document_title: Mitochondrion

question_text: where is the mitochondrion located in the cell

question_tokens: where is the mitochondrion located in the cell

text: Mitochondrion

text: History

text: The first observations of intracellular structures that probably represented mitochondria were published in the 1840s.[19] Richard Altmann, in 1890, established them as cell organelles and called them "bioblasts".[19][20] The term "mitochondria" was coined by Carl Benda in 1898.[19][21] Leonor Michaelis discovered that Janus green can be used as a supravital stain for mitochondria in 1900. In 1904, Friedrich Meves, made the first recorded observation of mitochondria in plants in cells of the white waterlily, Nymphaea alba[19][22] and in 1908, along with Claudius Regaud, suggested that they contain proteins and lipids. Benjamin F. Kingsbury, in 1912, first related them with cell respiration, but almost exclusively based on morphological observations.[19] In 1913, particles from extracts of guinea-pig liver were linked to respiration by Otto Heinrich Warburg, which he called "grana". Warburg and Heinrich Otto Wieland, who had also postulated a similar particle mechanism, disagreed on the chemical nature of the respiration. It was not until 1925, when David Keilin discovered cytochromes, that the respiratory chain was described.[19]

text: In 1939, experiments using minced muscle cells demonstrated that cellular respiration using one oxygen atom can form two adenosine triphosphate (ATP) molecules, and, in 1941, the concept of the phosphate bonds of ATP being a form of energy in cellular metabolism was developed by Fritz Albert Lipmann. In the following years, the mechanism behind cellular respiration was further elaborated, although its link to the mitochondria was not known.[19] The introduction of tissue fractionation by Albert Claude allowed mitochondria to be isolated from other cell fractions and biochemical analysis to be conducted on them alone. In 1946, he concluded that cytochrome oxidase and other enzymes responsible for the respiratory chain were isolated to the mitchondria. Eugene Kennedy and Albert Lehninger discovered in 1948 that mitochondria are the site of oxidative phosphorylation in eukaryotes. Over time, the fractionation method was further developed, improving the quality of the mitochondria isolated, and other elements of cell respiration were determined to occur in the mitochondria.[19]

text: The first high-resolution electron micrographs appeared in 1952, replacing the Janus Green stains as the preferred way of visualising the mitochondria.[19] This led to a more detailed analysis of the structure of the mitochondria, including confirmation that they were surrounded by a membrane. It also showed a second membrane inside the mitochondria that folded up in ridges dividing up the inner chamber and that the size and shape of the mitochondria varied from cell to cell.

text: The popular term "powerhouse of the cell" was coined by Philip Siekevitz in 1957.[23]

text: In 1967, it was discovered that mitochondria contained ribosomes.[24] In 1968, methods were developed for mapping the mitochondrial genes, with the genetic and physical map of yeast mitochondrial DNA being completed in 1976.[19]

text: Origin and evolution

text: There are two hypotheses about the origin of mitochondria: endosymbiotic and autogenous. The endosymbiotic hypothesis suggests that mitochondria were originally prokaryotic cells, capable of implementing oxidative mechanisms that were not possible for eukaryotic cells; they became endosymbionts living inside the eukaryote.[25] In the autogenous hypothesis, mitochondria were born by splitting off a portion of DNA from the nucleus of the eukaryotic cell at the time of divergence with the prokaryotes; this DNA portion would have been enclosed by membranes, which could not be crossed by proteins. Since mitochondria have many features in common with bacteria, the endosymbiotic hypothesis is more widely accepted.[25][26]

text: A mitochondrion contains DNA, which is organized as several copies of a single, usually circular, chromosome. This mitochondrial chromosome contains genes for redox proteins, such as those of the respiratory chain. The CoRR hypothesis proposes that this co-location is required for redox regulation. The mitochondrial genome codes for some RNAs of ribosomes, and the 22 tRNAs necessary for the translation of messenger RNAs into protein. The circular structure is also found in prokaryotes. The proto-mitochondrion was probably closely related to the Rickettsia.[27][28] However, the exact relationship of the ancestor of mitochondria to the alphaproteobacteria and whether the mitochondrion was formed at the same time or after the nucleus, remains controversial.[29]

text: A recent study[30] by researchers of the University of Hawaii at Manoa and the Oregon State University indicates that the SAR11 clade of bacteria shares a relatively recent common ancestor with the mitochondria existing in most eukaryotic cells.

text:
Schematic phylogeny of Alphaproteobacteria, according to Ferla et al. (2013) [31]

Magnetococcidae

Magnetococcales

Magnetococcaceae

Magnetococcus marinus

Caulobacteridae

Rhodospirillales, Sphingomonadales, Rhodobacteraceae, Rhizobiales, etc.

Holosporales

Rickettsidae

Pelagibacterales

Pelagibacteraceae

Pelagibacter

subgroups Ib, II, IIIa, IIIb, IV and V

Proto-mitochondria

Anaplasmataceae

Ehrlichia

Anaplasma

Wolbachia

Neorickettsia

Midichloriaceae

Midichloria

Rickettsiaceae

Rickettsia

Robust 16S + 23S phylogeny of Rickettsidae from Ferla et al. [31]

text: The ribosomes coded for by the mitochondrial DNA are similar to those from bacteria in size and structure.[32] They closely resemble the bacterial 70S ribosome and not the 80S cytoplasmic ribosomes, which are coded for by nuclear DNA.

text: The endosymbiotic relationship of mitochondria with their host cells was popularized by Lynn Margulis.[33] The 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 respiration in host cells that had relied on glycolysis and fermentation would have provided a considerable evolutionary advantage. This symbiotic relationship probably developed 1.7[34] to 2[35] billion years ago.

text: A few groups of unicellular eukaryotes have only vestigial mitochondria or derived structures: the microsporidians, metamonads, and archamoebae.[36] These groups appear as the most primitive eukaryotes on phylogenetic trees constructed using rRNA information, which once suggested that they appeared before the origin of mitochondria. However, this is now known to be an artifact of long-branch attraction—they are derived groups and retain genes or organelles derived from mitochondria (e.g., mitosomes and hydrogenosomes).[1]

text: Monocercomonoides appear to have lost their mitochondria completely and at least some of the mitochondrial functions seem to be carried out by cytoplasmic proteins now.[37]

text: Structure

text: A mitochondrion contains outer and inner membranes composed of phospholipid bilayers and proteins.[13] The two membranes have different properties. Because of this double-membraned organization, there are five distinct parts to a mitochondrion. They are:

text:
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 matrix (space within the inner membrane).

text: Mitochondria stripped of their outer membrane are called mitoplasts.

text: Outer membrane

text: The outer mitochondrial membrane, which encloses the entire organelle, is 60 to 75 angstroms (Å) thick. It 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 membrane proteins called porins. These porins form channels that allow molecules of 5000 daltons or less in molecular weight to freely diffuse from one side of the membrane to the other.[13] Larger proteins can enter the mitochondrion if a signaling sequence at their N-terminus binds to a large multisubunit protein called translocase of the outer membrane, which then actively moves them across the membrane.[39] Mitochondrial pro-proteins are imported through specialised translocation complexes. The outer membrane also contains enzymes involved in such diverse activities as the elongation of fatty acids, oxidation of epinephrine, and the degradation of tryptophan. These enzymes include monoamine oxidase, rotenone-insensitive NADH-cytochrome c-reductase, kynurenine hydroxylase and fatty acid Co-A ligase. Disruption of the outer membrane permits proteins in the intermembrane space to leak into the cytosol, leading to certain cell death.[40] The mitochondrial outer membrane can associate with the endoplasmic reticulum (ER) membrane, in a structure called MAM (mitochondria-associated ER-membrane). This is important in the ER-mitochondria calcium signaling and is involved in the transfer of lipids between the ER and mitochondria. [41] Outside the outer membrane there are small (diameter: 60Å) particles named sub-units of Parson.

text: Intermembrane space

text: The intermembrane space is the space between the outer membrane and the inner membrane. It is also known as perimitochondrial space. 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 in the cytosol.[13] However, large proteins must have a specific signaling sequence to be transported across the outer membrane, so the protein composition of this space is different from the protein composition of the cytosol. One protein that is localized to the intermembrane space in this way is cytochrome c.[40]

text: Inner membrane

text: The inner mitochondrial membrane contains proteins with five types of functions:[13]

text:
Those that perform the redox reactions of oxidative phosphorylation
ATP synthase, which generates ATP in the matrix
Specific transport proteins that regulate metabolite passage into and out of the matrix
Protein import machinery
Mitochondrial fusion and fission protein

text: It contains more than 151 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). The inner membrane is home to around 1/5 of the total protein in a mitochondrion.[13] In addition, the inner membrane is rich in an unusual phospholipid, cardiolipin. This phospholipid was originally discovered in cow hearts in 1942, and is usually characteristic of mitochondrial and bacterial plasma membranes.[42] Cardiolipin contains four fatty acids rather than two, and may help to make the inner membrane impermeable.[13] Unlike the outer membrane, the inner membrane doesn't 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.[39] In addition, there is a membrane potential across the inner membrane, formed by the action of the enzymes of the electron transport chain.

text: Cristae

text: The inner mitochondrial membrane is compartmentalized into numerous cristae, which expand the surface area of the inner mitochondrial membrane, enhancing its ability to produce ATP. For typical liver mitochondria, the area of the inner membrane is about five times as large as the outer membrane. This ratio is variable and mitochondria from cells that have a greater demand for ATP, such as muscle cells, contain even more cristae. These folds are studded with small round bodies known as F1 particles or oxysomes. These are not simple random folds but rather invaginations of the inner membrane, which can affect overall chemiosmotic function.[43]

text: One recent mathematical modeling study has suggested that the optical properties of the cristae in filamentous mitochondria may affect the generation and propagation of light within the tissue.[44]

text: Matrix

text: The matrix is the space enclosed by the inner membrane. It contains about 2/3 of the total protein in a mitochondrion.[13] 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.[13]

text: Mitochondria have their own genetic material, and the machinery to manufacture their own RNAs and proteins (see: protein biosynthesis). A published human mitochondrial DNA sequence revealed 16,569 base pairs encoding 37 genes: 22 tRNA, 2 rRNA, and 13 peptide genes.[45] 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.

text: Mitochondria-associated ER membrane (MAM)

text: The mitochondria-associated ER membrane (MAM) is another structural element that is increasingly recognized for its critical role in cellular physiology and homeostasis. Once considered a technical snag in cell fractionation techniques, the alleged ER vesicle contaminants that invariably appeared in the mitochondrial fraction have been re-identified as membranous structures derived from the MAM—the interface between mitochondria and the ER.[46] Physical coupling between these two organelles had previously been observed in electron micrographs and has more recently been probed with fluorescence microscopy.[46] Such studies estimate that at the MAM, which may comprise up to 20% of the mitochondrial outer membrane, the ER and mitochondria are separated by a mere 10–25 nm and held together by protein tethering complexes.[46][47][48]

text: Purified MAM from subcellular fractionation has been shown to be enriched in enzymes involved in phospholipid exchange, in addition to channels associated with Ca2+ signaling.[46][48] These hints of a prominent role for the MAM in the regulation of cellular lipid stores and signal transduction have been borne out, with significant implications for mitochondrial-associated cellular phenomena, as discussed below. Not only has the MAM provided insight into the mechanistic basis underlying such physiological processes as intrinsic apoptosis and the propagation of calcium signaling, but it also favors a more refined view of the mitochondria. Though often seen as static, isolated 'powerhouses' hijacked for cellular metabolism through an ancient endosymbiotic event, the evolution of the MAM underscores the extent to which mitochondria have been integrated into overall cellular physiology, with intimate physical and functional coupling to the endomembrane system.

text: Phospholipid transfer

text: The MAM is enriched in enzymes involved in lipid biosynthesis, such as phosphatidylserine synthase on the ER face and phosphatidylserine decarboxylase on the mitochondrial face.[49][50] Because mitochondria are dynamic organelles constantly undergoing fission and fusion events, they require a constant and well-regulated supply of phospholipids for membrane integrity.[51][52] But mitochondria are not only a destination for the phospholipids they finish synthesis of; rather, this organelle also plays a role in inter-organelle trafficking of the intermediates and products of phospholipid biosynthetic pathways, ceramide and cholesterol metabolism, and glycosphingolipid anabolism.[50][52]

text: Such trafficking capacity depends on the MAM, which has been shown to facilitate transfer of lipid intermediates between organelles.[49] In contrast to the standard vesicular mechanism of lipid transfer, evidence indicates that the physical proximity of the ER and mitochondrial membranes at the MAM allows for lipid flipping between opposed bilayers.[52] Despite this unusual and seemingly energetically unfavorable mechanism, such transport does not require ATP.[52] Instead, in yeast, it has been shown to be dependent on a multiprotein tethering structure termed the ER-mitochondria encounter structure, or ERMES, although it remains unclear whether this structure directly mediates lipid transfer or is required to keep the membranes in sufficiently close proximity to lower the energy barrier for lipid flipping.[52][53]

text: The MAM may also be part of the secretory pathway, in addition to its role in intracellular lipid trafficking. In particular, the MAM appears to be an intermediate destination between the rough ER and the Golgi in the pathway that leads to very-low-density lipoprotein, or VLDL, assembly and secretion.[50][54] The MAM thus serves as a critical metabolic and trafficking hub in lipid metabolism.

text: Calcium signaling

text: A critical role for the ER in calcium signaling was acknowledged before such a role for the mitochondria was widely accepted, in part because the low affinity of Ca2+ channels localized to the outer mitochondrial membrane seemed to fly in the face of this organelle's purported responsiveness to changes in intracellular Ca2+ flux.[46][55] But the presence of the MAM resolves this apparent contradiction: the close physical association between the two organelles results in Ca2+ microdomains at contact points that facilitate efficient Ca2+ transmission from the ER to the mitochondria.[46] Transmission occurs in response to so-called "Ca2+ puffs" generated by spontaneous clustering and activation of IP3R, a canonical ER membrane Ca2+ channel.[46][47]

text: The fate of these puffs—in particular, whether they remain restricted to isolated locales or integrated into Ca2+ waves for propagation throughout the cell—is determined in large part by MAM dynamics. Although reuptake of Ca2+ by the ER (concomitant with its release) modulates the intensity of the puffs, thus insulating mitochondria to a certain degree from high Ca2+ exposure, the MAM often serves as a firewall that essentially buffers Ca2+ puffs by acting as a sink into which free ions released into the cytosol can be funneled.[46][56][57] This Ca2+ tunneling occurs through the low-affinity Ca2+ receptor VDAC1, which recently has been shown to be physically tethered to the IP3R clusters on the ER membrane and enriched at the MAM.[46][47][58] The ability of mitochondria to serve as a Ca2+ sink is a result of the electrochemical gradient generated during oxidative phosphorylation, which makes tunneling of the cation an exergonic process.[58] Normally, mild calcium influx from cytosol into the mitochondrial matrix causes transient depolarization that is corrected by pumping out protons.

text: But transmission of Ca2+ is not unidirectional; rather, it is a two-way street.[55] The properties of the Ca2+ pump SERCA and the channel IP3R present on the ER membrane facilitate feedback regulation coordinated by MAM function. In particular, the clearance of Ca2+ by the MAM allows for spatio-temporal patterning of Ca2+ signaling because Ca2+ alters IP3R activity in a biphasic manner.[46] SERCA is likewise affected by mitochondrial feedback: uptake of Ca2+ by the MAM stimulates ATP production, thus providing energy that enables SERCA to reload the ER with Ca2+ for continued Ca2+ efflux at the MAM.[56][58] Thus, the MAM is not a passive buffer for Ca2+ puffs; rather it helps modulate further Ca2+ signaling through feedback loops that affect ER dynamics.

text: Regulating ER release of Ca2+ at the MAM is especially critical because only a certain window of Ca2+ uptake sustains the mitochondria, and consequently the cell, at homeostasis. Sufficient intraorganelle Ca2+ signaling is required to stimulate metabolism by activating dehydrogenase enzymes critical to flux through the citric acid cycle.[59] However, once Ca2+ signaling in the mitochondria passes a certain threshold, it stimulates the intrinsic pathway of apoptosis in part by collapsing the mitochondrial membrane potential required for metabolism.[46] Studies examining the role of pro- and anti-apoptotic factors support this model; for example, the anti-apoptotic factor Bcl-2 has been shown to interact with IP3Rs to reduce Ca2+ filling of the ER, leading to reduced efflux at the MAM and preventing collapse of the mitochondrial membrane potential post-apoptotic stimuli.[46] Given the need for such fine regulation of Ca2+ signaling, it is perhaps unsurprising that dysregulated mitochondrial Ca2+ has been implicated in several neurodegenerative diseases, while the catalogue of tumor suppressors includes a few that are enriched at the MAM.[58]

text: Molecular basis for tethering

text: Recent advances in the identification of the tethers between the mitochondrial and ER membranes suggest that the scaffolding function of the molecular elements involved is secondary to other, non-structural functions. In yeast, ERMES, a multiprotein complex of interacting ER- and mitochondrial-resident membrane proteins, is required for lipid transfer at the MAM and exemplifies this principle. One of its components, for example, is also a constituent of the protein complex required for insertion of transmembrane beta-barrel proteins into the lipid bilayer.[52] However, a homologue of the ERMES complex has not yet been identified in mammalian cells. Other proteins implicated in scaffolding likewise have functions independent of structural tethering at the MAM; for example, ER-resident and mitochondrial-resident mitofusins form heterocomplexes that regulate the number of inter-organelle contact sites, although mitofusins were first identified for their role in fission and fusion events between individual mitochondria.[46] Glucose-related protein 75 (grp75) is another dual-function protein. In addition to the matrix pool of grp75, a portion serves as a chaperone that physically links the mitochondrial and ER Ca2+ channels VDAC and IP3R for efficient Ca2+ transmission at the MAM.[46][47] Another potential tether is Sigma-1R, a non-opioid receptor whose stabilization of ER-resident IP3R may preserve communication at the MAM during the metabolic stress response.[60][61]

text: Perspective

text: The MAM is a critical signaling, metabolic, and trafficking hub in the cell that allows for the integration of ER and mitochondrial physiology. Coupling between these organelles is not simply structural but functional as well and critical for overall cellular physiology and homeostasis. The MAM thus offers a perspective on mitochondria that diverges from the traditional view of this organelle as a static, isolated unit appropriated for its metabolic capacity by the cell. Instead, this mitochondrial-ER interface emphasizes the integration of the mitochondria, the product of an endosymbiotic event, into diverse cellular processes.

text: Organization and distribution

text: Mitochondria (and related structures) are found in all eukaryotes (except one—the Oxymonad Monocercomonoides sp.).[2][62] Although commonly depicted as bean-like structures they form a highly dynamic network in the majority of cells where they constantly undergo fission and fusion. Mitochondria vary in number and location according to cell type. A single mitochondrion is often found in unicellular organisms. Conversely, numerous mitochondria are found in human liver cells, with about 1000–2000 mitochondria per cell, making up 1/5 of the cell volume.[13] The population of all the mitochondria of a given cell constitutes the chondriome. The mitochondrial content of otherwise similar cells can vary substantially in size and membrane potential,[63] with differences arising from sources including uneven partitioning at cell divisions, leading to extrinsic differences in ATP levels and downstream cellular processes.[64] The mitochondria can be found nestled between myofibrils of muscle or wrapped around the sperm flagellum.[13] 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:[65] different structures of the mitochondrial network may afford the population a variety of physical, chemical, and signalling advantages or disadvantages.[66] Mitochondria in cells are always distributed along microtubules and the distribution of these organelles is also correlated with the endoplasmic reticulum.[67] Recent evidence suggests that vimentin, one of the components of the cytoskeleton, is also critical to the association with the cytoskeleton.[68]

text: Function

text: The most prominent roles of mitochondria are to produce the energy currency of the cell, ATP (i.e., phosphorylation of ADP), through respiration, and to regulate cellular metabolism.[14] The central set of reactions involved in ATP production are collectively known as the citric acid cycle, or the Krebs cycle. However, the mitochondrion has many other functions in addition to the production of ATP.

text: Energy conversion

text: 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 glucose: pyruvate, and NADH, which are produced in the cytosol.[14] This type of cellular respiration known as aerobic respiration, is dependent on the presence of oxygen. When oxygen is limited, the glycolytic products will be metabolized by anaerobic fermentation, a process that is independent of the mitochondria.[14] The production of ATP from glucose has an approximately 13-times higher yield during aerobic respiration compared to fermentation.[69] Recently it has been shown that plant mitochondria can produce a limited amount of ATP without oxygen by using the alternate substrate nitrite.[70] ATP crosses out through the inner membrane with the help of a specific protein, and across the outer membrane via porins. ADP returns via the same route.

text: Pyruvate and the citric acid cycle

text: Pyruvate molecules produced by glycolysis are actively transported across the inner mitochondrial membrane, and into the matrix where they can either be oxidized and combined with coenzyme A to form CO2, acetyl-CoA, and NADH,[14] or they can be carboxylated (by pyruvate carboxylase) to form oxaloacetate. This latter reaction ”fills up” the amount of oxaloacetate in the citric acid cycle, and is therefore an anaplerotic reaction, increasing the cycle’s capacity to metabolize acetyl-CoA when the tissue's energy needs (e.g. in muscle) are suddenly increased by activity.[71]

text: In the citric acid cycle, all the intermediates (e.g. citrate, iso-citrate, alpha-ketoglutarate, succinate, fumarate, malate and oxaloacetate) are regenerated during each turn of the cycle. Adding more of any of these intermediates to the mitochondrion therefore means that the additional amount is retained within the cycle, increasing all the other intermediates as one is converted into the other. Hence, the addition of any one of them to the cycle has an anaplerotic effect, and its removal has a cataplerotic effect. These anaplerotic and cataplerotic reactions will, during the course of the cycle, increase or decrease the amount of oxaloacetate available to combine with acetyl-CoA to form citric acid. This in turn increases or decreases the rate of ATP production by the mitochondrion, and thus the availability of ATP to the cell.[71]

text: Acetyl-CoA, on the other hand, derived from pyruvate oxidation, or from the beta-oxidation of fatty acids, is the only fuel to enter the citric acid cycle. With each turn of the cycle one molecule of acetyl-CoA is consumed for every molecule of oxaloacetate present in the mitochondrial matrix, and is never regenerated. It is the oxidation of the acetate portion of acetyl-CoA that produces CO2 and water, with the energy thus released captured in the form of ATP.[71]

text: In the liver, the carboxylation of cytosolic pyruvate into intra-mitochondrial oxaloacetate is an early step in the gluconeogenic pathway, which converts lactate and de-aminated alanine into glucose,[14][71] under the influence of high levels of glucagon and/or epinephrine in the blood.[71] Here, the addition of oxaloacetate to the mitochondrion does not have a net anaplerotic effect, as another citric acid cycle intermediate (malate) is immediately removed from the mitochondrion to be converted into cytosolic oxaloacetate, which is ultimately converted into glucose, in a process that is almost the reverse of glycolysis.[71]

text: 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.[72] 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).[14]

text: NADH and FADH2: the electron transport chain

text: 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.[14] Protein complexes in the inner membrane (NADH dehydrogenase (ubiquinone), 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.[14] This can cause oxidative stress in the mitochondria and may contribute to the decline in mitochondrial function associated with the aging process.[73]

text: 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).[14] This process is called chemiosmosis, and was first described by Peter Mitchell[74][75] 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.[76]

text: Heat production

text: 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.[14] The process is mediated by a proton channel called thermogenin, or UCP1.[77] Thermogenin is a 33 kDa protein first discovered in 1973.[78] 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.[77]

text: Storage of calcium ions

text: The concentrations of free calcium in the cell can regulate an array of reactions and is important for signal transduction in the cell. Mitochondria can transiently store calcium, a contributing process for the cell's homeostasis of calcium.[79] [80] In fact, their ability to rapidly take in calcium for later release makes them very good "cytosolic buffers" for calcium.[81][82][83] The endoplasmic reticulum (ER) is the most significant storage site of calcium,[55] and there is a significant interplay between the mitochondrion and ER with regard to calcium.[84] The calcium is taken up into the matrix by the mitochondrial calcium uniporter on the inner mitochondrial membrane.[85] It is primarily driven by the mitochondrial membrane potential.[80] 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.[85] 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 neurotransmitter release in nerve cells and release of hormones in endocrine cells.[86]

text: Ca2+ influx to the mitochondrial matrix has recently been implicated as a mechanism to regulate respiratory bioenergetics by allowing the electrochemical potential across the membrane to transiently "pulse" from ΔΨ-dominated to pH-dominated, facilitating a reduction of oxidative stress.[87] In neurons, concomitant increases in cytosolic and mitochondrial calcium act to synchronize neuronal activity with mitochondrial energy metabolism. Mitochondrial matrix calcium levels can reach the tens of micromolar levels, which is necessary for the activation of isocitrate dehydrogenase, one of the key regulatory enzymes of the Krebs cycle.[88]

text: Additional functions

text: Mitochondria play a central role in many other metabolic tasks, such as:

text:
Signaling through mitochondrial reactive oxygen species[89]
Regulation of the membrane potential[14]
Apoptosis-programmed cell death[90]
Calcium signaling (including calcium-evoked apoptosis)[91]
Regulation of cellular metabolism[92]
Certain heme synthesis reactions[93] (see also: porphyrin)
Steroid synthesis.[81]
Hormonal signaling [94] Mitochondria are sensitive and responsive to hormones, in part by the action of mitochondrial estrogen receptors (mtERs). These receptors have been found in various tissues and cell types, including brain [95] and heart [96]

text: 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.

text: Cellular proliferation regulation

text: The relationship between cellular proliferation and mitochondria has been investigated using cervical cancer HeLa cells. Tumor cells require an ample amount of ATP (Adenosine triphosphate) in order to synthesize bioactive compounds such as lipids, proteins, and nucleotides for rapid cell proliferation.[97] The majority of ATP in tumor cells is generated via the oxidative phosphorylation pathway (OxPhos).[98] Interference with OxPhos have shown to cause cell cycle arrest suggesting that mitochondria play a role in cell proliferation.[98] Mitochondrial ATP production is also vital for cell division in addition to other basic functions in the cell including the regulation of cell volume, solute concentration, and cellular architecture.[99][100][101] ATP levels differ at various stages of the cell cycle suggesting that there is a relationship between the abundance of ATP and the cell's ability to enter a new cell cycle.[102] ATP's role in the basic functions of the cell make the cell cycle sensitive to changes in the availability of mitochondrial derived ATP.[102] The variation in ATP levels at different stages of the cell cycle support the hypothesis that mitochondria play an important role in cell cycle regulation.[102] Although the specific mechanisms between mitochondria and the cell cycle regulation is not well understood, studies have shown that low energy cell cycle checkpoints monitor the energy capability before committing to another round of cell division.[103]

text: Genome

text: Mitochondria contain their own genome, an indication that they are derived from bacteria through endosymbiosis. However, the ancestral endosymbiont genome has lost most of its genes so that the mitochondrial genome is one of the most reduced genomes across organisms.

text: The human mitochondrial genome is a circular DNA molecule of about 16 kilobases.[104] It encodes 37 genes: 13 for subunits of respiratory complexes I, III, IV and V, 22 for mitochondrial tRNA (for the 20 standard amino acids, plus an extra gene for leucine and serine), and 2 for rRNA.[104] One mitochondrion can contain two to ten copies of its DNA.[105]

text: 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. 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 are imported into the mitochondrion.[45] The exact number of genes encoded by the nucleus and the mitochondrial genome differs between species. Most mitochondrial genomes are circular, although exceptions have been reported.[106] In general, mitochondrial DNA lacks introns, as is the case in the human mitochondrial genome;[45] however, introns have been observed in some eukaryotic mitochondrial DNA,[107] such as that of yeast[108] and protists,[109] including Dictyostelium discoideum.[110] Between protein-coding regions, tRNAs are present. During transcription, the tRNAs acquire their characteristic L-shape that gets recognized and cleaved by specific enzymes. Mitochondrial tRNA genes have different sequences from the nuclear tRNAs but lookalikes of mitochondrial tRNAs have been found in the nuclear chromosomes with high sequence similarity.[111]

text: In animals, the mitochondrial genome is typically a single circular chromosome that is approximately 16 kb long and has 37 genes. The genes, while highly conserved, may vary in location. Curiously, this pattern is not found in the human body louse (Pediculus humanus). Instead, this mitochondrial genome is arranged in 18 minicircular chromosomes, each of which is 3–4 kb long and has one to three genes.[112] This pattern is also found in other sucking lice, but not in chewing lice. Recombination has been shown to occur between the minichromosomes. The reason for this difference is not known.

text: Alternative genetic code

text: While slight variations on the standard genetic code had been predicted earlier,[113] none was discovered until 1979, when researchers studying human mitochondrial genes determined that they used an alternative code.[114] However, the mitochondria of many other eukaryotes, including most plants, use the standard code.[115] Many slight variants have been discovered since,[116] including various alternative mitochondrial codes.[117] Further, the AUA, AUC, and AUU codons are all allowable start codons.

text:
Exceptions to the standard genetic code in mitochondria[13]

Organism
Codon
Standard
Mitochondria

Mammals
AGA, AGG
Arginine
Stop codon

Invertebrates
AGA, AGG
Arginine
Serine

Fungi
CUA
Leucine
Threonine

All of the above
AUA
Isoleucine
Methionine

UGA
Stop codon
Tryptophan

text: 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 standard genetic code for tryptophan.[118] Of note, the arthropod mitochondrial genetic code has undergone parallel evolution within a phylum, with some organisms uniquely translating AGG to lysine.[119]

text: Evolution and diversity

text: Mitochondrial genomes have far fewer genes than the bacteria from which they are thought to be descended. Although some have been lost altogether, many have been transferred to the nucleus, such as the respiratory complex II protein subunits.[104] 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.[120] 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.[120]

text: Replication and inheritance

text: Mitochondria divide by binary fission, similar to bacterial cell division.[121] 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 mammals 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. Understanding of mitochondrial dynamics, which is described as the balance between mitochondrial fusion and fission, has revealed that functional and structural alterations in mitochondrial morphology are important factors in pathologies associated with several disease conditions.[122]

text: The hypothesis of mitochondrial binary fission has relied on the visualization by fluorescence microscopy and conventional transmission electron microscopy (TEM). The resolution of fluorescence microscopy(~200 nm) is insufficient to distinguish structural details, such as double mitochondrial membrane in mitochondrial division or even to distinguish individual mitochondria when several are close together. Conventional TEM has also some technical limitations[which?] in verifying mitochondrial division. Cryo-electron tomography was recently used to visualize mitochondrial division in frozen hydrated intact cells. It revealed that mitochondria divide by budding.[123]

text: An individual's mitochondrial genes are not inherited by the same mechanism as nuclear genes. Typically, the mitochondria are inherited from one parent only. In humans, when an egg cell is fertilized 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 come from the egg only. The sperm's mitochondria enter the egg, but do not contribute genetic information to the embryo.[124] Instead, paternal mitochondria are marked with ubiquitin to select them for later destruction inside the embryo.[125] 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 only from mothers, a pattern known as maternal inheritance. This mode is seen in most organisms, including the majority of animals. However, mitochondria in some species can sometimes be inherited paternally. This is the norm among certain coniferous plants, although not in pine trees and yews.[126] For Mytilids, paternal inheritance only occurs within males of the species.[127][128][129] It has been suggested that it occurs at a very low level in humans.[130] There is a recent suggestion that mitochondria that shorten male lifespan stay in the system because they are inherited only through the mother. By contrast, natural selection weeds out mitochondria that reduce female survival as such mitochondria are less likely to be passed on to the next generation. Therefore, it is suggested that human females and female animals tend to live longer than males. The authors claim that this is a partial explanation.[131]

text: Uniparental inheritance leads to little opportunity for genetic recombination between different lineages of mitochondria, although a single mitochondrion can contain 2–10 copies of its DNA.[105] For this reason, mitochondrial DNA is usually 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.[132] Further, evidence suggests that animal mitochondria can undergo recombination.[133] The data are a bit more controversial in humans, although indirect evidence of recombination exists.[134][135] 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.

text: Entities undergoing uniparental inheritance and with little to no recombination may be expected to be subject to Muller's ratchet, the inexorable accumulation of deleterious mutations until functionality is lost. Animal populations of mitochondria avoid this buildup through a developmental process known as the mtDNA bottleneck. The bottleneck exploits stochastic processes in the cell to increase in the cell-to-cell variability in mutant load as an organism develops: a single egg cell with some proportion of mutant mtDNA thus produces an embryo where different cells have different mutant loads. Cell-level selection may then act to remove those cells with more mutant mtDNA, leading to a stabilisation or reduction in mutant load between generations. The mechanism underlying the bottleneck is debated,[136][137][138] with a recent mathematical and experimental metastudy providing evidence for a combination of random partitioning of mtDNAs at cell divisions and random turnover of mtDNA molecules within the cell.[139]

text: Population genetic studies

text: 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.[140] 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.[141][142] This is often interpreted as strong support for a recent modern human expansion out of Africa.[143] 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 the lack of interbreeding between Neanderthals and anatomically modern humans.[144]

text: However, mitochondrial DNA reflects only the history of the 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 non-recombining region of the Y-chromosome.[143] In a broader sense, only studies that also include nuclear DNA can provide a comprehensive evolutionary history of a population.[145]

text: Recent measurements of the molecular clock for mitochondrial DNA[146] reported a value of 1 mutation every 7884 years dating back to the most recent common ancestor of humans and apes, which is consistent with estimates of mutation rates of autosomal DNA (10−8 per base per generation[147]).

text: Dysfunction and disease

text: Mitochondrial diseases

text: Damage and subsequent dysfunction in mitochondria is an important factor in a range of human diseases due to their influence in cell metabolism. Mitochondrial disorders often present themselves as neurological disorders, including autism.[12] They can also manifest as myopathy, diabetes, multiple endocrinopathy, and a variety of other systemic disorders.[148] Diseases caused by mutation in the mtDNA include Kearns-Sayre syndrome, MELAS syndrome and Leber's hereditary optic neuropathy.[149] 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 syndrome, and progressive external ophthalmoplegia are thought to be due to large-scale mtDNA rearrangements, whereas other diseases such as MELAS syndrome, Leber's hereditary optic neuropathy, myoclonic epilepsy with ragged red fibers (MERRF), and others are due to point mutations in mtDNA.[148]

text: 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.[150] 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.[148] Environmental influences may 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.[151][152] Other pathologies with etiology involving mitochondrial dysfunction include schizophrenia, bipolar disorder, dementia, Alzheimer's disease,[153] Parkinson's disease, epilepsy, stroke, cardiovascular disease, chronic fatigue syndrome, retinitis pigmentosa, and diabetes mellitus.[154][155]

text: Mitochondria-mediated oxidative stress plays a role in cardiomyopathy in Type 2 diabetics. Increased fatty acid delivery to the heart increases fatty acid uptake by cardiomyocytes, resulting in increased fatty acid oxidation in these cells. This process increases the reducing equivalents available to the electron transport chain of the mitochondria, ultimately increasing reactive oxygen species (ROS) production. ROS increases uncoupling proteins (UCPs) and potentiate proton leakage through the adenine nucleotide translocator (ANT), the combination of which uncouples the mitochondria. Uncoupling then increases oxygen consumption by the mitochondria, compounding the increase in fatty acid oxidation. This creates a vicious cycle of uncoupling; furthermore, even though oxygen consumption increases, ATP synthesis does not increase proportionally because the mitochondria is uncoupled. Less ATP availability ultimately results in an energy deficit presenting as reduced cardiac efficiency and contractile dysfunction. To compound the problem, impaired sarcoplasmic reticulum calcium release and reduced mitochondrial reuptake limits peak cytosolic levels of the important signaling ion during muscle contraction. The decreased intra-mitochondrial calcium concentration increases dehydrogenase activation and ATP synthesis. So in addition to lower ATP synthesis due to fatty acid oxidation, ATP synthesis is impaired by poor calcium signaling as well, causing cardiac problems for diabetics.[156]

text: Possible relationships to aging

text: 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 was thought to result in significant oxidative stress in the mitochondria with high mutation rates of mitochondrial DNA (mtDNA).[157] Hypothesized links between aging and oxidative stress are not new and were proposed in 1956,[158] which was later refined into the mitochondrial free radical theory of aging.[159] A vicious cycle was thought to occur, as oxidative stress leads to mitochondrial DNA mutations, which can lead to enzymatic abnormalities and further oxidative stress.

text: A number of changes can occur to mitochondria during the aging process.[160] Tissues from elderly patients show a decrease in enzymatic activity of the proteins of the respiratory chain.[161] However, mutated mtDNA can only be found in about 0.2% of very old cells.[162] Large deletions in the mitochondrial genome have been hypothesized to lead to high levels of oxidative stress and neuronal death in Parkinson's disease.[163]

text: In popular culture

text: Madeleine L'Engle's 1973 science fantasy novel A Wind in the Door prominently features the mitochondria of main character Charles Wallace Murry, as being inhabited by creatures known as the farandolae. The novel also features other characters travelling inside one of Murry's mitochondria.

text: The 1995 horror fiction novel Parasite Eve by Hideaki Sena depicts mitochondria as having some consciousness and mind control abilities, attempting to use these to overtake eukaryotes as the dominant life form. This text was adapted into an eponymous film, video game, and video game sequel all involving a similar premise.

text: In the Star Wars franchise, microorganisms referred to as "midi-chlorians" give some characters the ability to sense and use the Force. George Lucas, director of the 1999 film Star Wars: Episode I – The Phantom Menace, in which midi-chlorians were introduced, described them as "a loose depiction of mitochondria".[164] The non-fictional Midichloria genus of bacteria was later named after the midi-chlorians of Star Wars.

text: As a result of the mitochondrion's prominence in modern science education, the phrase "mitochondria is [sic] the powerhouse of the cell" became a popular Internet meme.[165] The meme is used to imply that secondary education places an insufficient focus on life skills, compared to academic knowledge such as the role of the mitochondrion, which has been considered comparatively impractical.[166]


document_title: Neuromuscular junction

question_text: which component of the neuromuscular (myoneural) junction is considered the presynaptic membrane

question_tokens: which component of the neuromuscular ( myoneural ) junction is considered the presynaptic membrane

root

text: Neuromuscular junction

text: Structure and function[edit]

text: The neuromuscular junction differs from chemical synapses between neurons. Presynaptic motor axons stop 30 nanometers from the sarcolemma, the cell membrane of a muscle cell. This 30-nanometer space forms the synaptic cleft through which signalling molecules are released. The sarcolemma has invaginations called postjunctional folds, which increase the surface area of the membrane exposed to the synaptic cleft.[2] These postjunctional folds form what is referred to as the motor endplate, which possess nicotinic acetylcholine receptors (nAChRs) at a density of 10,000 receptors/micrometer2 in skeletal muscle.[3] The presynaptic axons form bulges called terminal boutons (or presynaptic terminals) that project into the postjunctional folds of the sarcolemma. The presynaptic terminals have active zones that contain vesicles, also called quanta, full of acetylcholine molecules. These vesicles can fuse with the presynaptic membrane and release ACh molecules into the synaptic cleft via exocytosis after depolarization.[2] AChRs are localized opposite the presynaptic terminals by protein scaffolds at the postjunctional folds of the sarcolemma. Dystrophin, a structural protein, connects the sarcomere, sarcolemma, and extracellular matrix components. Rapsyn is another protein that docks AChRs and structural proteins to the cytoskeleton. Also present is the receptor tyrosine kinase protein MuSK, a signaling protein involved in the development of the neuromuscular junction, which is also held in place by rapsyn.[2]

tag: p

text: Mechanism of action[edit]

text: The neuromuscular junction is where a neuron activates a muscle to contract. Upon the arrival of an action potential at the presynaptic neuron terminal, voltage-dependent calcium channels open and Ca2+ ions flow from the extracellular fluid into the presynaptic neuron's cytosol. This influx of Ca2+ causes neurotransmitter-containing vesicles to dock and fuse to the presynaptic neuron's cell membrane through SNARE proteins. Fusion of the vesicular membrane with the presynaptic cell membrane results in the emptying of the vesicle's contents (acetylcholine) into the synaptic cleft, a process known as exocytosis. Acetylcholine diffuses into the synaptic cleft and can bind to the nicotinic acetylcholine receptors on the motor endplate, causing calcium ions to flow into the muscle cell, initiating a sequence of steps that finally produce muscle contraction.

text: Acetylcholine receptors[edit]

text:
Ion channel linked receptor
Ions
Ligand (such as acetylcholine)

tag: ol

text: Acetylcholine is a neurotransmitter synthesized from dietary choline and acetyl-CoA (ACoA), and is involved in the stimulation of muscle tissue in vertebrates as well as in some invertebrate animals. In vertebrate animals, the acetylcholine receptor subtype that is found at the neuromuscular junction of skeletal muscles is the nicotinic acetylcholine receptor (nAChR), which is a ligand-gated ion channel. Each subunit of this receptor has a characteristic "cys-loop", which is composed of a cysteine residue followed by 13 amino acid residues and another cysteine residue. The two cysteine residues form a disulfide linkage which results in the "cys-loop" receptor that is capable of binding acetylcholine and other ligands. These cys-loop receptors are found only in eukaryotes, but prokaryotes possess ACh receptors with similar properties.[3] Not all species use a cholinergic neuromuscular junction; e.g. crayfish and fruit flies have a glutamatergic neuromuscular junction.[2]

text: AChRs at the skeletal neuromuscular junction form heteropentamers composed of two α, one β, one ɛ, and one δ subunits.[4] When a single ACh ligand binds to one of the α subunits of the ACh receptor it induces a conformational change at the interface with the second AChR α subunit. This conformational change results in the increased affinity of the second α subunit for a second ACh ligand. AChRs therefore exhibit a sigmoidal dissociation curve due to this cooperative binding.[3] The presence of the inactive, intermediate receptor structure with a single-bound ligand keeps ACh in the synapse that might otherwise be lost by cholinesterase hydrolysis or diffusion. The persistence of these ACh ligands in the synapse can cause a prolonged post-synaptic response.[5]

text: Development[edit]

text: The development of the neuromuscular junction requires signaling from both the motor neuron's terminal and the muscle cell's central region. During development, muscle cells produce acetylcholine receptors (AChRs) and express them in the central regions in a process called prepatterning. Agrin, a heparin proteoglycan, and MuSK kinase are thought to help stabilize the accumulation of AChR in the central regions of the myocyte. MuSK is a receptor tyrosine kinase—meaning that it induces cellular signaling by binding phosphate molecules to self regions like tyrosines, and to other targets in the cytoplasm.[6] Upon activation by its ligand agrin, MuSK signals via two proteins called "Dok-7" and "rapsyn", to induce "clustering" of acetylcholine receptors.[7] ACh release by developing motor neurons produces postsynaptic potentials in the muscle cell that positively reinforces the localization and stabilization of the developing neuromuscular junction.[8]

text: These findings were demonstrated in part by mouse "knockout" studies. In mice which are deficient for either agrin or MuSK, the neuromuscular junction does not form. Further, mice deficient in Dok-7 did not form either acetylcholine receptor clusters or neuromuscular synapses.[9]

text: The development of neuromuscular junctions is mostly studied in model organisms, such as rodents. In addition, in 2015 an all-human neuromuscular junction has been created in vitro using human embryonic stem cells and somatic muscle stem cells.[10] In this model presynaptic motor neurons are activated by optogenetics and in response synaptically connected muscle fibers twitch upon light stimulation.

text: Research methods[edit]

text: José del Castillo and Bernard Katz used ionophoresis to determine the location and density of nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction. With this technique, a microelectrode was placed inside the motor endplate of the muscle fiber, and a micropipette filled with acetylcholine (ACh) is placed directly in front of the endplate in the synaptic cleft. A positive voltage was applied to the tip of the micropipette, which caused a burst of positively charged ACh molecules to be released from the pipette. These ligands flowed into the space representing the synaptic cleft and bound to AChRs. The intracellular microelectrode monitored the amplitude of the depolarization of the motor endplate in response to ACh binding to nicotinic (ionotropic) receptors. Katz and del Castillo showed that the amplitude of the depolarization (excitatory postsynaptic potential) depended on the proximity of the micropipette releasing the ACh ions to the endplate. The farther the micropipette was from the motor endplate, the smaller the depolarization was in the muscle fiber. This allowed the researchers to determine that the nicotinic receptors were localized to the motor endplate in high density.[2][3]

text: Toxins are also used to determine the location of acetylcholine receptors at the neuromuscular junction. α-Bungarotoxin is a toxin found in the snake species Bungarus multicinctus that acts as an ACh antagonist and binds to AChRs irreversibly. By coupling assayable enzymes such as horseradish peroxidase (HRP) or fluorescent proteins such as green fluorescent protein (GFP) to the α-bungarotoxin, AChRs can be visualized and quantified.[2]

text: Toxins that affect the neuromuscular junction[edit]

text: Nerve gases[edit]

text: Nerve gases and liquor damage this area.

text: Botulinum toxin[edit]

text: Botulinum toxin (aka botulinum neurotoxin, BoNT, and sold under the trade name Botox) inhibits the release of acetylcholine at the neuromuscular junction by interfering with SNARE proteins.[2] This toxin crosses into the nerve terminal through the process of endocytosis and subsequently interferes with SNARE proteins, which are necessary for ACh release. By doing so, it induces a transient flaccid paralysis and chemical denervation localized to the striated muscle that it has affected. The inhibition of the ACh release does not set in until approximately two weeks after the injection is made. Three months after the inhibition occurs, neuronal activity begins to regain partial function, and six months, complete neuronal function is regained.[11]

text: Tetanus toxin[edit]

text: Tetanus toxin, also known as tetanospasmin is a potent neurotoxin produced by Clostridium tetani and causes the disease state, tetanus. The LD50 of this toxin has been measured to be approximately 1 ng/kg, making it second only to Botulinum toxin D as the deadliest toxin in the world. It functions very similarly to botunlinum neurotoxin (BoNT) by attaching and endocytosing into the presynaptic nerve terminal and interfering with SNARE protein complexes. It differs from BoNT in a few ways, most apparently in its end state, wherein tetanospasmin demonstrates a rigid / spastic paralysis as opposed to the flaccid paralysis demonstrated with BoNT.

text: Latrotoxin[edit]

text: Latrotoxin (α-Latrotoxin) found in venom of widow spiders also affects the neuromuscular junction by causing the release of acetylcholine from the presynaptic cell. Mechanisms of action include binding to receptors on the presynaptic cell activating the IP3/DAG pathway and release of calcium from intracellular stores and pore formation resulting in influx of calcium ions directly. Either mechanism causes increased calcium in presynaptic cell, which then leads to release of synaptic vesicles of acetylcholine. Latrotoxin causes pain, muscle contraction and if untreated potentially paralysis and death.

text: Snake venom[edit]

text: Snake venoms act as toxins at the neuromuscular junction and can induce weakness and paralysis. Venoms can act as both presynaptic and postsynaptic neurotoxins.[12]

text: Presynaptic neurotoxins, commonly known as β-neurotoxins, affect the presynaptic regions of the neuromuscular junction. The majority of these neurotoxins act by inhibiting the release of neurotransmitters, such as acetylcholine, into the synapse between neurons. However, some of these toxins have also been known to enhance neurotransmitter release. Those that inhibit neurotransmitter release create a neuromuscular blockade that prevents signaling molecules from reaching their postsynaptic target receptors. In doing so, the victim of these snake bite suffer from profound weakness. Such neurotoxins do not respond well to anti-venoms. After one hour of inoculation of these toxins, including notexin and taipoxin, many of the affected nerve terminals show signs of irreversible physical damage, leaving them devoid of any synaptic vesicles.[12]

text: Postsynaptic neurotoxins, otherwise known as α-neurotoxins, act oppositely to the presynaptic neurotoxins by binding to the postsynaptic acetylcholine receptors. This prevents interaction between the acetylcholine released by the presynaptic terminal and the receptors on the postsynaptic cell. In effect, the opening of sodium channels associated with these acetylcholine receptors is prohibited, resulting in a neuromuscular blockade, similar to the effects seen due to presynaptic neurotoxins. This causes paralysis in the muscles involved in the affected junctions. Unlike presynaptic neurotoxins, postsynaptic toxins are more easily affected by anti-venoms, which accelerate the dissociation of the toxin from the receptors, ultimately causing a reversal of paralysis. These neurotoxins experimentally and qualitatively aid in the study of acetylcholine receptor density and turnover, as well as in studies observing the direction of antibodies toward the affected acetylcholine receptors in patients diagnosed with myasthenia gravis.[12]

text: Diseases[edit]

text: Any disorder that compromises the synaptic transmission between a motor neuron and a muscle cell is categorized under the umbrella term of neuromuscular diseases. These disorders can be inherited or acquired and can vary in their severity and mortality. In general, most of these disorders tend to be caused by mutations or autoimmune disorders. Autoimmune disorders, in the case of neuromuscular diseases, tend to be humoral mediated, B cell mediated, and result in an antibody improperly created against a motor neuron or muscle fiber protein that interferes with synaptic transmission or signaling.

text: Autoimmune[edit]

text: Myasthenia gravis[edit]

text: Myasthenia gravis is an autoimmune disorder where the body makes antibodies against either the acetylcholine receptor (AchR) (in 80% of cases), or against postsynaptic muscle-specific kinase (MuSK) (0–10% of cases). In seronegative myasthenia gravis low density lipoprotein receptor-related protein 4 is targeted by IgG1, which acts as a competitive inhibitor of its ligand, preventing the ligand from binding its receptor. It is not known if seronegative myasthenia gravis will respond to standard therapies.[13]

text: Neonatal MG[edit]

text: Neonatal MG is an autoimmune disorder that affects 1 in 8 children born to mothers who have been diagnosed with myasthenia gravis (MG). MG can be transferred from the mother to the fetus by the movement of AChR antibodies through the placenta. Signs of this disease at birth include weakness, which responds to anticholinesterase medications, as well as fetal akinesia, or the lack of fetal movement. This form of the disease is transient, lasting for about three months. However, in some cases, neonatal MG can lead to other health effects, such as arthrogryposis and even fetal death. These conditions are thought to be initiated when maternal AChR antibodies are directed to the fetal AChR and can last until the 33rd week of gestation, when the γ subunit of AChR is replaced by the ε subunit.[14]

text: Lambert-Eaton myasthenic syndrome[edit]

text: Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder that affects the presynaptic portion of the neuromuscular junction. This rare disease can be marked by a unique triad of symptoms: proximal muscle weakness, autonomic dysfunction, and areflexia.[15] Proximal muscle weakness is a product of pathogenic autoantibodies directed against P/Q-type voltage-gated calcium channels, which in turn leads to a reduction of acetylcholine release from motor nerve terminals on the presynaptic cell. Examples of autonomic dysfunction caused by LEMS include erectile dysfunction in men, constipation, and, most commonly, dry mouth. Less common dysfunctions include dry eyes and altered perspiration. Areflexia is a condition in which tendon reflexes are reduced and it may subside temporarily after a period of exercise.[16]

text: 50–60% of the patients that are diagnosed with LEMS also have present an associated tumor, which is typically small-cell lung carcinoma (SCLC). This type of tumor also expresses voltage-gated calcium channels.[16] Oftentimes, LEMS also occurs alongside myasthenia gravis.[15]

text: Treatment for LEMS consists of using 3,4-diaminopyridine as a first measure, which serves to increase the compound muscle action potential as well as muscle strength by lengthening the time that voltage-gated calcium channels remain open after blocking voltage-gated potassium channels. In the US, treatment with 3,4-diaminopyridine for eligible LEMS patients is available at no cost under an expanded access program.[17][18] Further treatment includes the use of prednisone and azathioprine in the event that 3,4-diaminopyridine does not aid in treatment.[16]

text: Neuromyotonia[edit]

text: Neuromyotonia (NMT), otherwise known as Isaac’s syndrome, is unlike many other diseases present at the neuromuscular junction. Rather than causing muscle weakness, NMT leads to the hyperexcitation of motor nerves. NMT causes this hyperexcitation by producing longer depolarizations by down-regulating voltage-gated potassium channels, which causes greater neurotransmitter release and repetitive firing. This increase in rate of firing leads to more active transmission and as a result, greater muscular activity in the affected individual. NMT is also believed to be of autoimmune origin due to its associations with autoimmune symptoms in the individual affected.[14]

text: Genetic[edit]

text: Congenital myasthenic syndromes[edit]

text: Congenital myasthenic syndromes (CMS) are very similar to both MG and LEMS in their functions, but the primary difference between CMS and those diseases is that CMS is of genetic origins. Specifically, these syndromes are diseases incurred due to mutations, typically recessive, in 1 of at least 10 genes that affect presynaptic, synaptic, and postsynaptic proteins in the neuromuscular junction. Such mutations usually arise in the ε-subunit of AChR,[14] thereby affecting the kinetics and expression of the receptor itself. Single nucleotide substitutions or deletions may cause loss of function in the subunit. Other mutations, such as those affecting acetylcholinesterase and acetyltransferase, can also cause the expression of CMS, with the latter being associated specifically with episodic apnea.[19] These syndromes can present themselves at different times within the life of an individual. They may arise during the fetal phase, causing fetal akinesia, or the perinatal period, during which certain conditions, such as arthrogryposis, ptosis, hypotonia, ophthalmoplegia, and feeding or breathing difficulties, may be observed. They could also activate during adolescence or adult years, causing the individual to develop slow-channel syndrome.[14]

text: Treatment for particular subtypes of CMS (postsynaptic fast-channel CMS)[20][21] is similar to treatment for other neuromuscular disorders. 3,4-Diaminopyridine, the first-line treatment for LEMS, is under development as an orphan drug for CMS[22] in the US, and available to eligible patients under an expanded access program at no cost.[17][18]

text: Bulbospinal muscular atrophy[edit]

text: Bulbospinal muscular atrophy, also known as Kennedy’s disease, is a rare recessive trinucleotide, polyglutamine disorder that is linked to the X chromosome. Because of its linkage to the X chromosome, it is typically transmitted through females. However, Kennedy’s disease is only present in adult males and the onset of the disease is typically later in life. This disease is specifically caused by the expansion of a CAG-tandem repeat in exon 1 found on the androgen-receptor (AR) gene on chromosome Xq11-12. Poly-Q-expanded AR accumulates in the nuclei of cells, where it begins to fragment. After fragmentation, degradation of the cell begins, leading to a loss of both motor neurons and dorsal root ganglia.[23]

text: Symptoms of Kennedy’s disease include weakness and wasting of the facial bulbar and extremity muscles, as well as sensory and endocrinological disturbances, such as gynecomastia and reduced fertility. Other symptoms include elevated testosterone and other sexual hormone levels, development of hyper-CK-emia, abnormal conduction through motor and sensory nerves, and neuropathic or in rare cases myopathic alterations on biopsies of muscle cells.[23]

text: Duchenne muscular dystrophy[edit]

text: Duchenne muscular dystrophy is an X-linked genetic disorder that results in the absence of the structural protein dystrophin at the neuromuscular junction. It affects 1 in 3,600–6,000 males and frequently causes death by the age of 30. The absence of dystrophin causes muscle degeneration, and patients present with the following symptoms: abnormal gait, hypertrophy in the calf muscles, and elevated creatine kinase. If left untreated, patients may suffer from respiratory distress, which can lead to death.[24]


document_title: Vehicle identification number

question_text: what year is c in a vin number

question_tokens: what year is c in a vin number

text: Vehicle identification number

text: Classification[edit]

text: There are at least four competing standards used to calculate the VIN.

text:
FMVSS 115, Part 565: Used in United States and Canada[2]
ISO Standard 3779: Used in Europe and many other parts of the world
SAE J853: Very similar to the ISO standard
ADR 61/2 used in Australia, referring to ISO 3779 and 3780[3]

tag: ul

text: Components[edit]

text: Modern VINs are based on two related standards, originally issued by the International Organization for Standardization (ISO) in 1979 and 1980: ISO 3779[4] and ISO 3780,[5] respectively. Compatible but different implementations of these ISO standards have been adopted by the European Union and the United States, respectively.[6]

text: The VIN comprises the following sections:

text:
Standard
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17

ISO 3779
World manufacturer identifier
VDS
VIS

European Union[7]
more than 500 vehicles/year

World manufacturer identifier
Indication of "the general characteristics of the vehicle"
Indication that provides "clear identification of a particular vehicle"

European Union[7]
500 or fewer vehicles/year

World manufacturer identifier
9
Indication of "the general characteristics of the vehicle"
Indication that provides "clear identification of a particular vehicle"

North America
more than 2000 vehicles/year

World manufacturer identifier
Vehicle attributes
Check digit
Model year
Plant code
Sequential number

North America
2000 or fewer vehicles/year

World manufacturer identifier
9
Vehicle attributes
Check digit
Model year
Plant code
Manufacturer identifier
Sequential number

tag: table

text: World manufacturer identifier[edit]

text: The first three characters uniquely identify the manufacturer of the vehicle using the world manufacturer identifier or WMI code. A manufacturer who builds fewer than 1000 vehicles per year uses a 9 as the third digit, and the 12th, 13th and 14th position of the VIN for a second part of the identification. Some manufacturers use the third character as a code for a vehicle category (e.g., bus or truck), a division within a manufacturer, or both. For example, within 1G (assigned to General Motors in the United States), 1G1 represents Chevrolet passenger cars; 1G2, Pontiac passenger cars; and 1GC, Chevrolet trucks.

text: The Society of Automotive Engineers (SAE) in the U.S. assigns WMIs to countries and manufacturers.[8]

text: The first character of the WMI is the region in which the manufacturer is located. In practice, each is assigned to a country of manufacture, although in Europe the country where the continental headquarters is located can assign the WMI to all vehicles produced in that region (Example: Opel/Vauxhall cars whether produced in Germany, Spain, the United Kingdom or Poland carry a WMI of W0L because Adam Opel AG is based in Rüsselsheim, Germany).

text: In the notation below, assume that letters precede numbers and that zero is the last number. For example, 8X–82 denotes the range 8X, 8Y, 8Z, 81, 82, excluding 80. [8]

text: Country codes[edit]

text:
A–H = Africa
J–R = Asia
S–Z = Europe
1–5 = North America
6–7 = Oceania
8–9 = South America

AA-AH South Africa
AJ-AN Ivory Coast
AP-A0 not assigned
BA-BE Angola
BF-BK Kenya
BL-BR Tanzania
BS-B0 not assigned
CA-CE Benin
CF-CK Madagascar
CL-CR Tunisia
CS-C0 not assigned
DA-DE Egypt
DF-DK Morocco
DL-DR Zambia
DS-D0 not assigned
EA-EE Ethiopia
EF-EK Mozambique
EL-E0 not assigned
FA-FE Ghana
FF-FK Nigeria
FL-F0 not assigned
GA-G0 not assigned
HA-H0 not assigned

JA-J0 Japan
KA-KE Sri Lanka
KF-KK Israel
KL-KR Korea (South)
KS-K0 Kazakhstan
LA-L0 China
MA-ME India
MF-MK Indonesia
ML-MR Thailand
MS-M0 not assigned
NA-NE Iran
NF-NK Pakistan
NL-NR Turkey
NS-N0 not assigned
PA-PE Philippines
PF-PK Singapore
PL-PR Malaysia
PS-P0 not assigned
RA-RE United Arab Emirates
RF-RK Taiwan
RL-RR Vietnam
RS-R0 Saudi Arabia

SA-SM United Kingdom
SN-ST East Germany
SU-SZ Poland
S1-S4 Latvia
S5-S0 not assigned
TA-TH Switzerland
TJ-TP Czech Republic
TR-TV Hungary
TW-T1 Portugal
T2-T0 not assigned
UA-UG not assigned
UH-UM Denmark
UN-UT Ireland
UU-UZ Romania
U1-U4 not assigned
U5-U7 Slovakia
U8-U0 not assigned
VA-VE Austria
VF-VR France
VS-VW Spain
VX-V2 Serbia
V3-V5 Croatia
V6-V0 Estonia
WA-W0 West Germany
XA-XE Bulgaria
XF-XK Greece
XL-XR Netherlands
XS-XW USSR
XX-X2 Luxembourg
X3-X0 Russia
YA-YE Belgium
YF-YK Finland
YL-YR Malta
YS-YW Sweden
YX-Y2 Norway
Y3-Y5 Belarus
Y6-Y0 Ukraine
ZA-ZR Italy
ZS-ZW not assigned
ZX-Z2 Slovenia
Z3-Z5 Lithuania
Z6-Z0 not assigned

1A-10 United States
2A-20 Canada
3A-37 Mexico
38-39 Cayman Islands
4A-40 United States
5A-50 United States

6A-6W Australia
6X-60 not assigned
7A-7E New Zealand
7F-70 not assigned

8A-8E Argentina
8F-8K Chile
8L-8R Ecuador
8S-8W Peru
8X-82 Venezuela
83-80 not assigned
9A-9E Brazil
9F-9K Colombia
9L-9R Paraguay
9S-9W Uruguay
9X-92 Trinidad & Tobago
93–99 Brazil
90 not assigned

text: Vehicle descriptor section[edit]

text: The fourth to eighth positions in the VIN are the vehicle descriptor section or VDS. This is used, according to local regulations, to identify the vehicle type, and may include information on the automobile platform used, the model, and the body style. Each manufacturer has a unique system for using this field. Most manufacturers since the 1980s have used the eighth digit to identify the engine type whenever there is more than one engine choice for the vehicle. Example: for the 2007 Chevrolet Corvette, U is for a 6.0-liter V8 engine, and E is for a 7.0 L V8.

text: North American check digits[edit]

text: One element that is fairly consistent is the use of position nine as a check digit, compulsory for vehicles in North America, and used fairly consistently elsewhere.

text: Vehicle identifier section[edit]

text: The 10th to 17th positions are used as the 'vehicle identifier section' (VIS). This is used by the manufacturer to identify the individual vehicle in question. This may include information on options installed or engine and transmission choices, but often is a simple sequential number. In North America, the last five digits must be numeric.

text: Model year encoding[edit]

text: One consistent element of the VIS is the 10th digit, which is required worldwide to encode the model year of the vehicle. Besides the three letters that are not allowed in the VIN itself (I, O and Q), the letters U and Z and the digit 0 are not used for the model year code. The year code is the model year for the vehicle.

text: The year 1980 was encoded by some manufacturers, especially General Motors and Chrysler, as "A" (since the 17-digit VIN was not mandatory until 1981, and the "A" or zero was in the manufacturer's pre-1981 placement in the VIN), yet Ford and AMC still used a zero for 1980. Subsequent years increment through the allowed letters, so that "Y" represents the year 2000. 2001 to 2009 are encoded as the digits 1 to 9, and subsequent years are encoded as "A", "B", "C", etc.

text:
Code
Year

Code
Year

Code
Year

Code
Year

Code
Year

Code
Year

A =
1980

L =
1990

Y =
2000

A =
2010

L =
2020

Y =
2030

B =
1981

M =
1991

1 =
2001

B =
2011

M =
2021

1 =
2031

C =
1982

N =
1992

2 =
2002

C =
2012

N =
2022

2 =
2032

D =
1983

P =
1993

3 =
2003

D =
2013

P =
2023

3 =
2033

E =
1984

R =
1994

4 =
2004

E =
2014

R =
2024

4 =
2034

F =
1985

S =
1995

5 =
2005

F =
2015

S =
2025

5 =
2035

G =
1986

T =
1996

6 =
2006

G =
2016

T =
2026

6 =
2036

H =
1987

V =
1997

7 =
2007

H =
2017

V =
2027

7 =
2037

J =
1988

W =
1998

8 =
2008

J =
2018

W =
2028

8 =
2038

K =
1989

X =
1999

9 =
2009

K =
2019

X =
2029

9 =
2039

text: On April 30, 2008, the US National Highway Traffic Safety Administration adopted a final rule amending 49 CFR Part 565, "so that the current 17 character vehicle identification number (VIN) system, which has been in place for almost 30 years, can continue in use for at least another 30 years", in the process making several changes to the VIN requirements applicable to all motor vehicles manufactured for sale in the United States. There are three notable changes to the VIN structure that affect VIN deciphering systems:

text:
The make may only be identified after looking at positions one through three and another position, as determined by the manufacturer in the second section or fourth to eighth segment of the VIN.
In order to identify the exact year in passenger cars and multipurpose passenger vehicles with a GVWR of 10,000 or less, one must read position 7 as well as position 10. For passenger cars, and for multipurpose passenger vehicles and trucks with a gross vehicle weight rating of 10,000 lb (4,500 kg) or less, if position seven is numeric, the model year in position 10 of the VIN refers to a year in the range 1980–2009.[citation needed] If position seven is alphabetic, the model year in position 10 of VIN refers to a year in the range 2010–2039.
The model year for vehicles with a GVWR greater than 10,000 lb (4,500 kg), as well as buses, motorcycles, trailers and low-speed vehicles, may no longer be identified within a 30-year range. VIN characters 1–8 and 10 that were assigned from 1980–2009 can be repeated beginning with the 2010 model year.

text: Plant code[edit]

text: Compulsory in North America is the use of the 11th character to identify the factory at which the vehicle was built. Each manufacturer has its own set of plant codes.

text: Production number[edit]

text: In the United States, the 12th to 17th digits are the vehicle's serial or production number. This is unique to each vehicle, and every manufacturer uses its own sequence.

text: Check-digit calculation[edit]

text: Check-digit validation is compulsory for all road vehicles sold in North America.

text: When trying to validate a VIN with a check digit, first either (a) remove the check digit for the purpose of calculation or (b) use a weight of zero (see below) to cancel it out. The original value of the check digit is then compared with the calculated value. If the calculated value is 0–9, the check digit must match the calculated value. If the calculated value is 10, the check digit must be X. If the two values do not match (and there was no error in the calculation), then there is a mistake in the VIN. However, a match does not prove the VIN is correct, because there is still a 1/11 chance that any two distinct VINs have a matching check digit: for example, the valid VINs 5GZCZ43D13S812715 (correct with leading five) and SGZCZ43D13S812715 (incorrect with leading character "S"). The VINs in the Porsche image, WP0ZZZ99ZTS392124, and the GM-T body image, KLATF08Y1VB363636, do not pass the North American check-digit verification.

text: Transliterating the numbers[edit]

text: Transliteration consists of removing all of the letters, and substituting them with their appropriate numerical counterparts. These numerical alternatives (based on IBM's EBCDIC) are in the following chart. I, O, and Q are not allowed in a valid VIN; for this chart, they have been filled in with N/A (not applicable). Numerical digits use their own values.

text:
Transliteration key: values for VIN decoding

A: 1
B: 2
C: 3
D: 4
E: 5
F: 6
G: 7
H: 8
N/A

J: 1
K: 2
L: 3
M: 4
N: 5
N/A
P: 7
N/A
R: 9

S: 2
T: 3
U: 4
V: 5
W: 6
X: 7
Y: 8
Z: 9

text: S is 2, and not 1. There is no left-alignment linearity.

text: Weights used in calculation[edit]

text: The following is the weight factor for each position in the VIN. The 9th position is that of the check digit. It has been substituted with a 0, which will cancel it out in the multiplication step.

text:
Weight factor table

Position
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17

Weight
8
7
6
5
4
3
2
10
0
9
8
7
6
5
4
3
2

text: Worked example[edit]

text: Consider the hypothetical VIN 1M8GDM9A_KP042788, where the underscore will be the check digit.

text:
VIN
1
M
8
G
D
M
9
A

K
P
0
4
2
7
8
8

Value
1
4
8
7
4
4
9
1
0
2
7
0
4
2
7
8
8

Weight
8
7
6
5
4
3
2
10
0
9
8
7
6
5
4
3
2

Products
8
28
48
35
16
12
18
10
0
18
56
0
24
10
28
24
16

text:
The VIN's value is calculated from the above transliteration table. This number is used in the rest of the calculation.
Copy the weights from the above weight factor table.
The products row is the result of the multiplication of the vertical columns: Value and Weight.
The products (8, 28, 48, 35 ... 24, 16) are all added together to yield a sum, 351.
Find the remainder after dividing by 11
351 MOD 11 = 10
351 ÷ 11 = 31 10/11
The remainder is the check digit. If the remainder is 10, the check digit is X. In this example, the remainder is 10, so the check digit is transliterated as X.

text: With a check digit of X, the VIN 1M8GDM9A_KP042788 is written 1M8GDM9AXKP042788.

text: A VIN with straight-ones (seventeen consecutive 1s) has the nice feature that its check digit 1 matches the calculated value 1. This is because a value of one multiplied by 89 (sum of weights) is 89, and 89 divided by 11 is 8 with remainder  1⁄11; thus 1 is the check digit. This is a way to test a VIN-check algorithm.

text: Example code[edit]

text: VIN scanning[edit]

text: VINs may be optically read with barcode scanners or digital cameras, or digitally read via OBD-II in newer vehicles. There are smartphone applications that can pass the VIN to websites to decode the VIN.

text: List of common WMI[edit]

text: The Society of Automotive Engineers (SAE) assigns the WMI (world manufacturer identifier) to countries and manufacturers. The following list shows a small selection of world manufacturer codes.

text:
WMI
Manufacturer

AAV (South Africa)
Volkswagen

AHT (South Africa)
Toyota

AFA (South Africa)
Ford

CL9 (Tunisia)
Wallyscar

JA (Japan)
Isuzu

JC1 (Japan)
Fiat Automobiles/Mazda

JF (Japan)
Fuji Heavy Industries

JHL (Japan)
Honda

JHM (Japan)
Honda

JMB (Japan)
Mitsubishi

JM6 (Japan)
Mazda

JN (Japan)
Nissan

JS (Japan)
Suzuki

JT (Japan)
Toyota

JY (Japan)
Yamaha

KL (South Korea)
Daewoo/GM Korea

KMH (South Korea)
Hyundai

KN (South Korea)
Kia

KPT (South Korea)
SsangYong

L6T (China)
Geely

LBE (China)
Beijing Hyundai

LBV (China)
BMW Brilliance

LDC (China)
Dongfeng Peugeot-Citroën

LE4 (China)
Beijing Benz

LFM (China)
FAW Toyota (Sichuan)

LFP (China)
FAW Car

LFV (China)
FAW-Volkswagen

LGB (China)
Dongfeng Nissan

LGJ (China)
Dongfeng Fengshen

LGW (China)
Great Wall (Havel)

LGX (China)
BYD Auto

LH1 (China)
FAW Haima

LHG (China)
Guangzhou Honda

LJ1 (China)
JAC

LJD (China)
Dongfeng Yueda Kia

LLV (China)
Lifan

LMG (China)
GAC Trumpchi

LPA (China)
Changan PSA (DS Automobiles)

LS5 (China)
Changan Suzuki

LSG (China)
SAIC General Motors

LSJ (China)
SAIC MG

LSV (China)
SAIC Volkswagen

LTV (China)
FAW Toyota (Tianjin)

LVG (China)
GAC Toyota

LVH (China)
Dongfeng Honda

LVR (China)
Changan Mazda

LVS (China)
Changan Ford

LVV (China)
Chery

LWV (China)
GAC Fiat

LZW (China)
SAIC GM Wuling

NMT (Turkey)
Toyota

NM0 (Turkey)
Ford Otosan

PL1 (Malaysia)
Proton

SAJ (United Kingdom)
Jaguar

SAL (United Kingdom)
Land Rover

SAR (United Kingdom)
Rover

SAT (United Kingdom)
Triumph

SB1 (United Kingdom)
Toyota

SCC (United Kingdom)
Lotus Cars

SCE (United Kingdom)
DeLorean

SFD (United Kingdom)
Alexander Dennis

SHH (United Kingdom)
Honda

SHS (United Kingdom)
Honda

SJN (United Kingdom)
Nissan

TCC (Switzerland)
Micro Compact Car AG (SMART 1998-1999)

TMA (Czech Republic)
Hyundai

TMB (Czech Republic)
Škoda

TRU (Hungary)
Audi

TSM (Hungary)
Suzuki

U5Y (Slovakia)
Kia

UU (Romania)
Dacia

VA0 (Austria)
ÖAF

VF1 (France)
Renault

VF2 (France)
Renault

VF3 (France)
Peugeot

VF4 (France)
Talbot

VF5 (France)
Iveco Unic SA

VF6 (France)
Renault Trucks/Volvo

VF7 (France)
Citroën

VF8 (France)
Matra/Talbot/Simca

VF9 (France)
Bugatti

VFE (France)
IvecoBus

VNK (France)
Toyota

VSS (Spain)
SEAT

VV9 (Spain)
Tauro Sport Auto

WAG (Germany)
Neoplan

WAU (Germany)
Audi

WAP (Germany)
Alpina

WBA (Germany)
BMW

WBS (Germany)
BMW M

WBX (Germany)
BMW

WDB (Germany)
Mercedes-Benz

WDC, WDD, WMX (Germany)
DaimlerChrysler AG/Daimler AG

WEB (Germany)
EvoBus

WF0 (Germany)
Ford of Europe

WJM (Germany)
Iveco

WJR (Germany)
Irmscher

WKK (Germany)
Karl Kässbohrer Fahrzeugwerke

WMA (Germany)
MAN

WME (Germany)
Smart

WMW (Germany)
Mini

WP0 (Germany)
Porsche car

WP1 (Germany)
Porsche SUV

WUA (Germany)
Quattro

WVG (Germany)
Volkswagen

WVW (Germany)
Volkswagen

WV1 (Germany)
Volkswagen Commercial Vehicles

WV2 (Germany)
Volkswagen Commercial Vehicles

W0L (Germany)
Opel/Vauxhall

W0SV (Germany)
Opel Special Vehicles

XLR (Netherlands)
DAF Trucks

YK1 (Finland)
Saab

YS2 (Sweden)
Scania, Södertälje

YS3 (Sweden)
Saab

YS4 (Sweden)
Scania, Katrineholm

YTN (Sweden)
Saab NEVS

YV1 (Sweden)
Volvo Cars

YV2 (Sweden)
Volvo Trucks

YV3 (Sweden)
Volvo Buses

ZA9 (Italy)
Bugatti

ZAM (Italy)
Maserati

ZAR (Italy)
Alfa Romeo

ZCF (Italy)
Iveco

ZFA (Italy)
Fiat Automobiles

ZFF (Italy)
Ferrari

ZGA (Italy)
IvecoBus

ZHW (Italy)
Lamborghini

ZLA (Italy)
Lancia

1B (United States)
Dodge

1C (United States)
Chrysler

1F (United States)
Ford

1G (United States)
General Motors

1G1 (United States)
Chevrolet

1G3 (United States)
Oldsmobile

1G9 (United States)
Google

1GC (United States)
Chevrolet

1GM (United States)
Pontiac

1HG (United States)
Honda

1J (United States)
Jeep

1L (United States)
Lincoln

1M (United States)
Mercury

1N (United States)
Nissan

1VW (United States)
Volkswagen

1YV (United States)
Mazda

2DG (Canada)
Ontario Drive & Gear

2F (Canada)
Ford

2G (Canada)
General Motors

2G1 (Canada)
Chevrolet

2G2 (Canada)
Pontiac

2HG (Canada)
Honda

2HH (Canada)
Acura

2HJ (Canada)
Honda

2HK (Canada)
Honda

2HM (Canada)
Hyundai

2M (Canada)
Mercury

2T (Canada)
Toyota

3F (Mexico)
Ford

3G (Mexico)
General Motors

3HG (Mexico)
Honda

3HM (Mexico)
Honda

3KP (Mexico)
Kia

3N (Mexico)
Nissan

3VW (Mexico)
Volkswagen

4F (United States)
Mazda

4J (United States)
Mercedes-Benz

4M (United States)
Mercury

4S3 (United States)
Subaru

4S4 (United States)
Subaru

4S6 (United States)
Honda

4T (United States)
Toyota

4US (United States)
BMW

5FN (United States)
Honda

5J6 (United States)
Honda

5L (United States)
Lincoln

5N (United States)
Hyundai

5T (United States)
Toyota

5X (United States)
Hyundai/Kia

5YJ (United States)
Tesla

55 (United States)
Mercedes-Benz

6F (Australia)
Ford

6G (Australia)
General Motors

6G1 (Australia)
Chevrolet

6G2 (Australia)
Pontiac

6H (Australia)
Holden

6MM (Australia)
Mitsubishi

6T1 (Australia)
Toyota

7A3 (New Zealand)
Honda

8AP (Argentina)
Fiat

8AF (Argentina)
Ford

8AG (Argentina)
General Motors

8AW (Argentina)
Volkswagen

8AJ (Argentina)
Toyota

8A1 (Argentina)
Renault

8AC (Argentina)
Mercedes Benz

8BC (Argentina)
Citroën

8AD (Argentina)
Peugeot

8C3 (Argentina)
Honda

8AT (Argentina)
Iveco

9BD (Brazil)
Fiat Automóveis

9BG (Brazil)
General Motors

9BW (Brazil)
Volkswagen

9BF (Brazil)
Ford

93H (Brazil)
Honda

9BR (Brazil)
Toyota

936 (Brazil)
Peugeot

935 (Brazil)
Citroën

93Y (Brazil)
Renault

93X (Brazil)
Souza Ramos - Mitsubishi / Suzuki

9BH (Brazil)
Hyundai Motor Company / Hyundai

95P (Brazil)
CAOA / Hyundai

94D (Brazil)
Nissan

98R (Brazil)
Chery

988 (Brazil)
Jeep

98M (Brazil)
BMW

9BM (Brazil)
Mercedes Benz

99A (Brazil)
Audi

99J (Brazil)
JLR Jaguar Land Rover

9C2 (Brazil)
Honda Motorcycles

9C6 (Brazil)
Yamaha

9CD (Brazil)
Suzuki Motorcycles

93W (Brazil)
Fiat Professional

93Z (Brazil)
Iveco

953 (Brazil)
VW Trucks / MAN

9BS (Brazil)
Scania

9BV (Brazil)
Volvo Trucks

9UJ (Uruguay)
Chery

9UK (Uruguay)
Lifan

9UW (Uruguay)
Kia