Mitochondrion 19588 225030913 2008-07-11T15:31:35Z 144.30.79.69 /* Origin */ [[Image:Mitochondrion 186.jpg|right|frame|Electron [[micrograph]] of a mitochondrion showing its mitochondrial matrix and membranes]] In [[cell biology]], a '''mitochondrion''' (plural '''mitochondria''') is a membrane-enclosed [[organelle]] found in most [[eukaryote|eukaryotic]] [[cell (biology)|cells]].<ref name="mitosomes">{{cite journal |author=Henze K, Martin W |title=Evolutionary biology: essence of mitochondria |journal=Nature |volume=426 |issue=6963 |pages=127&ndash;8 |year=2003 |pmid=14614484 |doi=10.1038/426127a}}</ref> These organelles range from 1&ndash;10&nbsp;micrometers ([[Micrometre|μm]]) in size. Mitochondria are sometimes described as "cellular power plants" because they generate most of the cell's supply of [[adenosine triphosphate]] (ATP), used as a source of [[chemical energy]]. In addition to supplying cellular energy, mitochondria are involved in a range of other processes, such as [[cell signaling|signaling]], [[cellular differentiation]], [[apoptosis|cell death]], as well as the control of the [[cell cycle]] and [[cell growth]].<ref>{{cite journal |author=McBride HM, Neuspiel M, Wasiak S |title=Mitochondria: more than just a powerhouse |journal=Curr. Biol. |volume=16 |issue=14 | pages = R551 |year=2006 |pmid=16860735 | doi = 10.1016/j.cub.2006.06.054 <!--Retrieved from CrossRef by DOI bot-->}}</ref> Mitochondria have been implicated in several human diseases, including [[mental disorders]],<ref>{{cite journal | author=Gardner A, Boles RG |title=Is a "Mitochondrial Psychiatry" in the Future? A Review | journal=Curr. Psychiatry Review |volume=1 |issue=3 |pages=255&ndash;271 |year=2005| doi=10.2174/157340005774575064}}</ref> cardiac dysfunction,<ref>{{cite journal | author=Lesnefsky EJ, et al. |title=Mitochondrial dysfuntion in cardiac disease ischemia-reperfusion, aging and heart failure | journal=J. Mol. Cell. Cardiol. |volume=33 |issue=6 |pages=1065&ndash;1089 |year=2001| doi=10.1006/jmcc.2001.1378}}</ref> and may play a role in the [[aging process]]. The word mitochondrion comes from the [[Greek language|Greek]] ''μίτος '' or ''mitos'', thread + ''χονδρίον'' or ''khondrion'', granule. Their ancestry is not fully understood, but, according to the [[endosymbiotic theory]], mitochondria are descended from ancient [[prokaryote|bacteria]], which were engulfed by the ancestors of eukaryotic cells more than a billion years ago. Several characteristics make mitochondria unique. The number of mitochondria in a cell varies widely by [[organism]] and [[Tissue (biology)|tissue]] type. Many cells have only a single mitochondrion, whereas others can contain several thousand mitochondria.<ref name= "Alberts">{{cite book| last = Alberts| first = Bruce| authorlink = | coauthors = Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter| year = 1994| title = Molecular Biology of the Cell| publisher = Garland Publishing Inc.| location = New York| isbn = 0815332181}}</ref><ref name=Voet>{{cite book | last = Voet | first = Donald | coauthors = Judith G. Voet, Charlotte W. Pratt | title = Fundamentals of Biochemistry, 2nd Edition | publisher = John Wiley and Sons, Inc. | date = 2006 | pages = 547 |isbn=0471214957 }}</ref> The organelle is composed of compartments that carry out specialized functions. These compartments or regions include the [[outer mitochondrial membrane|outer membrane]], the [[intermembrane space]], the [[inner mitochondrial membrane|inner membrane]], and the [[cristae]] and [[mitochondrial matrix|matrix]]. Mitochondrial proteins vary depending on the tissues and species. In human, 615 distinct types of proteins were identified from cardiac mitochondria;<ref>{{cite journal | author=Taylor SW, Fahy E, Zhang B, Glenn GM, Warnock DE, Wiley S, Murphy AN, Gaucher SP, Capaldi RA, Gibson BW, Ghosh SS | title=Characterization of the human heart mitochondrial proteome | journal=Nat Biotechnol. | date=2003 March | volume=21 | issue=3 | pages=281&ndash;6 | pmid=12592411 | doi=10.1038/nbt793 }}</ref> whereas in [[Muridae|murine]], 940 proteins encoded by distinct genes were reported.<ref>{{cite journal | author=Zhang J, Li X, Mueller M, Wang Y, Zong C, Deng N, Vondriska TM, Liem DA, Yang J, Korge P, Honda H, Weiss JN, Apweiler R, Ping P | title=Systematic characterization of the murine mitochondrial proteome using functionally validated cardiac mitochondira | journal=Proteomics | date=2008 | volume=8 | issue=8 | pages=1564&ndash;1575 | pmid=18348319 | doi=10.1002/pmic.200700851}}</ref> Mitochondrial proteome is thought to be dynamically regulated.<ref>{{cite journal | author=Zhang J, Liem DA, Mueller M, Wang Y, Zong C, Deng N, Vondriska TM, Yang J, Korge P, Drews O, Maclellan WR, Honda H, Weiss JN, Apweiler R, Ping P | title=Altered Proteome Biology of Cardiac Mitochondria Under Stress Conditions | journal=J. Proteome Res | date=2008 | pmid=18484766 | doi=10.1021/pr070371f | volume=7 | pages=2204}}</ref> Although most of a cell's DNA is contained in the [[cell nucleus]], the mitochondrion has its own independent [[mitochondrial DNA|genome]]. Further, its DNA shows substantial similarity to [[bacteria]]l [[genome]]s.<ref>{{cite journal |author=Andersson SG, Karlberg O, Canbäck B, Kurland CG |title=On the origin of mitochondria: a genomics perspective |journal=Philos. Trans. R. Soc. Lond., B, Biol. Sci. |volume=358 |issue=1429 |pages=165–77; discussion 177–9 |year=2003 |month=January |pmid=12594925 |pmc=1693097 |doi=10.1098/rstb.2002.1193}}</ref> ==Structure== {{Mitochondrion imagemap}} A mitochondrion contains inner and outer membranes composed of [[phospholipid bilayer]]s and [[protein]]s.<ref name=Alberts/> The two membranes, however, have different properties. Because of this double-membraned organization, there are five distinct compartments within the mitochondrion. There is the [[outer mitochondrial membrane]], the [[intermembrane space]] (the space between the outer and inner membranes), the [[inner mitochondrial membrane]], the [[cristae]] space (formed by infoldings of the inner membrane), and the [[mitochondrial matrix|matrix]] (space within the inner membrane). ===Outer membrane=== {{main|Outer mitochondrial membrane}} The outer mitochondrial membrane, which encloses the entire [[organelle]], has a protein-to-[[phospholipid]] ratio similar to that of the eukaryotic plasma membrane (about 1:1 by weight). It contains large numbers of [[integral protein]]s called ''[[Porin (protein)|porins]]''. These porins form channels that allow molecules 5000&nbsp;[[Atomic mass unit|Daltons]] or less in molecular weight to freely [[diffusion|diffuse]] from one side of the membrane to the other.<ref name=Alberts/> Larger proteins can also enter the mitochondrion if a signaling sequence at their [[N-terminus]] binds to a large [[subunit|multisubunit]] protein called [[translocase of the outer membrane]], which then actively moves them across the membrane.<ref name=Neupert>{{cite journal | author=Herrmann JM, Neupert W | title=Protein transport into mitochondria | journal=Curr Opin Microbiol | volume=3 | issue=2 | date= 2000 April | pages=210&ndash;214 | doi=10.1016/S1369-5274(00)00077-1}}</ref> Disruption of the outer membrane permits proteins in the intermembrane space to leak into the cytosol, leading to certain cell death.<ref name=Chipuk>{{cite journal | author= Chipuk JE, Bouchier-Hayes L, Green DR | title= Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario | journal= Cell Death and Differentiation. | date=2006 | volume=13 | pages= 1396&ndash;1402 | doi=10.1038/sj.cdd.4401963 }}</ref> ===Intermembrane space=== The [[intermembrane space]] is the space between the outer membrane and the inner membrane. Because the outer membrane is freely permeable to small molecules, the concentrations of small molecules such as ions and sugars in the intermembrane space is the same as the [[cytosol]].<ref name=Alberts/> However, as large proteins must have a specific signaling sequence to be transported across the outer membrane, the protein composition of this space is different than the protein composition of the [[cytosol]]. One protein that is localized to the intermembrane space in this way is [[cytochrome c]].<ref name=Chipuk/> ===Inner membrane=== {{main|Inner mitochondrial membrane}} The inner mitochondrial membrane contains proteins with four types of functions:<ref name = "Alberts" /> # Those that perform the [[redox]] reactions of [[oxidative phosphorylation]] # [[ATP synthase]], which generates [[Adenosine triphosphate|ATP]] in the matrix # Specific transport proteins that regulate [[metabolite]] passage into and out of the matrix # Protein import machinery. It contains more than 100 different [[polypeptide]]s, and has a very high protein-to-phospholipid ratio (more than 3:1 by weight, which is about 1&nbsp;protein for 15&nbsp;phospholipids). The inner membrane is home to around 1/5 of the total protein in a mitochondrion.<ref name=Alberts/> In addition, 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.<ref name=McMillin>{{cite journal| author=McMillin JB, Dowhan W | title=Cardiolipin and apoptosis | journal=Biochim. et Biophys. Acta. | date=2002 December | volume=1585 | pages=97&ndash;107 | pmid=12531542 | doi=10.1016/S1388-1981(02)00329-3 }}</ref> Cardiolipin contains four fatty acids rather than two and may help to make the inner membrane impermeable.<ref name=Alberts/> Unlike the outer membrane, the inner membrane does not contain porins and is highly impermeable to all molecules. Almost all ions and molecules require special membrane transporters to enter or exit the matrix. Proteins are ferried into the matrix via the [[translocase of the inner membrane]] (TIM) complex or via Oxa1.<ref name=Neupert/> In addition, there is a membrane potential across the inner membrane formed by the action of the enzymes of the [[electron transport chain]]. ====Cristae==== {{main|crista}} [[Image:MitochondrionCAM.jpg|thumb|250 px|left|Cross-sectional image of cristae in rat liver mitochondrion to demonstrate the likely 3D structure and relationship to the inner membrane]] The inner mitochondrial membrane is compartmentalized into numerous [[crista]]e, which expand the surface area of the inner mitochondrial membrane, enhancing its ability to produce ATP. These are not simple random folds but rather invaginations of the inner membrane, which can affect overall [[Chemiosmosis|chemiosmotic]] function.<ref name=Mannella>{{ cite journal | author=Mannella CA | title= Structure and dynamics of the mitochondrial inner membrane cristae | journal=Biochimica et Biophysica Acta (BBA) - Mol Cell Res. | volume=1763 |issue=5&ndash;6|date=2006 | pages=542&ndash;548 | doi=10.1016/j.bbamcr.2006.04.006 | pmid=16730811 }}</ref> In typical [[liver]] mitochondria, for example, the surface area, including cristae, is about five times that of the outer membrane. Mitochondria of cells that have greater demand for ATP, such as muscle cells, contain more cristae than typical liver mitochondria.<ref name=Alberts/> ===Matrix=== {{main|mitochondrial matrix}} The matrix is the space enclosed by the inner membrane. It contains about 2/3 of the total protein in a mitochondrion.<ref name=Alberts/> 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, 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]].<ref name = "Alberts" /> Mitochondria have their own genetic material, and the machinery to manufacture their own [[RNA]]s and [[protein]]s (''see: [[protein biosynthesis]]''). A published human mitochondrial DNA sequence revealed 16,569&nbsp;[[base pair]]s encoding 37 total genes, 24&nbsp;[[tRNA]] and [[rRNA]] genes and 13&nbsp;[[peptide]] genes.<ref>{{cite journal | author=Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, et al. | title=Sequence and organization of the human mitochondrial genome | journal=Nature. | date=1981-04-09 | volume = 410 | issue=5806 | pages = 141 | doi = 10.1038/290457a0 <!--Retrieved from CrossRef by DOI bot-->}}</ref> The 13 mitochondrial [[peptides]] in humans are integrated into the inner mitochondrial membrane, along with [[protein]]s encoded by [[gene]]s that reside in the host cell's [[cell nucleus|nucleus]]. ==Organization and distribution== Mitochondria are found in nearly all [[eukaryote]]s. They vary in number and location according to cell type. Substantial numbers of mitochondria are in the liver, with about 1000&ndash;2000 mitochondria per cell making up 1/5th of the cell volume.<ref name=Alberts/> The mitochondria can be found nestled between [[myofibril]]s of [[muscle]] or wrapped around the [[sperm]] [[flagellum]].<ref name=Alberts/> Often they form a complex 3D branching network inside the cell with the [[cytoskeleton]]. The association with the cytoskeleton determines mitochondrial shape, which can affect the function as well.<ref>{{cite journal | author=Rappaport L, Oliviero P, Samuel JL | title=Cytoskeleton and mitochondrial morphology and function | journal=Mol and Cell Biochem. | volume=184 |pages=101&ndash;105 | date= 1998 | doi=10.1023/A:1006843113166}}</ref> Recent evidence suggests [[vimentin]], one of the components of the cytoskeleton, is critical to the association with the cytoskeleton.<ref>{{cite journal | author=Tang HL, Lung HL, Wu KC, Le AP, Tang HM, Fung MC | title=Vimentin supports mitochondrial morphology and organization | journal=Biochemical J | date=2007 | doi=10.1042/BJ20071072 | pmid=17983357 | volume=410 | pages=141 }}</ref> ==Function== The most prominent roles of the mitochondrion are its production of [[Adenosine triphosphate|ATP]] and regulation of cellular [[metabolism]].<ref name=Voet/> The central set of reactions involved in ATP production are collectively known as the [[citric acid cycle]]. However, the mitochondrion has many other functions in addition to the production of ATP. ===Energy conversion=== A dominant role for the mitochondria is the production of [[Adenosine triphosphate|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 [[glucose]], [[pyruvate]], and [[NADH]], which are produced in the cytosol.<ref name=Voet/> 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 metabolized by [[anaerobic respiration]], a process that is independent of the mitochondria.<ref name=Voet/> The production of ATP from glucose has an approximately 13-fold higher yield during aerobic respiration compared to anaerobic respiration.<ref>{{cite journal |author=Rich PR |title=The molecular machinery of Keilin's respiratory chain |journal=Biochem. Soc. Trans. |volume=31 |issue=Pt 6 |pages=1095&ndash;105 |year=2003 |pmid=14641005 |url=http://www.biochemsoctrans.org/bst/031/1095/bst0311095.htm}}</ref> ====Pyruvate: the citric acid cycle==== {{main|pyruvate decarboxylation|citric acid cycle}} Each pyruvate molecule produced by [[glycolysis]] is [[active transport|actively transported]] across the inner mitochondrial membrane, and into the matrix where it is [[oxidization|oxidized]] and combined with [[coenzyme A]] to form CO<sub>2</sub>, [[acetyl-CoA]], and [[NADH]].<ref name=Voet/> 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 as part of Complex II.<ref name= >{{cite journal | author=King A, Selak MA, Gottlieb E| journal=Oncogene. | date=2006 | volume=25 | pages=4675&ndash;4682 | doi=10.1038/sj.onc.1209594 | title=Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer}}</ref> 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|FADH<sub>2</sub>]]) that are a source of electrons for the ''[[electron transport chain]]'', and a molecule of [[Guanosine triphosphate|GTP]] (that is readily converted to an ATP).<ref name=Voet/> ====NADH and FADH<sub>2</sub>: the electron transport chain==== {{main|Electron transport chain|Oxidative phosphorylation}} [[Image:Biological cell.svg|thumb|300px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s:<br /> (1) [[nucleolus]]<br /> (2) [[cell nucleus|nucleus]]<br /> (3) ribosomes (little dots)<br /> (4) [[vesicle (biology)|vesicle]]<br /> (5) rough [[endoplasmic reticulum]] (ER)<br /> (6) [[Golgi apparatus]]<br /> (7) [[Cytoskeleton]]<br /> (8) smooth ER<br /> (9) [[mitochondrion|mitochondria]]<br /> (10) [[vacuole]]<br /> (11) [[cytoplasm]]<br /> (12) [[lysosome]]<br /> (13) [[centriole]]s within [[centrosome]]]] The redox energy from NADH and FADH<sub>2</sub> is transferred to oxygen (O<sub><small>2</small></sub>) 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]].<ref name=Voet/> [[Electron transport chain#Mitochondrial redox carriers|Protein complexes]] in the inner membrane ([[NADH dehydrogenase]], [[Coenzyme Q - cytochrome c reductase|cytochrome c reductase]], and [[cytochrome c oxidase]]) perform the transfer and the incremental release of energy is used to pump [[Hydrogen ion|protons]] (H<sup>+</sup>) 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]].<ref name=Voet/> This can cause [[oxidative stress]] in the mitochondria and may contribute to the decline in mitochondrial function associated with the aging process.<ref name="oxidativedamage">{{cite journal| first=K. |last=Huang| coauthors=K. G. Manton| year=2004| title=The role of oxidative damage in mitochondria during aging: A review| journal=Frontiers in Bioscience| volume=9|pages=1100&ndash;1117| doi=10.2741/1298}}</ref> 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 [[Adenosine triphosphate|ATP]] from ADP and inorganic phosphate (P<sub>i</sub>).<ref name=Voet/> This process is called [[chemiosmosis]], and was first described by [[Peter D. Mitchell|Peter Mitchell]]<ref name=Mitchella>{{cite journal | author=Mitchell P, Moyle J | title=Chemiosmotic hypothesis of oxidative phosphorylation | journal=Nature. | date= 1967-01-14 | volume=213 | issue=5072 | pages=137&ndash;9 | doi = 10.1038/213137a0 <!--Retrieved from CrossRef by DOI bot-->}}</ref><ref name=Mitchellb>{{cite journal | author=Mitchell P | title=Proton current flow in mitochondrial systems | journal=Nature. | date=1967-06-24 | volume = 25 | issue=5095 | pages=1327&ndash;8 | pmid=6056845 | doi = 10.1038/2141327a0 <!--Retrieved from CrossRef by DOI bot-->}}</ref> 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.<ref>{{cite web | last =Nobel Foundation | title =Chemistry 1997 | date = | url =http://nobelprize.org/nobel_prizes/chemistry/laureates/1997/ | accessdate =2007-12-16 }}</ref> ====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. The process results in the unharnessed potential energy of the proton electrochemical gradient being released as heat.<ref name=Voet/> The process is mediated by a proton channel called [[thermogenin]], or [[UCP1]].<ref name=Mozo>{{cite journal | author=Mozo J, Emre Y, Bouillaud F, Ricquier D, Criscuolo F | title=Thermoregulation: What Role for UCPs in Mammals and Birds? | journal=Bioscience Reports. | date=2005 November | pages=227&ndash;249 | doi=10.1007/s10540-005-2887-4 | volume=25 }}</ref> Thermogenin is a 33k[[atomic mass units|Da]] protein first discovered in 1973.<ref name=Nicholls>{{cite journal | author=Nicholls DG, Lindberg O | date=1973 | title=Brown-adipose-tissue mitochondria. The influence of albumin and nucleotides on passive ion permeabilities | journal=Eur. J. Biochem. | volume=37 | pages = R551 | pmid=4777251 | doi = 10.1111/j.1432-1033.1973.tb03014.x <!--Retrieved from CrossRef by DOI bot-->}}</ref> 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.<ref name=Mozo/> ===Storage of calcium ions=== The concentrations of free calcium in the cell can regulate an array of reactions and is important for [[Calcium in biology#Cell biology|signal transduction]] in the cell. Mitochondria can transiently [[Calcium storage|store calcium]], a contributing process for the cell's homeostasis of calcium.<ref name=Siegel_Basic_Neurochemistry>{{cite book | editor=Siegel GJ, Agranoff BW, Fisher SK, Albers RW, Uhler MD | title=Basic Neurochemistry | edition=6 | date=1999 | isbn=0-397-51820-X | publisher=Lippincott Williams & Wilkins }}</ref> In fact, their ability to rapidly take in calcium for later release makes them very good "cytosolic buffers" for calcium.<ref name=Rossier/> The [[endoplasmic reticulum]] (ER) is the most significant storage site of calcium, and there is a significant interplay between the mitochondrion and ER with regard to calcium.<ref>{{cite journal | title=Mitochondria–endoplasmic reticulum choreography: structure and signaling dynamics | author=Pizzo P, Pozzan T | journal=Trends Cell Bio. | volume=17 | issue=10 | date=2007 October | pages=511–517 | doi=10.1016/j.tcb.2007.07.011 | pmid=17851078}}</ref> The calcium is taken up into the [[mitochondrial matrix|matrix]] by a calcium [[uniporter]] on the [[inner mitochondrial membrane]].<ref name=MillerRJ>{{cite journal | author=Miller RJ | title=Mitochondria – the kraken wakes! | journal=Trends in Neurosci. | volume=21| issue=3| date=1998 | pages=95&ndash;97 doi=10.1016/S0166–2236(97)01206–X | doi=10.1016/S0166-2236(97)01206-X }}</ref> It is primarily driven by the mitochondrial [[membrane potential]].<ref name=Siegel_Basic_Neurochemistry/> Release of this calcium back into the cell's interior can occur via a sodium-calcium exchange protein or via "calcium-induced-calcium-release" pathways.<ref name=MillerRJ/> This can initiate calcium spikes or calcium waves with large changes in the [[membrane potential]]. These can activate a series of [[second messenger system]] proteins that can coordinate processes such as [[Synaptic vesicle#Neurotransmitter release|neurotransmitter release]] in nerve cells and release of [[hormone]]s in endocrine cells. ===Additional functions=== Mitochondria play a central role in many other [[metabolism|metabolic]] tasks, such as: * Regulation of the [[membrane potential]]<ref name=Voet/> * [[Apoptosis]]-programmed cell death<ref>{{cite journal | author=Green DR | title=Apoptotic pathways: the roads to ruin | journal=Cell. | date=1998 September | volume=94 | issue=6 | pages=695–8 | doi=10.1016/S0092-8674(00)81728-6 | pmid=9753316}}</ref> * [[Glutamate]]-mediated excitotoxic [[neuron]]al injury<ref>{{cite journal | journal=J Neurochem. | date=1998 December | volume=71 | issue=6 | pages=2392–400 | title=Effects of oxidants and glutamate receptor activation on mitochondrial membrane potential in rat forebrain neurons | author=Scanlon JM, Reynolds IJ | pmid=9832137 | doi=10.1046/j.1471-4159.1998.71062392.x | doi_brokendate=2008-06-24}}</ref> * Cellular proliferation regulation<ref name=McBride>{{cite journal | author=McBride HM, Neuspiel M, Wasiak S | title=Mitochondria: more than just a powerhouse | journal=Curr Biol. | date=2006 July | volume=16 | issue=14 | pages=R551–60 | pmid=16860735 | doi=10.1016/j.cub.2006.06.054 }}</ref> * Regulation of cellular [[metabolism]]<ref name=McBride/> * Certain [[heme]] synthesis reactions<ref>{{cite journal | journal=Orig Life Evol Biosph. | date=1997 August | volume=27 | issue=4 | pages=405–12| title=Evolutionary consideration on 5-aminolevulinate synthase in nature | author=Oh-hama T | pmid=9249985 | doi=10.1023/A:1006583601341 }}</ref> ''(see also: [[porphyrin]])'' * [[Steroid]] synthesis.<ref name=Rossier>{{cite journal | title=T channels and steroid biosynthesis: in search of a link with mitochondria | author=Rossier MF | journal=Cell Calcium. | date=2006 | volume=40 | issue=2 | pages=155–64 | pmid=16759697 | doi=10.1016/j.ceca.2006.04.020 }}</ref> 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 disease]]s. ==Origin== {{main|Endosymbiotic theory}} Mitochondria have many features in common with [[prokaryote]]s. As a result, they are believed to be originally derived from [[endosymbiosis|endosymbiotic]] prokaryotes. A mitochondrion contains [[mitochondrial DNA|DNA]], which is organized as several copies of a single, circular chromosome. This mitochondrial chromosome contains genes for [[ribosome]]s, and the twenty-one [[tRNA|tRNA's]] necessary for the translation of [[messenger RNA]]s into protein. The circular structure is also found in prokaryotes, and the similarity is extended by the fact that mitochondrial DNA is organized with a variant [[genetic code]] similar to that of [[Proteobacteria]].<ref name="Shoulders1">{{cite journal | author=Futuyma DJ | title=On Darwin's Shoulders | journal=Natural History | volume=114 | issue=9 | year=2005 | pages=64&ndash;68}}</ref> This suggests that their ancestor, the so-called [[proto-mitochondrion]], was a member of the [[Proteobacteria]].<ref name="Shoulders1"/> In particular, the proto-mitochondrion was probably related to the [[Rickettsiales|rickettsia]].<ref>{{cite journal | author=Emelyanov VV | date=2003 | title=Mitochondrial connection to the origin of the eukaryotic cell | journal=Eu J Biochem. | volume=270 | issue=8 | pages=1599–1618 | doi=10.1046/j.1432-1033.2003.03499.x | unused_data=|pm[id=12694174}}</ref> However, the exact relationship of the ancestor of mitochondria to the alpha-proteobacteria and whether the mitochondria was formed at the same time or after the nucleus, remains controversial.<ref>{{cite journal|author=Gray MW, Burger G, Lang BF |title=Mitochondrial evolution |journal=Science (journal) |volume=283 |issue=5407 |pages=1476–81 |year=1999 |month=March |pmid=10066161}}</ref> The ribosomes coded for by the mitochondrial DNA are similar to those from bacteria in size and structure.<ref name=O'Brien>{{cite journal | author=O'Brien TW | title=Properties of human mitochondrial ribosomes | journal=IUBMB Life. | date=2003 September | volume=55 | issue=9 | pages=505&ndash;13 | doi = 10.1080/15216540310001626610 <!--Retrieved from CrossRef by DOI bot-->}}</ref> They closely resemble the bacterial [[Ribosome#Structure|70S]] ribosome and not the [[Ribosome#Structure|80S]] [[cytoplasm]]ic ribosomes which are coded for by [[Cell nucleus|nuclear]] DNA. The [[endosymbiotic]] relationship of mitochondria with their host cells was popularized by [[Lynn Margulis]].<ref>{{cite journal | author=Lynn Sagan | date=1967 | title=On the origin of mitosing cells | journal=J Theor Bio. | volume=14 | issue=3 | pages=255–274 | pmid=11541392 | doi=10.1016/0022-5193(67)90079-3}}</ref> The [[Endosymbiotic theory|endosymbiotic hypothesis]] suggests that mitochondria descended from bacteria that somehow survived [[endocytosis]] by another cell, and became incorporated into the [[cytoplasm]]. The ability of these bacteria to conduct [[Cellular respiration|respiration]] in host cells that had relied on [[glycolysis]] and [[Fermentation (biochemistry)|fermentation]] would have provided a considerable evolutionary advantage. In a similar manner, host cells with symbiotic bacteria capable of [[photosynthesis]] would also have had an advantage. The incorporation of symbiotes would have increased the number of environments in which the cells could survive. This symbiotic relationship probably developed 1.7<ref>{{cite journal | author=Emelyanov VV | date=2001 | title=Rickettsiaceae, rickettsia-like endosymbionts, and the origin of mitochondria | journal=Biosci. Rep. | volume=21 | pages=1–17 | pmid=11508688 | doi = 10.1023/A:1010409415723 <!--Retrieved from CrossRef by DOI bot-->}}</ref>-2<ref>{{cite journal | author=Feng D-F, Cho G, Doolittle RF | date=1997 | title=Determining divergence times with a protein clock: update and reevaluation | journal=Proc. Natl Acad. Sci. | volume=94 | pages=13028–13033 | pmid=9371794 | doi = 10.1073/pnas.94.24.13028 <!--Retrieved from CrossRef by DOI bot-->}}</ref> billion years ago. A few groups of unicellular eukaryotes lack mitochondria: the [[microsporidia]]ns, [[metamonad]]s, and [[archamoebae]].<ref name=Cavlier-Smith>{{cite journal | author=Cavalier-Smith T | title=Archamoebae: the ancestral eukaryotes? | date=1991| journal=Biosystems. | volume=25 | pages = 1241 | pmid=1854912 | doi = 10.1016/0303-2647(91)90010-I <!--Retrieved from CrossRef by DOI bot-->}}</ref> 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]] &ndash; they are derived groups and retain genes or organelles derived from mitochondria (e.g., [[mitosome]]s and [[hydrogenosome]]s).<ref name="mitosomes" /> ==Genome== {{main|Mitochondrial DNA}} The human mitochondrial genome is a circular [[DNA]] molecule of about 16&nbsp;[[kilobase]]s.<ref name=ChanDC>{{cite journal | author=Chan DC | title= Mitochondria: Dynamic Organelles in Disease, Aging, and Development | journal= Cell | volume=125 | issue=7 | date=2006-06-30 | pages=1241&ndash;1252 | doi=10.1016/j.cell.2006.06.010 | pmid=16814712}}</ref> It encodes 37 genes: 13 for [[subunits]] of respiratory complexes I, III, IV, and V, 22 for mitochondrial [[tRNA]], and 2 for [[rRNA]].<ref name=ChanDC/> One mitochondrion can contain two to ten copies of its DNA.<ref name=Wiesner>{{cite journal | author=Wiesner RJ, Ruegg JC, Morano I |date=1992 |title=Counting target molecules by exponential polymerase chain reaction, copy number of mitochondrial DNA in rat tissues | journal=Biochim Biophys Acta | volume=183 |pages=553&ndash;559 | pmid=1550563}}</ref> As in prokaryotes, there is a very high proportion of coding DNA and an absence of repeats. Mitochondrial genes are [[transcription (genetics)|transcribed]] as multigenic transcripts, which are cleaved and [[Polyadenylation|polyadenylated]] to yield mature [[mRNA]]s. Not all proteins necessary for mitochondrial function are encoded by the mitochondrial genome; most are coded by genes in the [[cell nucleus]] and the corresponding proteins imported into the mitochondrion.<ref name=Anderson>{{cite journal | author=Anderson S, Bankier AT, Barrell BG, de-Bruijn MHL, Coulson AR, et al.|date=1981 | title=Sequence and organization of the human mitochondrial genome | journal=Nature | volume=290 | pages=427&ndash;465 | doi = 10.1038/290457a0 <!--Retrieved from CrossRef by DOI bot-->}}</ref> The exact number of genes encoded by the nucleus and the [[Mitochondrial DNA|mitochondrial genome]] differs between species. In general, mitochondrial genomes are circular, although exceptions have been reported.<ref name = Fukuhara> {{cite journal | author = Fukuhara H, Sor F, Drissi R, Dinouël N, Miyakawa I, Rousset, and Viola AM|date=1993 |title=Linear mitochondrial DNAs of yeasts: frequency of occurrence and general features |journal=Mol Cell Biol. |volume= 13 | issue=4 |pages=2309&ndash;2314 | pmid=8455612}}</ref> Also, in general, mitochondrial DNA lacks [[intron]]s, as is the case in the human mitochondrial genome;<ref name=Anderson/> however, introns have been observed in some eukaryotic mitochondrial DNA,<ref>{{cite journal | author=Bernardi G | title= Intervening sequences in the mitochondrial genome | journal=Nature. | date=1978 | volume=276 | issue= 5688| pages=558&ndash;559 | pmid=214710 | doi=10.1038/276558a0 }}</ref> such as that of [[yeast]]<ref>{{cite journal | author=Hebbar SK, Belcher SM, Perlman PS | title=A maturase-encoding group IIA intron of yeast mitochondria self-splices in vitro | journal=Nucleic Acids Res. | date=1992 April | volume=20 | issue=7 | pages=1747&ndash;54 | pmid=1579468 | doi = 10.1093/nar/20.7.1747 <!--Retrieved from CrossRef by DOI bot-->}}</ref> and [[protist]]s,<ref>{{cite journal | author= Gray MW, Lang BF, Cedergren R, Golding GB, Lemieux C, Sankoff D, et al | title= Genome structure and gene content in protist mitochondrial DNAs | journal= Nucl Acids Res. | volume= 26 | issue=4 | date=1998 | pages=865&ndash;878 | pmid=9461442 | doi = 10.1093/nar/26.4.865 <!--Retrieved from CrossRef by DOI bot-->}}</ref> including ''[[Dictyostelium]] discoideum''.<ref>{{cite journal | author= Gray MW, Lang BF, Burger G | title=Mitochondria of protists | journal=Ann Rev of Genetics. | volume=38 | pages=477&ndash;524 | date=2004 | doi=10.1146/annurev.genet.37.110801.142526 | pmid=15568984}} </ref> While slight variations on the standard code had been predicted earlier,<ref>Crick, F. H. C. and Orgel, L. E. (1973) "Directed panspermia." Icarus 19:341-346. p. 344: "It is a little surprising that organisms with somewhat different codes do not coexist." (Further discussion at [http://www.talkorigins.org/faqs/comdesc/section1.html])</ref> none was discovered until 1979, when researchers studying [[human mitochondrial genetics|human mitochondrial genes]] determined that they used an alternative code.<ref>{{cite journal | author= Barrell BG, Bankier AT, Drouin J | title= A different genetic code in human mitochondria | journal=Nature. | volume=282 | pages=189&ndash;194 | date=1979 |doi=10.1038/282189a0 }}</ref> Many slight variants have been discovered since,<ref>[http://130.14.29.110/Taxonomy/Utils/wprintgc.cgi?mode=c NCBI: "The Genetic Codes", Compiled by Andrzej (Anjay) Elzanowski and Jim Ostell]</ref> including various alternative mitochondrial codes.<ref>{{cite journal | author=Jukes TH, Osawa S | title=The genetic code in mitochondria and chloroplasts | journal=Experientia. | date=1990-12-01 | volume=46 | issue=11&ndash;12 | pages = 1117&ndash;26 | pmid=2253709 | doi = 10.1007/BF01936921 <!--Retrieved from CrossRef by DOI bot-->}}</ref> Further, the AUA, AUC, and AUU codons are all allowable start codons. {| class="wikitable" width=50% align="center" |+Exceptions to the universal genetic code (UGC) in mitochondria<ref name=Alberts/> |- !Organism!!Codon!!Standard!!Novel |- |rowspan=3|Mammalian |AGA, AGG |Arginine |Stop codon |- |AUA |Isoleucine |Methionine |- |UGA |Stop codon |Tryptophan |- |rowspan=3|Invertebrates |AGA, AGG |Arginine |Serine |- |AUA |Isoleucine |Methionine |- |UGA |Stop codon |Tryptophan |- |rowspan=3|Yeast |AUA |Isoleucine |Methionine |- |UGA |Stop codon |Tryptophan |- |CUA |Leucine |Threonine |} Some of these differences should be regarded as pseudo-changes in the genetic code due to the phenomenon of [[RNA editing]], which is common in mitochondria. In higher plants, it was thought that CGG encoded for [[tryptophan]] and not [[arginine]]; however, the codon in the processed RNA was discovered to be the UGG codon, consistent with the [[universal genetic code]] for tryptophan.<ref>{{cite journal | author=Hiesel R, Wissinger B, Schuster W, Brennicke A | date=1989 | title=RNA editing in plant mitochondria | journal=Science. | volume=246 | issue=4937 | pages=1632&ndash;4 | pmid=2480644 | year = 2006 | doi = 10.1126/science.2480644 <!--Retrieved from CrossRef by DOI bot-->}}</ref> Of note, the arthropod mitochondrial genetic code has undergone parallel evolution within a phylum, with some organisms uniquely translating AGG to lysine.<ref>{{cite journal | title=Parallel Evolution of the Genetic Code in Arthropod Mitochondrial Genomes | author=Abascal F, Posada D, Knight RD, Zardoya R | journal=PLoS Biology. | volume=4 | issue=5 | pages=0711&ndash;0718 | doi=10.1371/journal.pbio.0040127 | pmid=16620150 | year=2006}}</ref> Mitochondrial genomes have far fewer genes than the [[eubacteria]] from which they are thought to be descended. Although some have been lost altogether, many have been transferred to the [[Cell nucleus|nucleus]], such as the respiratory complex II protein subunits.<ref name=ChanDC/> This is thought to be relatively common over evolutionary time. A few organisms, such as the ''[[Cryptosporidium]]'', actually have mitochondria that lack any DNA, presumably because all their genes have been lost or transferred.<ref name=Henriquez>{{cite journal | author=Henriquez FL, Richards TA, Roberts F, McLeod R, Roberts CW | title=The unusual mitochondrial compartment of Cryptosporidium parvum | journal=Trends Parasitol. | date=2005 February | volume=21 | issue=2 | pages=68&ndash;74 | pmid=15664529| doi=10.1016/j.pt.2004.11.010}}</ref> In ''Cryptosporidium'', the mitochondria have an altered [[Adenosine triphosphate|ATP]] generation system that renders the parasite resistant to many classical mitochondrial [[Enzyme inhibitor|inhibitors]] such as [[cyanide]], [[azide]], and [[atovaquone]].<ref name=Henriquez/> ==Replication and inheritance== {{seealso|mitochondrial genome}} Mitochondria divide by [[binary fission]] similar to bacterial cell division; unlike bacteria, however, mitochondria can also fuse with other mitochondria.<ref name=ChanDC/><ref>{{cite journal | author=Hermann GJ, Thatcher JW, Mills JP, Hales KG, Fuller MT, Nunnari J, Shaw JM | title=Mitochondrial Fusion in Yeast Requires the Transmembrane GTPase Fzo1p | journal=J. Cell. Bio. | volume = 143 | number=2 | date=1998 October | pages=359&ndash;373 | pmid=9786948 | doi = 10.1083/jcb.143.2.359 <!--Retrieved from CrossRef by DOI bot-->}}</ref>. The regulation of this division differs between eukaryotes. In many single-celled eukaryotes, their growth and division is linked to the [[cell cycle]]. For example, a single mitochondrion may divide synchronously with the nucleus. This division and segregation process must be tightly controlled so that each daughter cell receives at least one mitochondrion. In other eukaryotes (in humans for example), mitochondria may replicate their DNA and divide mainly in response to the energy needs of the cell, rather than in phase with 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. In such examples, and in contrast to the situation in many single celled eukaryotes, mitochondria are apparently randomly distributed to the daughter cells during the division of the [[cytoplasm]]. An individual's mitochondrial genes are not inherited by the same mechanism as nuclear genes. At fertilization of an [[ovum|egg cell]] 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 enter the egg but does not contribute genetic information to the embryo.<ref>Kimball, J.W. (2006) [http://home.comcast.net/~john.kimball1/BiologyPages/S/Sexual_Reproduction.html#Copulation_and_Fertilization "Sexual Reproduction in Humans: Copulation and Fertilization,"] ''Kimball's Biology Pages'' (based on ''Biology'', 6th ed., 1996)]</ref> Instead, paternal mitochondria are marked with [[ubiquitin]] to select them for later destruction inside the [[embryo]].<ref>{{cite journal | author=Sutovsky, P., et. al|year=1999|title=Ubiquitin tag for sperm mitochondria|journal=[[Nature (journal)|Nature]]|volume=402|pages=371&ndash;372|doi=10.1038/46466}} Discussed in [http://www.sciencenews.org/20000101/fob3.asp ''Science News''].</ref> The egg cell 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, known as [[maternal inheritance]]. This mode is seen in most organisms including all animals. However, mitochondria in some species can sometimes be inherited paternally. This is the norm among certain [[conifer]]ous plants, although not in [[pine tree]]s and [[yew tree]]s.<ref>{{cite journal| author=Mogensen HL|year=1996| title=The Hows and Whys of Cytoplasmic Inheritance in Seed Plants| journal=American Journal of Botany| volume=83 | pages = 247 | doi = 10.2307/2446172 <!--Retrieved from CrossRef by DOI bot-->}}</ref> It has also been suggested that it occurs at a very low level in humans.<ref>{{cite journal| first=D. R.| last=Johns|date=2003|title=Paternal transmission of mitochondrial DNA is (fortunately) rare| journal=Annals of Neurology|volume=54| pages=422&ndash;4 | doi=10.1002/ana.10771 | pmid=14520651}}</ref> Uniparental inheritance leads to little opportunity for [[genetic recombination]] between different lineages of mitochondria, although a single mitochondrion can contain 2&ndash;10 copies of its DNA.<ref name=Wiesner>{{cite journal | author=Wiesner RJ, Ruegg JC, Morano I |date=1992 |title=Counting target molecules by exponential polymerase chain reaction, copy number of mitochondrial DNA in rat tissues | journal=Biochim Biophys Acta. | volume=183 |pages=553&ndash;559 | pmid=1550563}}</ref> For this reason, mitochondrial DNA usually is thought to reproduce by [[binary fission]]. What recombination does take place maintains genetic integrity rather than maintaining diversity. However, there are studies showing evidence of recombination in mitochondrial DNA. It is clear that the enzymes necessary for recombination are present in mammalian cells.<ref> {{cite journal | author=Thyagarajan B, Padua RA, Campbell C | title=Mammalian mitochondria possess homologous DNA recombination activity | journal=J. Biol. Chem. | volume=271 | issue=44 | date=1996 | pages=27536&ndash;27543 | pmid=8910339 | doi=10.1074/jbc.271.44.27536}}</ref> Further, evidence suggests that animal mitochondria can undergo recombination.<ref>{{cite journal| author=Lunt DB, Hyman BC | title=Animal mitochondrial DNA recombination | journal=Nature | volume=387 | date=15 May 1997 | pmid=9153388 | doi=10.1038/387247a0 | pages=247 }} </ref> The data are a bit more controversial in humans, although indirect evidence of recombination exists.<ref>{{cite journal | author=Eyre-Walker A, Smith NH, Maynard Smith J | title=How clonal are human mitochondria? | journal= Proc. Royal Soc. Biol. Sci. (Series B) | volume=266 | issue=1418 | date=1999-03-07 | pages=477&ndash;483 | pmid=10189711 | doi=10.1098/rspb.1999.0662 }}</ref><ref>{{cite journal | author=Awadalla P, Eyre-Walker A, Maynard Smith J | title=Linkage Disequilibrium and Recombination in Hominid Mitochondrial DNA | journal=Science. | date=24 December 1999 | volume=286 | issue=5449 | pages=2524&ndash;2525 | pmid=10617471 | doi=10.1126/science.286.5449.2524 }}</ref> 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. ==Population genetic studies== {{Main|Human mitochondrial genetics}} 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]].<ref>{{cite journal | author=Castro JA, Picornell A, Ramon M | title=Mitochondrial DNA: a tool for populational genetics studies | journal=Int Microbiol. | date=1998 | volume=1 | issue=4 | pages=327–32| pmid=10943382}}</ref> 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 [[phylogenetic tree|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]].<ref>{{cite journal | journal=Nature. | volume=325 | pages=31–36 | date=1987 January | doi=10.1038/325031a0 | title=Mitochondrial DNA and human evolution | author=Cann RL, Stoneking M, Wilson AC}}</ref><ref>{{cite journal |author=Torroni A, Achilli A, Macaulay V, Richards M, Bandelt HJ |title=Harvesting the fruit of the human mtDNA tree |journal=Trends Genet. |volume=22 |issue=6 |pages=339&ndash;45 |year=2006 |pmid=16678300 | doi=10.1016/j.tig.2006.04.001 }}</ref> This is often interpreted as strong support for a recent modern human expansion [[Recent single-origin hypothesis|out of Africa]].<ref name=Garrigan06>{{cite journal |author=Garrigan D, Hammer MF |title=Reconstructing human origins in the genomic era |journal=Nat. Rev. Genet. |volume=7 |issue=9 |pages=669&ndash;80 |year=2006 |pmid=16921345 | doi=10.1038/nrg1941}}</ref> 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.<ref>{{cite journal |author=Krings M, Stone A, Schmitz RW, Krainitzki H, Stoneking M, Pääbo S |title=Neandertal DNA sequences and the origin of modern humans |journal=Cell |volume=90 |issue=1 |pages=19&ndash;30 |year=1997 |pmid=9230299 | doi=10.1016/S0092-8674(00)80310-4}}</ref> However, mitochondrial DNA reflects the history of only females in a population and so may not represent the history of the population as a whole. This can be partially overcome by the use of paternal genetic sequences, such as the [[genetic recombination|non-recombining]] region of the [[Y-chromosome]].<ref name=Garrigan06/> In a broader sense, only studies that also include [[nuclear DNA]] can provide a comprehensive evolutionary history of a population.<ref>{{cite journal | journal=Am J Hum Genet. | date=1997 April | volume=60 | issue=4 | pages=772–89 | title=Archaic African and Asian lineages in the genetic ancestry of modern humans | author=Harding RM, Fullerton SM, Griffiths RC, Bond J, Cox MJ, Schneider JA, Moulin DS, Clegg JB | pmid=9106523}}</ref> ==Dysfunction and disease== ===Mitochondrial diseases=== {{main|Mitochondrial disease}} With their central place in cell metabolism, damage - and subsequent dysfunction - in mitochondria is an important factor in a wide range of human diseases. Mitochondrial disorders often present as neurological disorders, but can manifest as [[myopathy]], [[diabetes]], multiple endocrinopathy, or a variety of other systemic manifestations.<ref name=Zeviani>{{cite journal | author=Zeviani M, Di Donato S| title=Mitochondrial disorders | journal=Brain. | date=2004 | volume=127 | pages=2153&ndash;2172 | doi=10.1093/brain/awh259 | pmid=15358637}}</ref> Diseases caused by mutation in the mtDNA include [[Kearns-Sayre syndrome]], [[Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes|MELAS syndrome]] and [[Leber's hereditary optic neuropathy]].<ref name="pmid15861210">{{cite journal |author=Taylor RW, Turnbull DM |title=Mitochondrial DNA mutations in human disease |journal=Nat. Rev. Genet. |volume=6 |issue=5 |pages=389&ndash;402 |year=2005 |pmid=15861210 |doi=10.1038/nrg1606}}</ref> In the vast majority of cases, these diseases are transmitted by a female to her children, as the [[zygote]] derives its mitochondria and hence its mtDNA from the ovum. Diseases such as [[Kearns-Sayre syndrome]], Pearson's syndrome, and [[progressive external ophthalmoplegia]] are thought to be due to large-scale mtDNA rearrangements, whereas other diseases such as [[Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes|MELAS syndrome]], [[Leber's hereditary optic neuropathy]], myoclonic epilepsy with ragged red fibers (MERRF), and others are due to [[point mutation]]s in mtDNA.<ref name=Zeviani/> In other diseases, defects in nuclear genes lead to dysfunction of mitochondrial proteins. This is the case in [[Friedreich's ataxia]], [[hereditary spastic paraplegia]], and [[Wilson's disease]].<ref>{{cite journal |author=Chinnery PF, Schon EA |title=Mitochondria |journal=J. Neurol. Neurosurg. Psychiatr. |volume=74 |issue=9 |pages=1188&ndash;99 |year=2003 |pmid=12933917 |doi=10.1136/jnnp.74.9.1188}}</ref> These diseases are inherited in a [[dominance relationship]], as applies to most other genetic diseases. A variety of disorders can be caused by nuclear mutations of oxidative phosphorylation enzymes, such as [[coenzyme Q10]] deficiency and [[Barth syndrome]].<ref name=Zeviani/> Environmental influences may also interact with hereditary predispositions and cause mitochondrial disease. For example, there may be a link between [[pesticide]] exposure and the later onset of [[Parkinson's disease]].<ref>{{cite journal |author=Sherer TB, Betarbet R, Greenamyre JT |title=Environment, mitochondria, and Parkinson's disease |journal=The Neuroscientist. |volume=8 |issue=3 |pages=192&ndash;7 |year=2002 |pmid=12061498 | doi=10.1177/1073858402008003004}}</ref><ref>{{cite journal |author=Gomez C, Bandez MJ, Navarro A |title=Pesticides and impairment of mitochondrial function in relation with the parkinsonian syndrome |journal=Front. Biosci. |volume=12 |issue= |pages=1079&ndash;93 |year=2007 |pmid=17127363 | doi = 10.2741/2128 <!--Retrieved from CrossRef by DOI bot-->}}</ref> Other diseases not directly linked to mitochondrial enzymes may feature dysfunction of mitochondria. These include [[schizophrenia]], [[bipolar disorder]], [[dementia]], [[Alzheimer's disease]], Parkinson's disease, [[epilepsy]], [[stroke]], [[cardiovascular disease]], [[retinitis pigmentosa]], and [[diabetes mellitus]].<ref>{{cite journal |author=Schapira AH |title=Mitochondrial disease |journal=Lancet |volume=368 |issue=9529 |pages=70&ndash;82 |year=2006 |pmid=16815381 | doi=10.1016/S0140-6736(06)68970-8}}</ref><ref name=Pieczenik>{{cite journal |author=Pieczenik SR, Neustadt J |title=Mitochondrial dysfunction and molecular pathways of disease |journal=Exp. Mol. Pathol. |volume=83 |issue=1 |pages=84&ndash;92 |year=2007 |pmid=17239370 | doi=10.1016/j.yexmp.2006.09.008 }}</ref> 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.<ref name=Pieczenik/> ===Possible relationships to aging=== Given the role of mitochondria as the cell's powerhouse, there may be some leakage of the high-energy [[electrons]] in the respiratory chain to form [[reactive oxygen species]]. This can result in significant [[oxidative stress]] in the mitochondria with high mutation rates of mitochondrial DNA.<ref>{{ cite journal | author= Richter C, Park J, Ames BN | title=Normal Oxidative Damage to Mitochondrial and Nuclear DNA is Extensive | journal=PNAS | date =1988 September | volume=85 | issue=17 | pages=6465&ndash;6467 | pmid=3413108 | doi = 10.1073/pnas.85.17.6465 <!--Retrieved from CrossRef by DOI bot-->}}</ref> A vicious cycle is thought to occur, as oxidative stress leads to mitochondrial DNA mutations, which can lead to enzymatic abnormalities and further oxidative stress. A number of changes occur to mitochondria during the aging process.<ref>{{cite web|url=http://www.circuitblue.com/biogerontology/mito.shtml|title=Mitochondria and Aging.}}</ref> Tissues from elderly patients show a decrease in enzymatic activity of the proteins of the respiratory chain.<ref>{{cite journal | author=Boffoli D, Scacco SC, Vergari R, Solarino G, Santacroce G, Papa S | title=Decline with age of the respiratory chain activity in human skeletal muscle | journal=Biochim. Biophys. Acta. | volume=1226 | date=1994 | pages=73&ndash;82 | pmid=8155742}}</ref> Large deletions in the mitochondrial genome can lead to high levels of [[oxidative stress]] and neuronal death in [[Parkinson's disease]].<ref>{{cite journal | author=Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, Taylor RW, Turnbull DM| title=High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease |journal=Nat Gen. | volume=38 | pages=515&ndash;517 | date=2006 | pmid=16604074| doi=10.1038/ng1769}}</ref> Hypothesized links between aging and oxidative stress are not new and were proposed over 50 years ago;<ref>{{cite journal | author=Harman D |title=Aging: a theory based on free radical and radiation chemistry | journal= J. Gerontol. | volume=11 | date=1956 | pages=298&ndash;300 | pmid=13332224}}</ref> however, there is much debate over whether mitochondrial changes are causes of aging or merely characteristics of aging. One notable study in mice demonstrated no increase in reactive oxygen species despite increasing mitochondrial DNA mutations, suggesting that the aging process is not due to oxidative stress.<ref>{{cite journal | author= Trifunovic A, Hansson A, Wredenberg A, Rovio AT, Dufour E, Khvorostov I, Spelbrink JN, Wibom R, Jacobs HT, Larsson NG | title=Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production | journal=PNAS. | date=2005 | volume=102 | issue=50 | pages=17993&ndash;8 | pmid=16332961 | doi=10.1073/pnas.0508886102 }}</ref> As a result, the exact relationships between mitochondria, oxidative stress, and aging have not yet been settled. ==References== {{Reflist|2}} ==See also== {{Commons|Mitochondrion}} * [[Anti-mitochondrial antibodies]] * [[Bioenergetics]] * [[Human mitochondrial genetics]] * [[Mitochondrial permeability transition pore]] * [[Submitochondrial particle]] ==External links== * [http://www.uni-mainz.de/FB/Medizin/Anatomie/workshop/EM/EMMitoE.html Mitochondria Atlas] at [[University of Mainz]] * [http://www.mitochondrial.net Mitochondria Research Portal] at mitochondrial.net * [http://www.cytochemistry.net/Cell-biology/mitoch1.htm Mitochondria: Architecture dictates function] at cytochemistry.net * [http://bama.ua.edu/~hsmithso/class/bsc_495/mito-plastids/mito_web.html Mitochondria links] at [[University of Alabama]] * [http://www.sci.sdsu.edu/TFrey/MitoMovie.htm Mitochondrion Reconstructed by Electron Tomography] at [[San Diego State University]] * [http://www.wadsworth.org/databank/electron/cryomito_dis2.html Video Clip of Rat-liver Mitochondrion from Cryo-electron Tomography] at wadsworth.org * [http://opm.phar.umich.edu/localization.php?localization=Mitochondrial%20inner%20membrane 3D structures of proteins from inner mitochondrial membrane] at [[University of Michigan]] * [http://opm.phar.umich.edu/localization.php?localization=Mitochondrial%20outer%20membrane 3D structures of proteins associated with outer mitochondrial membrane] at [[University of Michigan]] {{organelles}} {{NCBI-scienceprimer}} [[Category:Cellular respiration]] [[Category:Organelles]] [[af:Mitochondrium]] [[ar:متقدرة]] [[az:Mitoxondriya]] [[bn:মাইটোকন্ড্রিয়া]] [[zh-min-nan:Soàⁿ-lia̍p-thé]] [[bs:Mitohondrije]] [[bg:Митохондрия]] [[ca:Mitocondri]] [[cs:Mitochondrie]] [[cy:Mitocondria]] [[da:Mitokondrie]] [[de:Mitochondrium]] [[et:Mitokonder]] [[el:Μιτοχόνδριο]] [[es:Mitocondria]] [[eo:Mitokondrio]] [[fa:میتوکندری]] [[fr:Mitochondrie]] [[gl:Mitocondria]] [[ko:미토콘드리아]] [[hr:Mitohondrij]] [[id:Mitokondria]] [[is:Hvatberi]] [[it:Mitocondrio]] [[he:מיטוכונדריון]] [[la:Mitochondrium]] [[lv:Mitohondrijs]] [[lb:Mitochondrie]] [[lt:Mitochondrija]] [[hu:Mitokondrium]] [[mk:Митохондрија]] [[ms:Mitokondrion]] [[nl:Mitochondrion]] [[ja:ミトコンドリア]] [[no:Mitokondrium]] [[oc:Mitocondria]] [[pl:Mitochondrium]] [[pt:Mitocôndria]] [[ro:Mitocondrie]] [[ru:Митохондрия]] [[simple:Mitochondria]] [[sk:Mitochondria]] [[sl:Mitohondrij]] [[sr:Митохондрије]] [[sh:Mitohondrije]] [[su:Mitokondria]] [[fi:Mitokondrio]] [[sv:Mitokondrie]] [[th:ไมโทคอนเดรีย]] [[vi:Ti thể]] [[tr:Mitokondri]] [[uk:Мітохондрія]] [[zh:線粒體]]