoA and NADH.
The acetyl-CoA is the primary substrate to enter the ''citric acid cycle'' , also known as the ''tricarboxylic acid (TCA) cycle'' or ''Krebs cycle''. The enzymes of the citric acid cycle are located in the mitochondrial matrix with the exception of succinate dehydrogenase, which is bound to the inner mitochondrial membrane. The citric acid cycle oxidizes the acetyl-CoA to carbon dioxide and in the process produces reduced cofactors (three molecules of NADH and one molecule of FADH2), that are a source of electrons for the ''electron transport chain'', and a molecule of GTP (that is readily converted to an ATP).
Main articles: Electron transport chain, Oxidative phosphorylation
The redox energy from NADH and FADH2 is transferred to oxygen (O2) in several steps via the electron transport chain. These energy-rich molecules are produced within the matrix via the citric acid cycle but are also produced in the cytoplasm by glycolysis; reducing equivalents from the cytoplasm can be imported via the malate-aspartate shuttle system of antiporter proteins or feed into the electron transport chain using a glycerol phosphate shuttle. Protein complexes in the inner membrane (NADH dehydrogenase, cytochrome c reductase and cytochrome c oxidase) perform the transfer and the incremental release of energy is used to pump protons (H+) into the intermembrane space. This process is efficient but a small percentage of electrons may prematurely reduce oxygen, forming reactive oxygen species such as superoxide. This can cause oxidative stress in the mitochondria and may contribute to the decline in mitochondrial function associated with the aging process.[4]
As the proton concentration increases in the intermembrane space, a strong electrochemical gradient is established across the inner membrane. The protons can return to the matrix through the ATP synthase complex and their potential energy is used to synthesize ATP from ADP and inorganic phosphate (Pi). This process is called chemiosmosis and was first described by Peter Mitchell Chemiosmotic hypothesis of oxidative phosphorylation, Mitchell P, Moyle J, , , Nature., Proton current flow in mitochondrial systems, Mitchell P, , , Nature., who was awarded the 1978 Nobel Prize in Chemistry for his work. Later, part of the 1997 Nobel Prize in Chemistry was awarded to Paul D. Boyer and John E. Walker for their clarification of the working mechanism of ATP synthase.
Under certain conditions, protons can re-enter the mitochondrial matrix without contributing to ATP synthesis. This process is known as ''proton leak'' or ''mitochondrial uncoupling'' and is due to the facilitated diffusion of protons into the matrix. This process results in the unharnessed potential energy of the proton electrochemical gradient being released as heat. The process is mediated by a proton channel called thermogenin, or UCP1. Thermoregulation: What Role for UCPs in Mammals and Birds?, Mozo J, Emre Y, Bouillaud F, Ricquier D, Criscuolo F, , , Bioscience Reports., Thermogenin is a 33kDa protein first discovered in 1973. Brown-adipose-tissue mitochondria. The influence of albumin and nucleotides on passive ion permeabilities., Nicholls DG, Lindberg O, , , Eur. J. Biochem., Thermogenin is primarily found in brown adipose tissue, or brown fat, and is responsible for non-shivering thermogenesis. Brown adipose tissue is found in mammals and is at its highest levels in early life and in hibernating animals. In humans, brown adipose tissue is present at birth and decreases with age.
The concentrations of free calcium in the cell can regulate an array of reactions and is important for signal transduction in the cell. Mitochondria store calcium, a process that is one important event for the homeostasis of calcium in the cell. Release of this calcium back into the cells interior can initiate calcium spikes or waves. These events coordinate processes such as neurotransmitter release in nerve cells and release of hormones in endocrine cells.
With their central place in cell metabolism, damage and dysfunction is mitochondria is an important factor in a wide range of human diseases. These diseases include schizophrenia, Bipolar disorder, dementia, Alzheimer's disease, Parkinson's disease, epilepsy, strokes, heart disease, retinitis pigmentosa and diabetes.[5] Mitochondrial dysfunction and molecular pathways of disease, Pieczenik SR, Neustadt J, , , Exp. Mol. Pathol., 2007 The common thread linking these seemingly-unrelated conditions is cellular damage causing oxidative stress and the accumulation of reactive oxygen species. These oxidants then damage the mitochondrial DNA, resulting in mitochondrial dysfunction and cell death.
Mutations in mitochondrial DNA can also be inherited, causing genetic disorders such as dominant optic atrophy, Friedreich's ataxia, hereditary spastic paraplegia, and Wilson's disease.[6] Environmental influences may also interact with hereditary predispositions and cause mitochondrial disease; an example of this is the possible role of pesticide exposure in causing some individuals to develop Parkinson's disease.[7][8]
Main articles: Endosymbiotic theory
As mitochondria contain ribosomes and DNA, and are only formed by the division of other mitochondria, it is generally accepted that they were originally derived from endosymbiotic prokaryotes. Studies of mitochondrial DNA, which is often circular and employs a variant genetic code, show their ancestor, the so-called proto-mitochondrion, was a member of the Proteobacteria.[9] In particular, the pre-mitochondrion was probably related to the rickettsias, although the exact position of the ancestor of mitochondria among the alpha-proteobacteria remains controversial. The endosymbiotic hypothesis suggests that mitochondria descended from specialized bacteria (probably purple non-sulfur bacteria) that somehow survived endocytosis by another species of prokaryote or some other cell type, and became incorporated into the cytoplasm. The ability of symbiont bacteria to conduct cellular respiration in host cells that had relied on glycolysis and fermentation would have provided a considerable evolutionary advantage. Similarly, host cells with symbiotic bacteria capable of photosynthesis would also have an advantage. In both cases, the number of environments in which the cells could survive would have been greatly expanded.
This relationship developed at least 2 billion years ago and mitochondria still show some signs of their ancient origin. Mitochondrial ribosomes in mammals are the 70S (bacterial) type, in contrast to the 80S ribosomes found elsewhere in the cell. Properties of human mitochondrial ribosomes., O'Brien TW, , , IUBMB Life., . One mitochondrion can contain 2-10 copies of its DNA. Counting target molecules by exponential polymerase chain reaction, copy number of mitochondrial DNA in rat tissues, Wiesner RJ, Ruegg JC, Morano I, , , Biochim Biophys Acta., As in prokaryotes, there is a very high proportion of coding DNA, and an absence of repeats. Mitochondrial genes are transcribed as multigenic transcripts which are cleaved and polyadenylated to yield mature mRNAs. Unlike their nuclear cousins, mitochondrial genes are small, and many chromosomes are circular, conforming to the bacterial pattern. In humans, mitochondrial genes lack introns, Sequence and organization of the human mitochondrial genome, Anderson S, Bankier AT, Barrell BG, de-Bruijn MHL, Coulson AR, et al., , , Nature, yet other Eukaryotic mitochondrial DNA has 1-37 of them. Further, there are codon differences in mitochondria: Replication and transcription of mammalian mitochondrial DNA, Fernandez-Silva P, Enriquez JA, Montoya, , , Exp Physiol., in the mitochondria, the UGA codon specifies tryptophan; AGA and AGG are stop codons; and AUA, AUC, and AUU are each allowable start codons.
A few groups of unicellular eukaryotes lack mitochondria: the microsporidians, metamonads, and archamoebae. Archamoebae: the ancestral eukaryotes?, Cavalier-Smith T, , , Biosystems., These groups appear as the most primitive eukaryotes on phylogenetic trees constructed using rRNA information, suggesting that they appeared before the origin of mitochondria. However, this is now known to be an artifact of long branch attraction — they are apparently derived groups and retain genes or organelles derived from mitochondria (e.g. mitosomes and hydrogenosomes).1 There are no primitively amitochondriate eukaryotes, and so the origin of mitochondria may have played a critical part in the development of eukaryotic cells.
Mitochondria replicate their DNA and divide mainly in response to the energy needs of the cell; in other words, their growth and division is not linked to the cell cycle. When the energy needs of a cell are high, mitochondria grow and divide. When the energy use is low, mitochondria are destroyed or become inactive. At cell division, mitochondria are distributed to the daughter cells more or less randomly during the division of the cytoplasm. Mitochondria divide by binary fission similar to bacterial cell division. Unlike bacteria, however, mitochondria can also fuse with other mitochondria.
Mitochondrial genes are not inherited by the same mechanism as nuclear genes. At fertilization of an egg by a sperm, the egg nucleus and sperm nucleus each contribute equally to the genetic makeup of the zygote nucleus. In contrast, the mitochondria, and therefore the mitochondrial DNA, usually comes from the egg only. The sperm's mitochondria enters the egg, but are almost always destroyed and do not contribute their genes to the embryo.[10] Paternal sperm mitochondria are marked with ubiquitin to select them for later destruction inside the embryo.[11] The egg contains relatively few mitochondria, but it is these mitochondria that survive and divide to populate the cells of the adult organism. Mitochondria are, therefore, in most cases inherited down the female line.
This maternal inheritance of mitochondrial DNA is seen in most organisms, including all animals. However, mitochondria in some species can sometimes be inherited through the father. This is the norm among certain coniferous plants although not in pines and yew trees.[12] It has been suggested to occur at a very low level in humans.[13]
Uniparental inheritance means that there is little opportunity for genetic recombination between different lineages of mitochondria, although a single mitochondrion can contain 2-10 copies of its DNA. Counting target molecules by exponential polymerase chain reaction, copy number of mitochondrial DNA in rat tissues, Wiesner RJ, Ruegg JC, Morano I, , , Biochim Biophys Acta., For this reason, mitochondrial DNA usually is thought of as reproducing by binary fission; what recombination that takes place is to maintain genetic integrity rather than to maintain diversity. However, there are several studies showing evidence of recombination in mitochondrial DNA. The enzymes necessary for recombination clearly are present in mammalian cells.[14] Further, evidence suggests that animal mitochondria can undergo recombination.[15] The data are a bit more controversial in humans, although, indirect evidence exists.[16][17] If recombination does not occur, the whole mitochondrial DNA sequence represents a single haplotype, which makes it useful for studying the evolutionary history of populations.
Mitochondrial genomes have many fewer genes than do the related eubacteria from which they are thought to be descended. Although some have been lost altogether, many have been transferred to the nucleus. This is thought to be relatively common over evolutionary time. A few organisms, such as the ''Cryptosporidium'', actually have mitochondria which lack any DNA, presumably because all their genes have either been lost or transferred. The unusual mitochondrial compartment of Cryptosporidium parvum, Henriquez FL, Richards TA, Roberts F, McLeod R, Roberts CW, , , Trends Parasitol., In Cryptosporidium, the mitochondria have an altered ATP generation system that renders the parasite resistant to many classical mitochondrial inhibitors such as cyanide, azide, and atovaquone.
The uniparental inheritance of mitochondria is thought to result in intragenomic conflict, such as seen in the petite mutant mitochondria of some yeast species. It is possible that the evolution of separate male and female sexes is a mechanism to resolve this organelle conflict.
The near-absence of genetic recombination in mitochondrial DNA makes it a useful source of information for scientists involved in population genetics and evolutionary biology. Because all the mitochondrial DNA is inherited as a single unit, or haplotype, the relationships between mitochondrial DNA from different individuals can be represented as a gene tree. Patterns in these gene trees can be used to infer the evolutionary history of populations. The classic example of this is in human evolutionary genetics, where the molecular clock can be used to provide a recent date for mitochondrial Eve. This is often interpreted as strong support for a recent modern human expansion out of Africa. Another human example is the sequencing of mitochondrial DNA from Neanderthal bones. The relatively large evolutionary distance between the mitochondrial DNA sequences of Neanderthals and living humans has been interpreted as evidence for lack of interbreeding between Neanderthals and anatomically modern humans.
However, mitochondrial DNA only reflects the history of females in a population, and so may not give a representative picture of the history of the population as a whole. For example, if dispersal is primarily undertaken by males, this will not be picked up by mitochondrial studies. This can be partially overcome by the use of patrilineal genetic sequences, if they are available (in mammals the non-recombining region of the Y-chromosome provides such a source). More broadly, only studies that also include nuclear DNA can provide a comprehensive evolutionary history of a population; unfortunately, genetic recombination means that these studies can be difficult to analyze.
★ The midi-clorians of the Star Wars universe are fictional life-forms inside cells that provide the Force. George Lucas took inspiration from the endosymbiotic theory.
★ Madeleine L'Engle's novel ''A Wind in the Door'' posits fictional "farandolae" which are to mitochondria what mitochondria are to cells.
★ In Hideaki Sena's novel ''Parasite Eve'' (and the video game based on it), mitochondria are independent organisms, using animals and plants as a form of "transportation," causing a major biological disaster when they decide to set themselves free.
1. Evolutionary biology: essence of mitochondria, Henze K, Martin W, , , Nature, 2003
2. Fundamentals of Biochemistry, 2nd Edition, , Donald, Voet, John Wiley and Sons, Inc., ,
3. Sequence and organization of the human mitochondrial genome, Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, et al., , , Nature.,
4. The role of oxidative damage in mitochondria during aging: A review, , K., Huang, Frontiers in Bioscience, 2004
5. Mitochondrial disease, Schapira AH, , , Lancet, 2006
6. Mitochondria, Chinnery PF, Schon EA, , , J. Neurol. Neurosurg. Psychiatr., 2003
7. Environment, mitochondria, and Parkinson's disease, Sherer TB, Betarbet R, Greenamyre JT, , , The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry, 2002
8. Pesticides and impairment of mitochondrial function in relation with the parkinsonian syndrome, Gomez C, Bandez MJ, Navarro A, , , Front. Biosci., 2007
9. On Darwin's Shoulders, , Douglas J., Futuyma, Natural History, 2005
10. Kimball, J.W. (2006) "Sexual Reproduction in Humans: Copulation and Fertilization," ''Kimball's Biology Pages'' (based on ''Biology'', 6th ed., 1996)]
11. {{cite journal | author=Sutovsky, P., et. al|year=1999|title=Ubiquitin tag for sperm mitochondria|journal=Nature|volume=402|pages=371-372|id= Discussed in ''Science News''.
12. The Hows and Whys of Cytoplasmic Inheritance in Seed Plants, , H. Lloyd, Mogensen, American Journal of Botany, 1996
13. Paternal transmission of mitochondrial DNA is (fortunately) rare, , D. R., Johns, Annals of Neurology,
14. Mammalian mitochondria possess homologous DNA recombination activity, Thyagarajan B, Padua RA, Campbell C, , , J. Biol. Chem.,
15. Animal mitochondrial DNA recombination, Lunt DB, Hyman BC, , , Nature,
16. How clonal are human mitochondria?, Eyre-Walker A, Smith NH, Maynard Smith J, , , Proc. Royal Soc. Biol. Sci. (Series B),
17. Linkage Disequilibrium and Recombination in Hominid Mitochondrial DNA, Awadalla P, Eyre-Walker A, Maynard Smith J, , , Science.,
★
★ Mitochondria Atlas at University of Mainz
★ Mitochondria Research Portal at mitochondrial.net
★ Mitochondria: Architecture dictates function at cytochemistry.net
★ Mitochondria links at University of Alabama
★ Mitochondrion Reconstructed by Electron Tomography at San Diego State University
★ Review of evidence addressing whether mitochondria form cellular networks or exist as discrete organelles at ELSO
★ Video Clip of Rat-liver Mitochondrion from Cryo-electron Tomography at wadsworth.org
★ Information on Mitochondrial Diseases at circuitblue.com
★ Mitochondria and Aging at circuitblue.com
★ 3D structures of proteins from inner mitochondrial membrane at University of Michigan
★ 3D structures of proteins associated with outer mitochondrial membrane at University of Michigan
★ Anti-mitochondrial antibodies
★ Chemiosmosis
★ Chloroplast
★ Electrochemical potential
★ Endosymbiotic theory
★ Glycolysis
★ Mitochondrial disease
★ Mitochondrial DNA
★ Human mitochondrial genetics
★ Mitochondrial permeability transition pore
★ Submitochondrial particle
Electron micrograph of a mitochondrion showing its mitochondrial matrix and membranes
In cell biology, a 'mitochondrion' (plural 'mitochondria') is a membrane-enclosed organelle that is found in most eukaryotic cells.[1] Mitochondria are sometimes described as "cellular power plants," because they generate most of the cell's supply of ATP, used as a source of chemical energy. The number of mitochondria in a cell varies widely by organism and tissue type. Many cells possess only a single mitochondrion, while others can contain several thousand mitochondria. Molecular Biology of the Cell, , Bruce, Alberts, Garland Publishing Inc., 1994, ISBN 0-815-33218-1 [2]
Although most of a cell's DNA is contained in the cell nucleus, mitochondria have their own independent genomes. This DNA shows similarity to bacterial genomes and according to the endosymbiotic theory, mitochondria are descended from free-living prokaryotes. The word mitochondrion comes from the Greek ''μίτος '' or ''mitos'', thread + ''χονδρίον'' or ''khondrion'', granule.
Mitochondrion structure
A mitochondrion contains inner and outer membranes composed of phospholipid bilayers and proteins. The two membranes, however, have different properties. Because of this double-membraned organization, there are 5 distinct compartments within mitochondria. There is the outer membrane, the intermembrane space (the space between the outer and inner membranes), the inner membrane, the cristae space (formed by infoldings of the inner membrane), and the matrix (space within the inner membrane). Mitochondria range from 1 to 10 micrometers (μm) in size.
Outer membrane
Main articles: Outer mitochondrial membrane
The outer mitochondrial membrane, which encloses the entire organelle, has a protein-to-phospholipid ratio similar to the eukaryotic plasma membrane (about 1:1 by weight). It contains numerous integral proteins called ''porins''.
Intermembrane space
The intermembrane space is the space between the outer membrane and the inner membrane.
Inner membrane
:''See also Inner mitochondrial membrane''
The inner mitochondrial membrane contains proteins with four types of functions:
# Those that carry out the oxidation reactions of the respiratory chain.
# ATP synthase, which makes ATP in the matrix.
# Specific transport proteins that regulate the passage of metabolites into and out of the matrix.
# Protein import machinery.
It contains more than 100 different polypeptides, and has a very high protein-to-phospholipid ratio (more than 3:1 by weight, which is about 1 protein for 15 phospholipids). Additionally the inner membrane is rich in an unusual phospholipid, cardiolipin. This phospholipid was originally discovered in beef hearts in 1942 and is usually characteristic of mitochondrial and bacterial plasma membranes. Cardiolipin and apoptosis, McMillin JB, Dowhan W, , , Biochim. et Biophys. Acta., Unlike the outer membrane, the inner membrane does not contain porins, and is highly impermeable; almost all ions and molecules require special membrane transporters to enter or exit the matrix. In addition, there is a membrane potential across the inner membrane.
The inner mitochondrial membrane is compartmentalized into numerous cristae, which expand the surface area of the inner mitochondrial membrane, enhancing its ability to generate ATP. In typical liver mitochondria, for example, the surface area, including cristae, is about five times that of the outer membrane. Mitochondria of cells which have greater demand for ATP, such as muscle cells, contain more cristae than typical liver mitochondria.
Mitochondrial matrix
:''See also mitochondrial matrix''
Image of cristae in rat liver mitochondrion
The matrix is the space enclosed by the inner membrane. The matrix is important in the production of ATP with the aid of the ATP synthase contained in the inner membrane. The matrix contains a highly concentrated mixture of hundreds of enzymes, in addition to the special mitochondrial ribosomes, tRNA, and several copies of the mitochondrial DNA genome. Of the enzymes, the major functions include oxidation of pyruvate and fatty acids, and the citric acid cycle.
Mitochondria possess their own genetic material, and the machinery to manufacture their own RNAs and proteins. (''See: protein synthesis''). A published human mitochondrial DNA sequence revealed 16,569 base pairs encoding 37 total genes, 24 tRNA and rRNA genes and 13 peptide genes.[3] The 13 mitochondrial peptides in humans are integrated into the inner mitochondrial membrane, along with proteins encoded by genes that reside in the host cell's nucleus.
Mitochondrial functions
Although it is well known that the mitochondria convert organic materials into cellular energy in the form of ATP, mitochondria play an important role in many metabolic tasks, such as:
★ Apoptosis-programmed cell death
★ Glutamate-mediated excitotoxic neuronal injury
★ Cellular proliferation
★ Regulation of the cellular redox state
★ Heme synthesis
★ Steroid synthesis
Some mitochondrial functions are performed only in specific types of cells. For example, mitochondria in liver cells contain enzymes that allow them to detoxify ammonia, a waste product of protein metabolism. A mutation in the genes regulating any of these functions can result in mitochondrial diseases.
Energy conversion
A dominant role for the mitochondria is the production of ATP as reflected by the large number of proteins in the inner membrane for this task. This is done by oxidizing the major products of glycolysis: pyruvate and NADH that are produced in the cytosol. This process of cellular respiration, also known as aerobic respiration, is dependent on the presence of oxygen. When oxygen is limited the glycolytic products will be metabolised by anaerobic respiration, a process that is independent of the mitochondria. The production of ATP from glucose has an approximately 15 fold higher yield during aerobic respiration compared to anaerobic respiration.
Pyruvate: the citric acid cycle
Main articles: pyruvate decarboxylation, citric acid cycle
Each pyruvate molecule produced by glycolysis is actively transported across the inner mitochondrial membrane, and into the matrix where it is oxidized and combined with coenzyme A to form CO2, acetyl-CoA and NADH.
The acetyl-CoA is the primary substrate to enter the ''citric acid cycle'' , also known as the ''tricarboxylic acid (TCA) cycle'' or ''Krebs cycle''. The enzymes of the citric acid cycle are located in the mitochondrial matrix with the exception of succinate dehydrogenase, which is bound to the inner mitochondrial membrane. The citric acid cycle oxidizes the acetyl-CoA to carbon dioxide and in the process produces reduced cofactors (three molecules of NADH and one molecule of FADH2), that are a source of electrons for the ''electron transport chain'', and a molecule of GTP (that is readily converted to an ATP).
NADH and FADH2: the electron transport chain
Main articles: Electron transport chain, Oxidative phosphorylation
Schematic of typical animal cell, showing subcellular components. Organelles: (1) nucleolus (2) nucleus (3) ribosome (4) vesicle (5) rough endoplasmic reticulum (ER) (6) Golgi apparatus (7) Cytoskeleton (8) smooth ER (9) 'mitochondria' (10) vacuole (11) cytoplasm (12) lysosome (13) centrioles
The redox energy from NADH and FADH2 is transferred to oxygen (O2) in several steps via the electron transport chain. These energy-rich molecules are produced within the matrix via the citric acid cycle but are also produced in the cytoplasm by glycolysis; reducing equivalents from the cytoplasm can be imported via the malate-aspartate shuttle system of antiporter proteins or feed into the electron transport chain using a glycerol phosphate shuttle. Protein complexes in the inner membrane (NADH dehydrogenase, cytochrome c reductase and cytochrome c oxidase) perform the transfer and the incremental release of energy is used to pump protons (H+) into the intermembrane space. This process is efficient but a small percentage of electrons may prematurely reduce oxygen, forming reactive oxygen species such as superoxide. This can cause oxidative stress in the mitochondria and may contribute to the decline in mitochondrial function associated with the aging process.[4]
As the proton concentration increases in the intermembrane space, a strong electrochemical gradient is established across the inner membrane. The protons can return to the matrix through the ATP synthase complex and their potential energy is used to synthesize ATP from ADP and inorganic phosphate (Pi). This process is called chemiosmosis and was first described by Peter Mitchell Chemiosmotic hypothesis of oxidative phosphorylation, Mitchell P, Moyle J, , , Nature., Proton current flow in mitochondrial systems, Mitchell P, , , Nature., who was awarded the 1978 Nobel Prize in Chemistry for his work. Later, part of the 1997 Nobel Prize in Chemistry was awarded to Paul D. Boyer and John E. Walker for their clarification of the working mechanism of ATP synthase.
Heat production
Under certain conditions, protons can re-enter the mitochondrial matrix without contributing to ATP synthesis. This process is known as ''proton leak'' or ''mitochondrial uncoupling'' and is due to the facilitated diffusion of protons into the matrix. This process results in the unharnessed potential energy of the proton electrochemical gradient being released as heat. The process is mediated by a proton channel called thermogenin, or UCP1. Thermoregulation: What Role for UCPs in Mammals and Birds?, Mozo J, Emre Y, Bouillaud F, Ricquier D, Criscuolo F, , , Bioscience Reports., Thermogenin is a 33kDa protein first discovered in 1973. Brown-adipose-tissue mitochondria. The influence of albumin and nucleotides on passive ion permeabilities., Nicholls DG, Lindberg O, , , Eur. J. Biochem., Thermogenin is primarily found in brown adipose tissue, or brown fat, and is responsible for non-shivering thermogenesis. Brown adipose tissue is found in mammals and is at its highest levels in early life and in hibernating animals. In humans, brown adipose tissue is present at birth and decreases with age.
Storage of calcium ions
The concentrations of free calcium in the cell can regulate an array of reactions and is important for signal transduction in the cell. Mitochondria store calcium, a process that is one important event for the homeostasis of calcium in the cell. Release of this calcium back into the cells interior can initiate calcium spikes or waves. These events coordinate processes such as neurotransmitter release in nerve cells and release of hormones in endocrine cells.
Mitochondrial dysfunction and disease
With their central place in cell metabolism, damage and dysfunction is mitochondria is an important factor in a wide range of human diseases. These diseases include schizophrenia, Bipolar disorder, dementia, Alzheimer's disease, Parkinson's disease, epilepsy, strokes, heart disease, retinitis pigmentosa and diabetes.[5] Mitochondrial dysfunction and molecular pathways of disease, Pieczenik SR, Neustadt J, , , Exp. Mol. Pathol., 2007 The common thread linking these seemingly-unrelated conditions is cellular damage causing oxidative stress and the accumulation of reactive oxygen species. These oxidants then damage the mitochondrial DNA, resulting in mitochondrial dysfunction and cell death.
Mutations in mitochondrial DNA can also be inherited, causing genetic disorders such as dominant optic atrophy, Friedreich's ataxia, hereditary spastic paraplegia, and Wilson's disease.[6] Environmental influences may also interact with hereditary predispositions and cause mitochondrial disease; an example of this is the possible role of pesticide exposure in causing some individuals to develop Parkinson's disease.[7][8]
Origin
Main articles: Endosymbiotic theory
As mitochondria contain ribosomes and DNA, and are only formed by the division of other mitochondria, it is generally accepted that they were originally derived from endosymbiotic prokaryotes. Studies of mitochondrial DNA, which is often circular and employs a variant genetic code, show their ancestor, the so-called proto-mitochondrion, was a member of the Proteobacteria.[9] In particular, the pre-mitochondrion was probably related to the rickettsias, although the exact position of the ancestor of mitochondria among the alpha-proteobacteria remains controversial. The endosymbiotic hypothesis suggests that mitochondria descended from specialized bacteria (probably purple non-sulfur bacteria) that somehow survived endocytosis by another species of prokaryote or some other cell type, and became incorporated into the cytoplasm. The ability of symbiont bacteria to conduct cellular respiration in host cells that had relied on glycolysis and fermentation would have provided a considerable evolutionary advantage. Similarly, host cells with symbiotic bacteria capable of photosynthesis would also have an advantage. In both cases, the number of environments in which the cells could survive would have been greatly expanded.
This relationship developed at least 2 billion years ago and mitochondria still show some signs of their ancient origin. Mitochondrial ribosomes in mammals are the 70S (bacterial) type, in contrast to the 80S ribosomes found elsewhere in the cell. Properties of human mitochondrial ribosomes., O'Brien TW, , , IUBMB Life., . One mitochondrion can contain 2-10 copies of its DNA. Counting target molecules by exponential polymerase chain reaction, copy number of mitochondrial DNA in rat tissues, Wiesner RJ, Ruegg JC, Morano I, , , Biochim Biophys Acta., As in prokaryotes, there is a very high proportion of coding DNA, and an absence of repeats. Mitochondrial genes are transcribed as multigenic transcripts which are cleaved and polyadenylated to yield mature mRNAs. Unlike their nuclear cousins, mitochondrial genes are small, and many chromosomes are circular, conforming to the bacterial pattern. In humans, mitochondrial genes lack introns, Sequence and organization of the human mitochondrial genome, Anderson S, Bankier AT, Barrell BG, de-Bruijn MHL, Coulson AR, et al., , , Nature, yet other Eukaryotic mitochondrial DNA has 1-37 of them. Further, there are codon differences in mitochondria: Replication and transcription of mammalian mitochondrial DNA, Fernandez-Silva P, Enriquez JA, Montoya, , , Exp Physiol., in the mitochondria, the UGA codon specifies tryptophan; AGA and AGG are stop codons; and AUA, AUC, and AUU are each allowable start codons.
A few groups of unicellular eukaryotes lack mitochondria: the microsporidians, metamonads, and archamoebae. Archamoebae: the ancestral eukaryotes?, Cavalier-Smith T, , , Biosystems., These groups appear as the most primitive eukaryotes on phylogenetic trees constructed using rRNA information, suggesting that they appeared before the origin of mitochondria. However, this is now known to be an artifact of long branch attraction — they are apparently derived groups and retain genes or organelles derived from mitochondria (e.g. mitosomes and hydrogenosomes).1 There are no primitively amitochondriate eukaryotes, and so the origin of mitochondria may have played a critical part in the development of eukaryotic cells.
Replication and gene inheritance
Mitochondria replicate their DNA and divide mainly in response to the energy needs of the cell; in other words, their growth and division is not linked to the cell cycle. When the energy needs of a cell are high, mitochondria grow and divide. When the energy use is low, mitochondria are destroyed or become inactive. At cell division, mitochondria are distributed to the daughter cells more or less randomly during the division of the cytoplasm. Mitochondria divide by binary fission similar to bacterial cell division. Unlike bacteria, however, mitochondria can also fuse with other mitochondria.
Mitochondrial genes are not inherited by the same mechanism as nuclear genes. At fertilization of an egg by a sperm, the egg nucleus and sperm nucleus each contribute equally to the genetic makeup of the zygote nucleus. In contrast, the mitochondria, and therefore the mitochondrial DNA, usually comes from the egg only. The sperm's mitochondria enters the egg, but are almost always destroyed and do not contribute their genes to the embryo.[10] Paternal sperm mitochondria are marked with ubiquitin to select them for later destruction inside the embryo.[11] The egg contains relatively few mitochondria, but it is these mitochondria that survive and divide to populate the cells of the adult organism. Mitochondria are, therefore, in most cases inherited down the female line.
This maternal inheritance of mitochondrial DNA is seen in most organisms, including all animals. However, mitochondria in some species can sometimes be inherited through the father. This is the norm among certain coniferous plants although not in pines and yew trees.[12] It has been suggested to occur at a very low level in humans.[13]
Uniparental inheritance means that there is little opportunity for genetic recombination between different lineages of mitochondria, although a single mitochondrion can contain 2-10 copies of its DNA. Counting target molecules by exponential polymerase chain reaction, copy number of mitochondrial DNA in rat tissues, Wiesner RJ, Ruegg JC, Morano I, , , Biochim Biophys Acta., For this reason, mitochondrial DNA usually is thought of as reproducing by binary fission; what recombination that takes place is to maintain genetic integrity rather than to maintain diversity. However, there are several studies showing evidence of recombination in mitochondrial DNA. The enzymes necessary for recombination clearly are present in mammalian cells.[14] Further, evidence suggests that animal mitochondria can undergo recombination.[15] The data are a bit more controversial in humans, although, indirect evidence exists.[16][17] If recombination does not occur, the whole mitochondrial DNA sequence represents a single haplotype, which makes it useful for studying the evolutionary history of populations.
Mitochondrial genomes have many fewer genes than do the related eubacteria from which they are thought to be descended. Although some have been lost altogether, many have been transferred to the nucleus. This is thought to be relatively common over evolutionary time. A few organisms, such as the ''Cryptosporidium'', actually have mitochondria which lack any DNA, presumably because all their genes have either been lost or transferred. The unusual mitochondrial compartment of Cryptosporidium parvum, Henriquez FL, Richards TA, Roberts F, McLeod R, Roberts CW, , , Trends Parasitol., In Cryptosporidium, the mitochondria have an altered ATP generation system that renders the parasite resistant to many classical mitochondrial inhibitors such as cyanide, azide, and atovaquone.
The uniparental inheritance of mitochondria is thought to result in intragenomic conflict, such as seen in the petite mutant mitochondria of some yeast species. It is possible that the evolution of separate male and female sexes is a mechanism to resolve this organelle conflict.
Use in population genetic studies
The near-absence of genetic recombination in mitochondrial DNA makes it a useful source of information for scientists involved in population genetics and evolutionary biology. Because all the mitochondrial DNA is inherited as a single unit, or haplotype, the relationships between mitochondrial DNA from different individuals can be represented as a gene tree. Patterns in these gene trees can be used to infer the evolutionary history of populations. The classic example of this is in human evolutionary genetics, where the molecular clock can be used to provide a recent date for mitochondrial Eve. This is often interpreted as strong support for a recent modern human expansion out of Africa. Another human example is the sequencing of mitochondrial DNA from Neanderthal bones. The relatively large evolutionary distance between the mitochondrial DNA sequences of Neanderthals and living humans has been interpreted as evidence for lack of interbreeding between Neanderthals and anatomically modern humans.
However, mitochondrial DNA only reflects the history of females in a population, and so may not give a representative picture of the history of the population as a whole. For example, if dispersal is primarily undertaken by males, this will not be picked up by mitochondrial studies. This can be partially overcome by the use of patrilineal genetic sequences, if they are available (in mammals the non-recombining region of the Y-chromosome provides such a source). More broadly, only studies that also include nuclear DNA can provide a comprehensive evolutionary history of a population; unfortunately, genetic recombination means that these studies can be difficult to analyze.
Fiction
★ The midi-clorians of the Star Wars universe are fictional life-forms inside cells that provide the Force. George Lucas took inspiration from the endosymbiotic theory.
★ Madeleine L'Engle's novel ''A Wind in the Door'' posits fictional "farandolae" which are to mitochondria what mitochondria are to cells.
★ In Hideaki Sena's novel ''Parasite Eve'' (and the video game based on it), mitochondria are independent organisms, using animals and plants as a form of "transportation," causing a major biological disaster when they decide to set themselves free.
References
1. Evolutionary biology: essence of mitochondria, Henze K, Martin W, , , Nature, 2003
2. Fundamentals of Biochemistry, 2nd Edition, , Donald, Voet, John Wiley and Sons, Inc., ,
3. Sequence and organization of the human mitochondrial genome, Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, et al., , , Nature.,
4. The role of oxidative damage in mitochondria during aging: A review, , K., Huang, Frontiers in Bioscience, 2004
5. Mitochondrial disease, Schapira AH, , , Lancet, 2006
6. Mitochondria, Chinnery PF, Schon EA, , , J. Neurol. Neurosurg. Psychiatr., 2003
7. Environment, mitochondria, and Parkinson's disease, Sherer TB, Betarbet R, Greenamyre JT, , , The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry, 2002
8. Pesticides and impairment of mitochondrial function in relation with the parkinsonian syndrome, Gomez C, Bandez MJ, Navarro A, , , Front. Biosci., 2007
9. On Darwin's Shoulders, , Douglas J., Futuyma, Natural History, 2005
10. Kimball, J.W. (2006) "Sexual Reproduction in Humans: Copulation and Fertilization," ''Kimball's Biology Pages'' (based on ''Biology'', 6th ed., 1996)]
11. {{cite journal | author=Sutovsky, P., et. al|year=1999|title=Ubiquitin tag for sperm mitochondria|journal=Nature|volume=402|pages=371-372|id= Discussed in ''Science News''.
12. The Hows and Whys of Cytoplasmic Inheritance in Seed Plants, , H. Lloyd, Mogensen, American Journal of Botany, 1996
13. Paternal transmission of mitochondrial DNA is (fortunately) rare, , D. R., Johns, Annals of Neurology,
14. Mammalian mitochondria possess homologous DNA recombination activity, Thyagarajan B, Padua RA, Campbell C, , , J. Biol. Chem.,
15. Animal mitochondrial DNA recombination, Lunt DB, Hyman BC, , , Nature,
16. How clonal are human mitochondria?, Eyre-Walker A, Smith NH, Maynard Smith J, , , Proc. Royal Soc. Biol. Sci. (Series B),
17. Linkage Disequilibrium and Recombination in Hominid Mitochondrial DNA, Awadalla P, Eyre-Walker A, Maynard Smith J, , , Science.,
External links
★
★ Mitochondria Atlas at University of Mainz
★ Mitochondria Research Portal at mitochondrial.net
★ Mitochondria: Architecture dictates function at cytochemistry.net
★ Mitochondria links at University of Alabama
★ Mitochondrion Reconstructed by Electron Tomography at San Diego State University
★ Review of evidence addressing whether mitochondria form cellular networks or exist as discrete organelles at ELSO
★ Video Clip of Rat-liver Mitochondrion from Cryo-electron Tomography at wadsworth.org
★ Information on Mitochondrial Diseases at circuitblue.com
★ Mitochondria and Aging at circuitblue.com
★ 3D structures of proteins from inner mitochondrial membrane at University of Michigan
★ 3D structures of proteins associated with outer mitochondrial membrane at University of Michigan
See also
★ Anti-mitochondrial antibodies
★ Chemiosmosis
★ Chloroplast
★ Electrochemical potential
★ Endosymbiotic theory
★ Glycolysis
★ Mitochondrial disease
★ Mitochondrial DNA
★ Human mitochondrial genetics
★ Mitochondrial permeability transition pore
★ Submitochondrial particle
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