Mitochondrion

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Mitochondrion
Two mitochondria from mammalian lung tissue displaying their matrix and membranes as shown by electron microscopy
Diagram of animal mitochondrion
Details
Pronunciation	/ˌmaɪtəˈkɒndriən/
Part of	Cell
Identifiers
Latin	organella
MeSH	D008928
FMA	63835

Cell biology
Animal cell diagram
Components of a typical animal cell: Nucleolus Nucleus Ribosome (dots as part of 5) Vesicle Rough endoplasmic reticulum Golgi apparatus (or, Golgi body) Cytoskeleton Smooth endoplasmic reticulum Mitochondrion Vacuole Cytosol (fluid that contains organelles; with which, comprises cytoplasm) Lysosome Centrosome Cell membrane

A mitochondrion (pl. mitochondria) is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used throughout the cell as a source of chemical energy. They were discovered by Albert von Kölliker in 1857 in the voluntary muscles of insects. Meaning a thread-like granule, the term mitochondrion was coined by Carl Benda in 1898. The mitochondrion is popularly nicknamed the "powerhouse of the cell", a phrase popularized by Philip Siekevitz in a 1957 Scientific American article of the same name.

Some cells in some multicellular organisms lack mitochondria (for example, mature mammalian red blood cells). The multicellular animal Henneguya salminicola is known to have retained mitochondrion-related organelles despite a complete loss of their mitochondrial genome. A large number of unicellular organisms, such as microsporidia, parabasalids and diplomonads, have reduced or transformed their mitochondria into other structures, e.g. hydrogenosomes and mitosomes. The oxymonads Monocercomonoides, Streblomastix, and Blattamonas have completely lost their mitochondria.

Mitochondria are commonly between 0.75 and 3 μm² in cross section, but vary considerably in size and structure. Unless specifically stained, they are not visible. In addition to supplying cellular energy, mitochondria are involved in other tasks, such as signaling, cellular differentiation, and cell death, as well as maintaining control of the cell cycle and cell growth. Mitochondrial biogenesis is in turn temporally coordinated with these cellular processes. Mitochondria have been implicated in several human disorders and conditions, such as mitochondrial diseases, cardiac dysfunction, heart failure and autism.

The number of mitochondria in a cell can vary widely by organism, tissue, and cell type. A mature red blood cell has no mitochondria, whereas a liver cell can have more than 2000. The mitochondrion is composed of compartments that carry out specialized functions. These compartments or regions include the outer membrane, intermembrane space, inner membrane, cristae, and matrix.

Although most of a eukaryotic cell's DNA is contained in the cell nucleus, the mitochondrion has its own genome ("mitogenome") that is substantially similar to bacterial genomes. This finding has led to general acceptance of the endosymbiotic hypothesis - that free-living prokaryotic ancestors of modern mitochondria permanently fused with eukaryotic cells in the distant past, evolving such that modern animals, plants, fungi, and other eukaryotes are able to respire to generate cellular energy.

Structure

Cell biology
mitochondrion
Components of a typical mitochondrion 1 Outer membrane 1.1 Porin 2 Intermembrane space 2.1 Intracristal space 2.2 Peripheral space 3 Lamella 3.1 Inner membrane 3.11 Inner boundary membrane 3.12 Cristal membrane 3.2 Matrix 3.3 Cristæ 4 Mitochondrial DNA 5 Matrix granule 6 Ribosome 7 ATP synthase

Mitochondria may have a number of different shapes. A mitochondrion contains outer and inner membranes composed of phospholipid bilayers and proteins. The two membranes have different properties. Because of this double-membraned organization, there are five distinct parts to a mitochondrion:

1. The outer mitochondrial membrane,
2. The intermembrane space (the space between the outer and inner membranes),
3. The inner mitochondrial membrane,
4. The cristae space (formed by infoldings of the inner membrane), and
5. The matrix (space within the inner membrane), which is a fluid.

Mitochondria have folding to increase surface area, which in turn increases ATP (adenosine triphosphate) production. Mitochondria stripped of their outer membrane are called mitoplasts.

Outer membrane

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 cell membrane (about 1:1 by weight). It contains large numbers of integral membrane proteins called porins. A major trafficking protein is the pore-forming voltage-dependent anion channel (VDAC). The VDAC is the primary transporter of nucleotides, ions and metabolites between the cytosol and the intermembrane space. It is formed as a beta barrel that spans the outer membrane, similar to that in the gram-negative bacterial outer membrane. Larger proteins can enter the mitochondrion if a signaling sequence at their N-terminus binds to a large multisubunit protein called translocase in the outer membrane, which then actively moves them across the membrane. 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 cell death. The outer mitochondrial 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. Outside the outer membrane are small (diameter: 60 Å) particles named sub-units of Parson.

Intermembrane space

The mitochondrial 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. 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.

Inner membrane

Main article: Inner mitochondrial membrane

The inner mitochondrial membrane contains proteins with three types of functions:

1. Those that perform the electron transport chain redox reactions
2. ATP synthase, which generates ATP in the matrix
3. Specific transport proteins that regulate metabolite passage into and out of the mitochondrial matrix

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. Additionally, 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. Cardiolipin contains four fatty acids rather than two, and may help to make the inner membrane impermeable, and its disruption can lead to multiple clinical disorders including neurological disorders and cancer. Unlike the outer membrane, the inner membrane does not contain porins, and is highly impermeable to all molecules. Almost all ions and molecules require special membrane transporters to enter or exit the matrix. Proteins are ferried into the matrix via the translocase of the inner membrane (TIM) complex or via OXA1L. In addition, there is a membrane potential across the inner membrane, formed by the action of the enzymes of the electron transport chain. Inner membrane fusion is mediated by the inner membrane protein OPA1.

Cristae

Cross-sectional image of cristae in a rat liver mitochondrion to demonstrate the likely 3D structure and relationship to the inner membrane

Main article: Crista

The inner mitochondrial membrane is compartmentalized into numerous folds called 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 that of 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. Mitochondria within the same cell can have substantially different crista-density, with the ones that are required to produce more energy having much more crista-membrane surface. These folds are studded with small round bodies known as F₁ particles or oxysomes.

Matrix

Main article: Mitochondrial matrix

The matrix is the space enclosed by the inner membrane. It contains about 2/3 of the total proteins in a mitochondrion. 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. The DNA molecules are packaged into nucleoids by proteins, one of which is TFAM.

Function

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. The central set of reactions involved in ATP production are collectively known as the citric acid cycle, or the Krebs cycle, and oxidative phosphorylation. However, the mitochondrion has many other functions in addition to the production of ATP.

Energy conversion

A dominant role for the mitochondria is the production of 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. 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. The production of ATP from glucose and oxygen has an approximately 13-times higher yield during aerobic respiration compared to fermentation. Plant mitochondria can also produce a limited amount of ATP either by breaking the sugar produced during photosynthesis or without oxygen by using the alternate substrate nitrite. ATP crosses out through the inner membrane with the help of a specific protein, and across the outer membrane via porins. After conversion of ATP to ADP by dephosphorylation that releases energy, ADP returns via the same route.

Pyruvate and the citric acid cycle

Main article: Citric acid cycle

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, 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.

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.

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.

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, under the influence of high levels of glucagon and/or epinephrine in the blood. 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 to cytosolic oxaloacetate, and ultimately to glucose, in a process that is almost the reverse of glycolysis.

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. 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 (which is readily converted to an ATP).

O₂ and NADH: energy-releasing reactions

Main articles: Oxidative phosphorylation and electron transport chain

Electron transport chain in the mitochondrial intermembrane space

The electrons from NADH and FADH₂ are transferred to oxygen (O₂) and hydrogen (protons) in several steps via an electron transport chain. NADH and FADH₂ molecules are produced within the matrix via the citric acid cycle and in the cytoplasm by glycolysis. Reducing equivalents from the cytoplasm can be imported via the malate-aspartate shuttle system of antiporter proteins or fed into the electron transport chain using a glycerol phosphate shuttle.

The major energy-releasing reactions that make the mitochondrion the "powerhouse of the cell" occur at protein complexes I, III and IV in the inner mitochondrial membrane (NADH dehydrogenase (ubiquinone), cytochrome c reductase, and cytochrome c oxidase). At complex IV, O₂ reacts with the reduced form of iron in cytochrome c:

${\displaystyle {\text{O}}_2^{}+4{\text{H}}^{+}(\text{aq})+4{\text{Fe}}^{2+}(\text{cyt}\text{c})⟶2{\text{H}}_2^{}\text{O}+4{\text{Fe}}^{3+}(\text{cyt}\text{c})}$ ${\displaystyle {\mathrm{\Delta }}_r{G}^{o^{\prime }}=-218\text{ kJ/mol}}$

releasing a lot of free energy from the reactants without breaking bonds of an organic fuel. The free energy put in to remove an electron from Fe²⁺ is released at complex III when Fe³⁺ of cytochrome c reacts to oxidize ubiquinol (QH₂):

${\displaystyle 2{\text{Fe}}^{3+}(\text{cyt}\text{c})+{\text{QH}}_2^{}⟶2{\text{Fe}}^{2+}(\text{cyt}\text{c})+\text{Q}+2{\text{H}}^{+}(\text{aq})}$ ${\displaystyle {\mathrm{\Delta }}_r{G}^{o^{\prime }}=-30\text{ kJ/mol}}$

The ubiquinone (Q) generated reacts, in complex I, with NADH:

${\displaystyle \text{Q}+{\text{H}}^{+}(\text{aq})+\text{NADH}⟶{\text{QH}}_2^{}+{\text{NAD}}^{+}}$ ${\displaystyle {\mathrm{\Delta }}_r{G}^{o^{\prime }}=-81\text{ kJ/mol}}$

While the reactions are controlled by an electron transport chain, free electrons are not amongst the reactants or products in the three reactions shown and therefore do not affect the free energy released, which is used to pump protons (H⁺) into the intermembrane space. This process is efficient, but a small percentage of electrons may prematurely reduce oxygen, forming reactive oxygen species such as superoxide. This can cause oxidative stress in the mitochondria and may contribute to the decline in mitochondrial function associated with aging.

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 (P_i). This process is called chemiosmosis, and was first described by Peter Mitchell, who was awarded the 1978 Nobel Prize in Chemistry for his work. Later, part of the 1997 Nobel Prize in Chemistry was awarded to Paul D. Boyer and John E. Walker for their clarification of the working mechanism of ATP synthase.

Heat production

Under certain conditions, protons can re-enter the mitochondrial matrix without contributing to ATP synthesis. This process is known as proton leak or mitochondrial uncoupling and is due to the facilitated diffusion of protons into the matrix. The process results in the unharnessed potential energy of the proton electrochemical gradient being released as heat. The process is mediated by a proton channel called thermogenin, or UCP1. 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.

Mitochondrial fatty acid synthesis

Mitochondrial fatty acid synthesis (mtFASII) is essential for cellular respiration and mitochondrial biogenesis. It is also thought to play a role as a mediator in intracellular signaling due to its influence on the levels of bioactive lipids, such as lysophospholipids and sphingolipids.

Octanoyl-ACP (C8) is considered to be the most important end product of mtFASII, which also forms the starting substrate of lipoic acid biosynthesis. Since lipoic acid is the cofactor of important mitochondrial enzyme complexes, such as the pyruvate dehydrogenase complex (PDC), α-ketoglutarate dehydrogenase complex (OGDC), branched-chain α-ketoacid dehydrogenase complex (BCKDC), and in the glycine cleavage system (GCS), mtFASII has an influence on energy metabolism.

Other products of mtFASII play a role in the regulation of mitochondrial translation, FeS cluster biogenesis and assembly of oxidative phosphorylation complexes.

Furthermore, with the help of mtFASII and acylated ACP, acetyl-CoA regulates its consumption in mitochondria.

Uptake, storage and release of calcium ions

Transmission electron micrograph of a chondrocyte, stained for calcium, showing its nucleus (N) and mitochondria (M)

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. Their ability to rapidly take in calcium for later release makes them good "cytosolic buffers" for calcium. The endoplasmic reticulum (ER) is the most significant storage site of calcium, and there is a significant interplay between the mitochondrion and ER with regard to calcium. The calcium is taken up into the matrix by the mitochondrial calcium uniporter on the inner mitochondrial membrane. It is primarily driven by the mitochondrial membrane potential. 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. 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.

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. 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.

Cellular proliferation regulation

The relationship between cellular proliferation and mitochondria has been investigated. Tumor cells require ample ATP to synthesize bioactive compounds such as lipids, proteins, and nucleotides for rapid proliferation. The majority of ATP in tumor cells is generated via the oxidative phosphorylation pathway (OxPhos). Interference with OxPhos cause cell cycle arrest suggesting that mitochondria play a role in cell proliferation. Mitochondrial ATP production is also vital for cell division and differentiation in infection  in addition to basic functions in the cell including the regulation of cell volume, solute concentration, and cellular architecture. 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. ATP's role in the basic functions of the cell make the cell cycle sensitive to changes in the availability of mitochondrial derived ATP. 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. 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.

Programmed cell death and innate immunity

Further information: Programmed cell death § Intrinsic Pathway

Programmed cell death (PCD) is crucial for various physiological functions , including organ development and cellular homeostasis. It serves as an intrinsic mechanism to prevent malignant transformation and plays a fundamental role in immunity by aiding in antiviral defense, pathogen elimination, inflammation, and immune cell recruitment.

Mitochondria have long been recognized for their central role in the intrinsic pathway of apoptosis, a form of PCD. In recent decades, they have also been identified as a signalling hub for much of the innate immune system. The endosymbiotic origin of mitochondria distinguishes them from other cellular components, and the exposure of mitochondrial elements to the cytosol can trigger the same pathways as infection markers. These pathways lead to apoptosis, autophagy, or the induction of proinflammatory genes.

Mitochondria contribute to apoptosis by releasing cytochrome c, which directly induces the formation of apoptosomes. Additionally, they are a source of various damage-associated molecular patterns (DAMPs). These DAMPs are often recognised by the same pattern-recognition receptors (PRRs) that respond to pathogen-associated molecular patterns (PAMPs) during infections. For example, mitochondrial mtDNA resembles bacterial DNA due to its lack of CpG methylation and can be detected by Toll-like receptor 9 and cGAS. Double-stranded RNA (dsRNA), produced due to bidirectional mitochondrial transcription, can activate viral sensing pathways through RIG-I-like receptors. Additionally, the N-formylation of mitochondrial proteins, similar to that of bacterial proteins, can be recognized by formyl peptide receptors.

Normally, these mitochondrial components are sequestered from the rest of the cell but are released following mitochondrial membrane permeabilization during apoptosis or passively after mitochondrial damage. However, mitochondria also play an active role in innate immunity, releasing mtDNA in response to metabolic cues. Mitochondria are also the localization site for immune and apoptosis regulatory proteins, such as BAX, MAVS (located on the outer membrane), and NLRX1 (found in the matrix). These proteins are modulated by the mitochondrial metabolic status and mitochondrial dynamics.

Additional functions

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

• Signaling through mitochondrial reactive oxygen species
• Regulation of the membrane potential
• Calcium signaling (including calcium-evoked apoptosis)
• Regulation of cellular metabolism
• Certain heme synthesis reactions (see also: Porphyrin)
• Steroid synthesis
• Hormonal signaling – 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 and heart
• Development and function of immune cells
• Neuronal mitochondria also contribute to cellular quality control by reporting neuronal status towards microglia through specialised somatic-junctions.
• Mitochondria of developing neurons contribute to intercellular signaling towards microglia, which communication is indispensable for proper regulation of brain development.

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.

Mitochondrial proteins (proteins transcribed from mitochondrial DNA) vary depending on the tissue and the species. In humans, 615 distinct types of proteins have been identified from cardiac mitochondria, whereas in rats, 940 proteins have been reported. The mitochondrial proteome is thought to be dynamically regulated.

Organization and distribution

Typical mitochondrial network (green) in two human cells (HeLa cells)

Mitochondria (or related structures) are found in all eukaryotes (except the Oxymonad Monocercomonoides). 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. The population of all the mitochondria of a given cell constitutes the chondriome. Mitochondria vary in number and location according to cell type. A single mitochondrion is often found in unicellular organisms, while human liver cells have about 1000–2000 mitochondria per cell, making up 1/5 of the cell volume. The mitochondrial content of otherwise similar cells can vary substantially in size and membrane potential, with differences arising from sources including uneven partitioning at cell division, leading to extrinsic differences in ATP levels and downstream cellular processes. The mitochondria can be found nestled between myofibrils of muscle or wrapped around the sperm flagellum. 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: different structures of the mitochondrial network may afford the population a variety of physical, chemical, and signalling advantages or disadvantages. Mitochondria in cells are always distributed along microtubules and the distribution of these organelles is also correlated with the endoplasmic reticulum. Recent evidence suggests that vimentin, one of the components of the cytoskeleton, is also critical to the association with the cytoskeleton.

Mitochondria-associated ER membrane (MAM)

Main article: Mitochondria associated membranes

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. Physical coupling between these two organelles had previously been observed in electron micrographs and has more recently been probed with fluorescence microscopy. 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.

Purified MAM from subcellular fractionation is enriched in enzymes involved in phospholipid exchange, in addition to channels associated with Ca²⁺ signaling. 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.

Phospholipid transfer

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. Because mitochondria are dynamic organelles constantly undergoing fission and fusion events, they require a constant and well-regulated supply of phospholipids for membrane integrity. 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.

Such trafficking capacity depends on the MAM, which has been shown to facilitate transfer of lipid intermediates between organelles. 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. Despite this unusual and seemingly energetically unfavorable mechanism, such transport does not require ATP. 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.

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. The MAM thus serves as a critical metabolic and trafficking hub in lipid metabolism.

Calcium signaling

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 contradict this organelle's purported responsiveness to changes in intracellular Ca²⁺ flux. 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. Transmission occurs in response to so-called "Ca²⁺ puffs" generated by spontaneous clustering and activation of IP3R, a canonical ER membrane Ca²⁺ channel.

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. 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. 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. Normal, mild calcium influx from cytosol into the mitochondrial matrix causes transient depolarization that is corrected by pumping out protons.

But transmission of Ca²⁺ is not unidirectional; rather, it is a two-way street. 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. 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. 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.

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.^] 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. 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. 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.

Molecular basis for tethering

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. 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.^[102] 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. 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.

Model of the yeast multimeric tethering complex, ERMES

Perspective

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. Recently it has also been shown, that mitochondria and MAM-s in neurons are anchored to specialised intercellular communication sites (so called somatic-junctions). Microglial processes monitor and protect neuronal functions at these sites, and MAM-s are supposed to have an important role in this type of cellular quality-control.

Origin and evolution

Main article: Symbiogenesis

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. 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 the more widely accepted of the two accounts.

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 mRNAs into protein. The circular structure is also found in prokaryotes. The proto-mitochondrion was probably closely related to Rickettsia. 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. For example, it has been suggested that the SAR11 clade of bacteria shares a relatively recent common ancestor with the mitochondria, while phylogenomic analyses indicate that mitochondria evolved from a Pseudomonadota lineage that is closely related to or a member of alphaproteobacteria. Some papers describe mitochondria as sister to the alphaproteobactera, together forming the sister the marineproteo1 group, together forming the sister to Magnetococcidae.

Proteobacteria	Alphaproteobacteria s.l. Magnetococcales MarineProteo1 Mitochondria Alphaproteobacteria s.s.

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

The endosymbiotic relationship of mitochondria with their host cells was popularized by Lynn Margulis. The endosymbiotic hypothesis suggests that mitochondria descended from aerobic 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 to 2 billion years ago.

Evolution of MROs

A few groups of unicellular eukaryotes have only vestigial mitochondria or derived structures: The microsporidians, metamonads, and archamoebae. These groups appear as the most primitive eukaryotes on phylogenetic trees constructed using  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). Hydrogenosomes, mitosomes, and related organelles as found in some loricifera (e. g. Spinoloricus) and myxozoa (e. g. Henneguya zschokkei) are together classified as MROs, mitochondrion-related organelles.

Monocercomonoides and other oxymonads appear to have lost their mitochondria completely and at least some of the mitochondrial functions seem to be carried out by cytoplasmic proteins now.

Mitochondrial genetics

The circular 16,569 bp human mitochondrial genome encoding 37 genes, i.e., 28 on the H-strand and 9 on the L-strand

Main article: Mitochondrial DNA

Mitochondria contain their own genome. The human mitochondrial genome is a circular double-stranded DNA molecule of about 16 kilobases. 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 (12S and 16S rRNA). One mitochondrion can contain two to ten copies of its DNA. One of the two mitochondrial DNA (mtDNA) strands has a disproportionately higher ratio of the heavier nucleotides adenine and guanine, and this is termed the heavy strand (or H strand), whereas the other strand is termed the light strand (or L strand). The weight difference allows the two strands to be separated by centrifugation. mtDNA has one long non-coding stretch known as the non-coding region (NCR), which contains the heavy strand promoter (HSP) and light strand promoter (LSP) for RNA transcription, the origin of replication for the H strand (OriH) localized on the L strand, three conserved sequence boxes (CSBs 1–3), and a termination-associated sequence (TAS). The origin of replication for the L strand (OriL) is localized on the H strand 11,000 bp downstream of OriH, located within a cluster of genes coding for tRNA.

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. Most proteins necessary for mitochondrial function are encoded by genes in the cell nucleus and the corresponding proteins are imported into the mitochondrion. The exact number of genes encoded by the nucleus and the mitochondrial genome differs between species. Most mitochondrial genomes are circular. In general, mitochondrial DNA lacks introns, as is the case in the human mitochondrial genome; however, introns have been observed in some eukaryotic mitochondrial DNA, such as that of yeast and protists, including Dictyostelium discoideum. Between protein-coding regions, tRNAs are present. 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.

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. This pattern is also found in other sucking lice, but not in chewing lice. Recombination has been shown to occur between the minichromosomes.

Human population genetic studies

Main article: Human mitochondrial genetics

The near-absence of genetic recombination in mitochondrial DNA makes it a useful source of information for studying population genetics and evolutionary biology. Because all the mitochondrial DNA is inherited as a single unit, or haplotype, the relationships between mitochondrial DNA from different individuals can be represented as a gene tree. Patterns in these gene trees can be used to infer the evolutionary history of populations. The classic example of this is in human evolutionary genetics, where the molecular clock can be used to provide a recent date for mitochondrial Eve. This is often interpreted as strong support for a recent modern human expansion out of Africa. Another human example is the sequencing of mitochondrial DNA from Neanderthal bones. The relatively large evolutionary distance between the mitochondrial DNA sequences of Neanderthals and living humans has been interpreted as evidence for the lack of interbreeding between Neanderthals and modern humans.

However, mitochondrial DNA reflects only the history of the females in a population. This can be partially overcome by the use of paternal genetic sequences, such as the non-recombining region of the Y-chromosome.

Recent measurements of the molecular clock for mitochondrial DNA^[157] 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).^[158]

Alternative genetic code

Exceptions to the standard genetic code in mitochondria

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

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

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.^[163] Of note, the arthropod mitochondrial genetic code has undergone parallel evolution within a phylum, with some organisms uniquely translating AGG to lysine.^[164]

Replication and inheritance

Main article: Mitochondrial fission

Mitochondria divide by mitochondrial fission, a form of binary fission that is also done by bacteria^[165] although the process is tightly regulated by the host eukaryotic cell and involves communication between and contact with several other organelles. The regulation of this division differs between eukaryotes. In many single-celled eukaryotes, their growth and division are 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 energy use is low, mitochondria are destroyed or become inactive. In such examples mitochondria are apparently randomly distributed to the daughter cells during the division of the cytoplasm. Mitochondrial dynamics, the balance between mitochondrial fusion and fission, is an important factor in pathologies associated with several disease conditions.

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 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.

An individual's mitochondrial genes are inherited only from the mother, with rare exceptions.^[168] In humans, when an egg cell is fertilized by a sperm, 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. Instead, paternal mitochondria are marked with ubiquitin to select them for later destruction inside the embryo. The egg cell contains relatively few mitochondria, but these mitochondria divide to populate the cells of the adult organism. 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. For Mytilids, paternal inheritance only occurs within males of the species. It has been suggested that it occurs at a very low level in humans.

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. 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. Further, evidence suggests that animal mitochondria can undergo recombination. The data are more controversial in humans, although indirect evidence of recombination exists.

Entities undergoing uniparental inheritance and with little to no recombination may be expected to be subject to Muller's ratchet, the 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 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 stabilization or reduction in mutant load between generations. The mechanism underlying the bottleneck is debated, 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.

DNA repair

Mitochondria can repair oxidative DNA damage by mechanisms analogous to those occurring in the cell nucleus. The proteins employed in mtDNA repair are encoded by nuclear genes, and are translocated to the mitochondria. The DNA repair pathways in mammalian mitochondria include base excision repair, double-strand break repair, direct reversal and mismatch repair. Alternatively, DNA damage may be bypassed, rather than repaired, by translesion synthesis.

Of the several DNA repair process in mitochondria, the base excision repair pathway has been most comprehensively studied. Base excision repair is carried out by a sequence of enzyme-catalyzed steps that include recognition and excision of a damaged DNA base, removal of the resulting abasic site, end processing, gap filling and ligation. A common damage in mtDNA that is repaired by base excision repair is 8-oxoguanine produced by oxidation of guanine.

Double-strand breaks can be repaired by homologous recombinational repair in both mammalian mtDNA and plant mtDNA. Double-strand breaks in mtDNA can also be repaired by microhomology-mediated end joining. Although there is evidence for the repair processes of direct reversal and mismatch repair in mtDNA, these processes are not well characterized.

Lack of mitochondrial DNA

Some organisms have lost mitochondrial DNA altogether. In these cases, genes encoded by the mitochondrial DNA have been lost or transferred to the nucleus. Cryptosporidium have mitochondria that lack any DNA, presumably because all their genes have been lost or transferred. 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. Mitochondria that lack their own DNA have been found in a marine parasitic dinoflagellate from the genus Amoebophyra. This microorganism, A. cerati, has functional mitochondria that lack a genome. In related species, the mitochondrial genome still has three genes, but in A. cerati only a single mitochondrial gene — the cytochrome c oxidase I gene (cox1) — is found, and it has migrated to the genome of the nucleus.

Dysfunction and disease

Mitochondrial diseases

Main article: Mitochondrial disease

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 as neurological disorders, including autism. They can also manifest as myopathy, diabetes, multiple endocrinopathy, and a variety of other systemic disorders. Diseases caused by mutation in the mtDNA include Kearns–Sayre syndrome, MELAS syndrome and Leber's hereditary optic neuropathy. 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, MERRF syndrome, and others are due to point mutations in mtDNA.

It has also been reported that drug tolerant cancer cells have an increased number and size of mitochondria which suggested an increase in mitochondrial biogenesis. A 2022 study in Nature Nanotechnology has reported that cancer cells can hijack the mitochondria from immune cells via physical tunneling nanotubes.

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. 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. 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. Other pathologies with etiology involving mitochondrial dysfunction include schizophrenia, bipolar disorder, dementia, Alzheimer's disease, Parkinson's disease, epilepsy, stroke, cardiovascular disease, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), retinitis pigmentosa, and diabetes mellitus.

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 are 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. 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.

Mitochondria also modulate processes such as testicular somatic cell development, spermatogonial stem cell differentiation, luminal acidification, testosterone production in testes, and more. Thus, dysfunction of mitochondria in spermatozoa can be a cause for infertility.

In efforts to combat mitochondrial disease, mitochondrial replacement therapy (MRT) has been developed. This form of in vitro fertilization uses donor mitochondria, which avoids the transmission of diseases caused by mutations of mitochondrial DNA. However, this therapy is still being researched and can introduce genetic modification, as well as safety concerns. These diseases are rare but can be extremely debilitating and progressive diseases, thus posing complex ethical questions for public policy.

Relationships to aging

See also: Hallmarks of aging § Mitochondrial dysfunction

There may be some leakage of the electrons transferred 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. Hypothesized links between aging and oxidative stress are not new and were proposed in 1956, which was later refined into the mitochondrial free radical theory of aging. 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.

A number of changes can occur to mitochondria during the aging process. Tissues from elderly humans show a decrease in enzymatic activity of the proteins of the respiratory chain. However, mutated mtDNA can only be found in about 0.2% of very old cells. Large deletions in the mitochondrial genome have been hypothesized to lead to high levels of oxidative stress and neuronal death in Parkinson's disease. Mitochondrial dysfunction has also been shown to occur in amyotrophic lateral sclerosis. Since mitochondria cover a pivotal role in the ovarian function, by providing ATP necessary for the development from germinal vesicle to mature oocyte, a decreased mitochondria function can lead to inflammation, resulting in premature ovarian failure and accelerated ovarian aging. The resulting dysfunction is then reflected in quantitative (such as mtDNA copy number and mtDNA deletions), qualitative (such as mutations and strand breaks) and oxidative damage (such as dysfunctional mitochondria due to ROS), which are not only relevant in ovarian aging, but perturb oocyte-cumulus crosstalk in the ovary, are linked to genetic disorders (such as Fragile X) and can interfere with embryo selection.

History

The first observations of intracellular structures that probably represented mitochondria were published in 1857, by the physiologist Albert von Kolliker. Richard Altmann, in 1890, established them as cell organelles and called them "bioblasts." In 1898, Carl Benda coined the term "mitochondria" from the Greek μίτος, mitos, "thread", and χονδρίον, chondrion, "granule." 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, 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. In 1913, Otto Heinrich Warburg linked respiration to particles which he had obtained from extracts of guinea-pig liver and 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.

In 1939, experiments using minced muscle cells demonstrated that cellular respiration using one oxygen molecule can form four 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. 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 mitochondria. 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.

The first high-resolution electron micrographs appeared in 1952, replacing the Janus Green stains as the preferred way to visualize mitochondria. 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.

The popular term "powerhouse of the cell" was coined by Philip Siekevitz in 1957.

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

Muscle cell

From Wikipedia, the free encyclopedia

(Redirected from Muscle fiber)

"Muscle fiber" and "Myofiber" redirect here. For protein structures inside cells, see Myofibril.

 

Muscle cell
General structure of a skeletal muscle cell and neuromuscular junction: Axon Neuromuscular junction Skeletal muscle fiber Myofibril
Details
Location	Muscle
Identifiers
Latin	myocytus
MeSH	D032342
TH	H2.00.05.0.00002
FMA	67328

A muscle cell, also known as a myocyte, is a mature contractile cell in the muscle of an animal. In humans and other vertebrates there are three types: skeletal, smooth, and cardiac (cardiomyocytes). A skeletal muscle cell is long and threadlike with many nuclei and is called a muscle fiber. Muscle cells develop from embryonic precursor cells called myoblasts.

Skeletal muscle cells form by fusion of myoblasts to produce multinucleated cells (syncytia) in a process known as myogenesis. Skeletal muscle cells and cardiac muscle cells both contain myofibrils and sarcomeres and form a striated muscle tissue.

Cardiac muscle cells form the cardiac muscle in the walls of the heart chambers, and have a single central nucleus. Cardiac muscle cells are joined to neighboring cells by intercalated discs, and when joined in a visible unit they are described as a cardiac muscle fiber.

Smooth muscle cells control involuntary movements such as the peristalsis contractions in the esophagus and stomach. Smooth muscle has no myofibrils or sarcomeres and is therefore non-striated. Smooth muscle cells have a single nucleus.

Structure

The unusual microscopic anatomy of a muscle cell gave rise to its terminology. The cytoplasm in a muscle cell is termed the sarcoplasm; the smooth endoplasmic reticulum of a muscle cell is termed the sarcoplasmic reticulum; and the cell membrane in a muscle cell is termed the sarcolemma. The sarcolemma receives and conducts stimuli.

Skeletal muscle cells

Main article: Skeletal muscle fibers

Diagram of skeletal muscle fiber structure

Skeletal muscle cells are the individual contractile cells within a muscle and are more usually known as muscle fibers because of their longer threadlike appearance. Broadly there are two types of muscle fiber performing in muscle contraction, either as slow twitch (type I) or fast twitch (type II).

A single muscle such as the biceps brachii in a young adult human male contains around 253,000 muscle fibers. Skeletal muscle fibers are the only muscle cells that are multinucleated with the nuclei usually referred to as myonuclei. This occurs during myogenesis with the fusion of myoblasts each contributing a nucleus to the newly formed muscle cell or myotube. Fusion depends on muscle-specific proteins known as fusogens called myomaker and myomerger.

A striated muscle fiber contains myofibrils consisting of long protein chains of myofilaments. There are three types of myofilaments: thin, thick, and elastic that work together to produce a muscle contraction. The thin myofilaments are filaments of mostly actin and the thick filaments are of mostly myosin and they slide over each other to shorten the fiber length in a muscle contraction. The third type of myofilament is an elastic filament composed of titin, a very large protein.

In striations of muscle bands, myosin forms the dark filaments that make up the A band. Thin filaments of actin are the light filaments that make up the I band. The smallest contractile unit in the fiber is called the sarcomere which is a repeating unit within two Z bands. The sarcoplasm also contains glycogen which provides energy to the cell during heightened exercise, and myoglobin, the red pigment that stores oxygen until needed for muscular activity.

The sarcoplasmic reticulum, a specialized type of smooth endoplasmic reticulum, forms a network around each myofibril of the muscle fiber. This network is composed of groupings of two dilated end-sacs called terminal cisternae, and a single T-tubule (transverse tubule), which bores through the cell and emerge on the other side; together these three components form the triads that exist within the network of the sarcoplasmic reticulum, in which each T-tubule has two terminal cisternae on each side of it. The sarcoplasmic reticulum serves as a reservoir for calcium ions, so when an action potential spreads over the T-tubule, it signals the sarcoplasmic reticulum to release calcium ions from the gated membrane channels to stimulate muscle contraction.

In skeletal muscle, at the end of each muscle fiber, the outer layer of the sarcolemma combines with tendon fibers at the myotendinous junction. Within the muscle fiber pressed against the sarcolemma are multiply flattened nuclei; embryologically, this multinucleate condition results from multiple myoblasts fusing to produce each muscle fiber, where each myoblast contributes one nucleus.

Cardiac muscle cells

Main article: Cardiac muscle

The cell membrane of a cardiac muscle cell has several specialized regions, which may include the intercalated disc, and transverse tubules. The cell membrane is covered by a lamina coat which is approximately 50  nm wide. The laminar coat is separable into two layers; the lamina densa and lamina lucida. In between these two layers can be several different types of ions, including calcium.

Cardiac muscle like the skeletal muscle is also striated and the cells contain myofibrils, myofilaments, and sarcomeres as the skeletal muscle cell. The cell membrane is anchored to the cell's cytoskeleton by anchor fibers that are approximately 10  nm wide. These are generally located at the Z lines so that they form grooves and transverse tubules emanate. In cardiac myocytes, this forms a scalloped surface.

The cytoskeleton is what the rest of the cell builds off of and has two primary purposes; the first is to stabilize the topography of the intracellular components and the second is to help control the size and shape of the cell. While the first function is important for biochemical processes, the latter is crucial in defining the surface-to-volume ratio of the cell. This heavily influences the potential electrical properties of excitable cells. Additionally, deviation from the standard shape and size of the cell can have a negative prognostic impact.

Smooth muscle cells

Main article: Smooth muscle

Further information: Basal electrical rhythm

Smooth muscle cells are so-called because they have neither myofibrils nor sarcomeres and therefore no striations. They are found in the walls of hollow organs, including the stomach, intestines, bladder and uterus, in the walls of blood vessels, and in the tracts of the respiratory, urinary, and reproductive systems. In the eyes, the ciliary muscles dilate and contract the iris and alter the shape of the lens. In the skin, smooth muscle cells such as those of the arrector pili cause hair to stand erect in response to cold temperature or fear.

Smooth muscle cells are spindle-shaped with wide middles, and tapering ends. They have a single nucleus and range from 30 to 200 micrometers in length. This is thousands of times shorter than skeletal muscle fibers. The diameter of their cells is also much smaller which removes the need for T-tubules found in striated muscle cells. Although smooth muscle cells lack sarcomeres and myofibrils they do contain large amounts of the contractile proteins actin and myosin. Actin filaments are anchored by dense bodies (similar to the Z discs in sarcomeres) to the sarcolemma.

Development

Main article: Myogenesis

A myoblast is an embryonic precursor cell that differentiates to give rise to the different muscle cell types. Differentiation is regulated by myogenic regulatory factors, including MyoD, Myf5, myogenin, and MRF4. GATA4 and GATA6 also play a role in myocyte differentiation.

Skeletal muscle fibers are made when myoblasts fuse together; muscle fibers therefore are cells with multiple nuclei, known as myonuclei, with each cell nucleus originating from a single myoblast. The fusion of myoblasts is specific to skeletal muscle, and not cardiac muscle or smooth muscle.

Myoblasts in skeletal muscle that do not form muscle fibers dedifferentiate back into myosatellite cells. These satellite cells remain adjacent to a skeletal muscle fiber, situated between the sarcolemma and the basement membrane of the endomysium (the connective tissue investment that divides the muscle fascicles into individual fibers). To re-activate myogenesis, the satellite cells must be stimulated to differentiate into new fibers.

Myoblasts and their derivatives, including satellite cells, can now be generated in vitro through directed differentiation of pluripotent stem cells.

Kindlin-2 plays a role in developmental elongation during myogenesis.

Function

Muscle contraction in striated muscle

Main article: Muscle contraction

Skeletal muscle contraction

When contracting, thin and thick filaments slide concerning each other by using adenosine triphosphate. This pulls the Z discs closer together in a process called the sliding filament mechanism. The contraction of all the sarcomeres results in the contraction of the whole muscle fiber. This contraction of the myocyte is triggered by the action potential over the cell membrane of the myocyte. The action potential uses transverse tubules to get from the surface to the interior of the myocyte, which is continuous within the cell membrane. Sarcoplasmic reticula are membranous bags that transverse tubules touch but remain separate from. These wrap themselves around each sarcomere and are filled with Ca²⁺.

Excitation of a myocyte causes depolarization at its synapses, the neuromuscular junctions, which triggers an action potential. With a singular neuromuscular junction, each muscle fiber receives input from just one somatic efferent neuron. Action potential in a somatic efferent neuron causes the release of the neurotransmitter acetylcholine.^[27]

When the acetylcholine is released it diffuses across the synapse and binds to a receptor on the sarcolemma, a term unique to muscle cells that refers to the cell membrane. This initiates an impulse that travels across the sarcolemma.^[28]

When the action potential reaches the sarcoplasmic reticulum it triggers the release of Ca²⁺ from the Ca²⁺ channels. The Ca²⁺ flows from the sarcoplasmic reticulum into the sarcomere with both of its filaments. This causes the filaments to start sliding and the sarcomeres to become shorter. This requires a large amount of ATP, as it is used in both the attachment and release of every myosin head. Very quickly Ca²⁺ is actively transported back into the sarcoplasmic reticulum, which blocks the interaction between the thin and thick filament. This in turn causes the muscle cell to relax.

There are four main types of muscle contraction: isometric, isotonic, eccentric and concentric. Isometric contractions are skeletal muscle contractions that do not cause movement of the muscle. and isotonic contractions are skeletal muscle contractions that do cause movement. Eccentric contraction is when a muscle moves under a load. Concentric contraction is when a muscle shortens and generates force.

Cardiac muscle contraction

See also: Bowditch effect

Specialized cardiomyocytes in the sinoatrial node generate electrical impulses that control the heart rate. These electrical impulses coordinate contraction throughout the remaining heart muscle via the electrical conduction system of the heart. Sinoatrial node activity is modulated, in turn, by nerve fibers of both the sympathetic and parasympathetic nervous systems. These systems act to increase and decrease, respectively, the rate of production of electrical impulses by the sinoatrial node.

Evolution

Further information: Evolution and Adaptation

The evolutionary origin of muscle cells in animals is highly debated: One view is that muscle cells evolved once, and thus all muscle cells have a single common ancestor. Another view is that muscles cells evolved more than once, and any morphological or structural similarities are due to convergent evolution, and the development of shared genes that predate the evolution of muscle – even the mesoderm (the mesoderm is the germ layer that gives rise to muscle cells in vertebrates).

Schmid & Seipel (2005) argue that the origin of muscle cells is a monophyletic trait that occurred concurrently with the development of the digestive and nervous systems of all animals, and that this origin can be traced to a single metazoan ancestor in which muscle cells are present. They argue that molecular and morphological similarities between the muscles cells in Cnidaria and Ctenophora are similar enough to those of bilaterians that there would be one ancestor in metazoans from which muscle cells derive. In this case, Schmid & Seipel argue that the last common ancestor of Bilateria, Ctenophora and Cnidaria, was a triploblast (an organism having three germ layers), and that diploblasty, meaning an organism with two germ layers, evolved secondarily, because of their observation of the lack of mesoderm or muscle found in most cnidarians and ctenophores. By comparing the morphology of cnidarians and ctenophores to bilaterians, Schmid & Seipel were able to conclude that there were myoblast-like structures in the tentacles and gut of some species of cnidarians and the tentacles of ctenophores. Since this is a structure unique to muscle cells, these scientists determined based on the data collected by their peers that this is a marker for striated muscles similar to that observed in bilaterians. The authors also remark that the muscle cells found in cnidarians and ctenophores are often contested due to the origin of these muscle cells being the ectoderm rather than the mesoderm or mesendoderm.

The origin of true muscle cells is argued by other authors to be the endoderm portion of the mesoderm and the endoderm. However, Schmid & Seipel (2005)^[30] counter skepticism – about whether the muscle cells found in ctenophores and cnidarians are "true" muscle cells – by considering that cnidarians develop through a medusa stage and polyp stage. They note that in the hydrozoans' medusa stage, there is a layer of cells that separate from the distal side of the ectoderm, which forms the striated muscle cells in a way similar to that of the mesoderm; they call this third separated layer of cells the ectocodon. Schmid & Seipel argue that even in bilaterians, not all muscle cells are derived from the mesendoderm: Their key examples are that in both the eye muscles of vertebrates, and the muscles of spiralians, these cells derive from the ectodermal mesoderm, rather than the endodermal mesoderm. Furthermore, they argue that since myogenesis does occur in cnidarians with the help of the same molecular regulatory elements found in the specification of muscle cells in bilaterians, that there is evidence for a single origin for striated muscle.

In contrast to this argument for a single origin of muscle cells, Steinmetz, Kraus, et al. (2012) argue that molecular markers such as the myosin II protein used to determine this single origin of striated muscle predate the formation of muscle cells. They use an example of the contractile elements present in the Porifera, or sponges, that do truly lack this striated muscle containing this protein. Furthermore, Steinmetz, Kraus, et al. present evidence for a polyphyletic origin of striated muscle cell development through their analysis of morphological and molecular markers that are present in bilaterians and absent in cnidarians, ctenophores, and bilaterians. Steinmetz, Kraus, et al. showed that the traditional morphological and regulatory markers such as actin, the ability to couple myosin side chains phosphorylation to higher concentrations of the positive concentrations of calcium, and other MyHC elements are present in all metazoans not just the organisms that have been shown to have muscle cells. Thus, the usage of any of these structural or regulatory elements in determining whether or not the muscle cells of the cnidarians and ctenophores are similar enough to the muscle cells of the bilaterians to confirm a single lineage is questionable according to Steinmetz, Kraus, et al. Furthermore, they explain that the orthologues of the Myc genes that have been used to hypothesize the origin of striated muscle occurred through a gene duplication event that predates the first true muscle cells (meaning striated muscle), and they show that the Myc genes are present in the sponges that have contractile elements but no true muscle cells. Steinmetz, Kraus, et al. also showed that the localization of this duplicated set of genes that serve both the function of facilitating the formation of striated muscle genes, and cell regulation and movement genes, were already separated into striated much and non-muscle MHC. This separation of the duplicated set of genes is shown through the localization of the striated much to the contractile vacuole in sponges, while the non-muscle much was more diffusely expressed during developmental cell shape and change. Steinmetz, Kraus, et al. found a similar pattern of localization in cnidarians except with the cnidarian N. vectensis having this striated muscle marker present in the smooth muscle of the digestive tract. Thus, they argue that the pleisiomorphic trait of the separated orthologues of much cannot be used to determine the monophylogeny of muscle, and additionally argue that the presence of a striated muscle marker in the smooth muscle of this cnidarian shows a fundamental different mechanism of muscle cell development and structure in cnidarians.

Steinmetz, Kraus, et al. (2012) further argue for multiple origins of striated muscle in the metazoans by explaining that a key set of genes used to form the troponin complex for muscle regulation and formation in bilaterians is missing from the cnidarians and ctenophores, and 47 structural and regulatory proteins observed, Steinmetz, Kraus, et al. were not able to find even on unique striated muscle cell protein that was expressed in both cnidarians and bilaterians. Furthermore, the Z-disc seemed to have evolved differently even within bilaterians and there is a great deal of diversity of proteins developed even between this clade, showing a large degree of radiation for muscle cells. Through this divergence of the Z-disc, Steinmetz, Kraus, et al. argue that there are only four common protein components that were present in all bilaterians muscle ancestors and that of these for necessary Z-disc components only an actin protein that they have already argued is an uninformative marker through its pleisiomorphic state is present in cnidarians. Through further molecular marker testing, Steinmetz et al. observe that non-bilaterians lack many regulatory and structural components necessary for bilaterians muscle formation and do not find any unique set of proteins to both bilaterians and cnidarians and ctenophores that are not present in earlier, more primitive animals such as the sponges and amoebozoans. Through this analysis, the authors conclude that due to the lack of elements that bilaterian muscles are dependent on for structure and usage, nonbilaterian muscles must be of a different origin with a different set of regulatory and structural proteins.

In another take on the argument, Andrikou & Arnone (2015) use the newly available data on gene regulatory networks to look at how the hierarchy of genes and morphogens and another mechanism of tissue specification diverge and are similar among early deuterostomes and protostomes. By understanding not only what genes are present in all bilaterians but also the time and place of deployment of these genes, Andrikou & Arnone discuss a deeper understanding of the evolution of myogenesis.

In their paper, Andrikou & Arnone (2015) argue that to truly understand the evolution of muscle cells the function of transcriptional regulators must be understood in the context of other external and internal interactions. Through their analysis, Andrikou & Arnone found that there were conserved orthologues of the gene regulatory network in both invertebrate bilaterians and cnidarians. They argue that having this common, general regulatory circuit allowed for a high degree of divergence from a single well-functioning network. Andrikou & Arnone found that the orthologues of genes found in vertebrates had been changed through different types of structural mutations in the invertebrate deuterostomes and protostomes, and they argue that these structural changes in the genes allowed for a large divergence of muscle function and muscle formation in these species. Andrikou & Arnone were able to recognize not only any difference due to mutation in the genes found in vertebrates and invertebrates but also the integration of species-specific genes that could also cause divergence from the original gene regulatory network function. Thus, although a common muscle patterning system has been determined, they argue that this could be due to a more ancestral gene regulatory network being coopted several times across lineages with additional genes and mutations causing very divergent development of muscles. Thus it seems that the myogenic patterning framework may be an ancestral trait. However, Andrikou & Arnone explain that the basic muscle patterning structure must also be considered in combination with the cis regulatory elements present at different times during development. In contrast with the high level of gene family apparatuses structure, Andrikou and Arnone found that the cis-regulatory elements were not well conserved both in time and place in the network which could show a large degree of divergence in the formation of muscle cells. Through this analysis, it seems that the myogenic GRN is an ancestral GRN with actual changes in myogenic function and structure possibly being linked to later coopts of genes at different times and places.

Evolutionarily, specialized forms of skeletal and cardiac muscles predated the divergence of the vertebrate / arthropod evolutionary line. This indicates that these types of muscle developed in a common ancestor sometime before 700 million years ago (mya). Vertebrate smooth muscle was found to have evolved independently from the skeletal and cardiac muscle types.

Invertebrate muscle cell types

The properties used for distinguishing fast, intermediate, and slow muscle fibers can be different for invertebrate flight and jump muscle. To further complicate this classification scheme, the mitochondrial content, and other morphological properties within a muscle fiber, can change in a tsetse fly with exercise and age.

Myopathy

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Myopathy 

 

Myopathy
Other names	Muscle disease
Specialty	Rheumatology, Neuromuscular medicine

In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. Myopathy means muscle disease (Greek : myo- muscle + patheia -pathy : suffering). This meaning implies that the primary defect is within the muscle, as opposed to the nerves ("neuropathies" or "neurogenic" disorders) or elsewhere (e.g., the brain).

This muscular defect typically results in myalgia (muscle pain), muscle weakness (reduced muscle force), or premature muscle fatigue (initially normal, but declining muscle force). Muscle cramps, stiffness, spasm, and contracture can also be associated with myopathy. Myopathy experienced over a long period (chronic) may result in the muscle becoming an abnormal size, such as muscle atrophy (abnormally small) or a pseudoathletic appearance (abnormally large).

Capture myopathy can occur in wild or captive animals, such as deer and kangaroos, and leads to morbidity and mortality. It usually occurs as a result of stress and physical exertion during capture and restraint.

Muscular disease can be classified as neuromuscular or musculoskeletal in nature. Some conditions, such as myositis, can be considered both neuromuscular and musculoskeletal. Different myopathies may be inherited, infectious, non-communicable, or idiopathic (cause unknown). The disease may be isolated to affecting only muscle (pure myopathy), or may be part of a systemic disease as is typical in mitochondrial myopathies.

Signs and symptoms

Common symptoms include muscle weakness, cramps, stiffness, and tetany.

Systemic diseases

Myopathies in systemic disease results from several different disease processes including endocrine, inflammatory, paraneoplastic, infectious, drug- and toxin-induced, critical illness myopathy, metabolic, collagen related, and myopathies with other systemic disorders. Patients with systemic myopathies often present acutely or sub acutely. On the other hand, familial myopathies or dystrophies generally present in a chronic fashion with exceptions of metabolic myopathies where symptoms on occasion can be precipitated acutely. Metabolic myopathies, which affect the production of ATP within the muscle cell, typically present with dynamic (exercise-induced) rather than static symptoms. Most of the inflammatory myopathies can have a chance association with malignant lesion; the incidence appears to be specifically increased only in patients with dermatomyositis.

There are many types of myopathy. ICD-10 codes are provided here where available.

Inherited forms

• (G71.0) Dystrophies (or muscular dystrophies) are a subgroup of myopathies characterized by muscle degeneration and regeneration. Clinically, muscular dystrophies are typically progressive, because the muscles' ability to regenerate is eventually lost, leading to progressive weakness, often leading to use of a wheelchair, and eventually death, usually related to respiratory weakness.
• (G71.1) Myotonia
  • Neuromyotonia
• (G71.2) The congenital myopathies do not show evidence for either a progressive dystrophic process (i.e., muscle death) or inflammation, but instead characteristic microscopic changes are seen in association with reduced contractile ability of the muscles. Congenital myopathies include, but are not limited to:
  • (G71.2) nemaline myopathy (characterized by presence of "nemaline rods" in the muscle),
  • (G71.2) multi/minicore myopathy (characterized by multiple small "cores" or areas of disruption in the muscle fibers),
  • (G71.2) centronuclear myopathy (or myotubular myopathy) (in which the nuclei are abnormally found in the center of the muscle fibers), a rare muscle wasting disorder
• (G71.3) Mitochondrial myopathies, which are due to defects in mitochondria, which provide a critical source of energy for muscle
• (G72.3) Familial periodic paralysis
• (G72.4) Inflammatory myopathies, which are caused by problems with the immune system attacking components of the muscle, leading to signs of inflammation in the muscle
• (G73.6) Metabolic myopathies, which result from defects in biochemical metabolism that primarily affect muscle
  • (G73.6/E74.0) Glycogen storage diseases, which may affect muscle
  • (G73.6/E75) Lipid storage disorder
• (G72.89) Other myopathies
  • Brody myopathy
  • Congenital myopathy with abnormal subcellular organelles
  • Fingerprint body myopathy
  • Inclusion body myopathy 2
  • Megaconial myopathy
  • Myofibrillar myopathy
  • Rimmed vacuolar myopathy

Acquired

• (G72.0 - G72.2) External substance induced myopathy
  • (G72.0) Drug-induced myopathy
    • Glucocorticoid myopathy is caused by this class of steroids increasing the breakdown of the muscle proteins leading to muscle atrophy.
  • (G72.1) Alcoholic myopathy
  • (G72.2) Myopathy due to other toxic agents - including atypical myopathy in horses caused by toxins in sycamore seeds and seedlings.
• (M33.0-M33.1)
  • Dermatomyositis produces muscle weakness and skin changes. The skin rash is reddish and most commonly occurs on the face, especially around the eyes, and over the knuckles and elbows. Ragged nail folds with visible capillaries can be present. It can often be treated by drugs like corticosteroids or immunosuppressants. (M33.2)
  • Polymyositis produces muscle weakness. It can often be treated by drugs like corticosteroids or immunosuppressants.
  • Inclusion body myositis is a slowly progressive disease that produces weakness of hand grip and straightening of the knees. No effective treatment is known.
• (M60.9) Benign acute childhood myositis
• (M61) Myositis ossificans
• (M62.89) Rhabdomyolysis and (R82.1) myoglobinurias

The Food and Drug Administration is recommending that physicians restrict prescribing high-dose Simvastatin (Zocor, Merck) to patients, given an increased risk of muscle damage. The FDA drug safety communication stated that physicians should limit using the 80-mg dose unless the patient has already been taking the drug for 12 months and there is no evidence of myopathy. "Simvastatin 80 mg should not be started in new patients, including patients already taking lower doses of the drug," the agency states.

• Statin-associated autoimmune myopathy

Myocardium / cardio-myopathy

• (I40) Acute myocarditis
• (I41) Myocarditis in diseases classified elsewhere
• (I42) Cardiomyopathy
  • (I42.0) Dilated cardiomyopathy
  • (I42.1) Obstructive hypertrophy cardiomyopathy
  • (I42.2) Other hypertrophic cardiomyopathy
  • (I42.3) Endomyocardial (eosinophilic) disease
    • Eosinophilic myocarditis
    • Endomyocardial (tropical) fibrosis
    • Löffler's endocarditis
  • (I42.4) Endocardial fibroelastosis
  • (I42.5) Other restrictive cardiomyopathy
  • (I42.6) Alcoholic cardiomyopathy
  • (I42.8) Other cardiomyopathies
    • Arrhythmogenic right ventricular dysplasia
• (I43) Cardiomyopathy in diseases classified elsewhere

Differential diagnosis

At birth

• None as systemic causes; mainly hereditary

Onset in childhood

• Inflammatory myopathies – dermatomyositis, polymyositis (rarely)
• Infectious myopathies
• Endocrine and metabolic disorders – hypokalemia, hypocalcemia, hypercalcemia

Onset in adulthood

• Inflammatory myopathies – polymyositis, dermatomyositis, inclusion body myositis, viral (HIV)
• Infectious myopathies
• Endocrine myopathies – thyroid, parathyroid, adrenal, pituitary disorders
• Toxic myopathies – alcohol, corticosteroids, narcotics, colchicines, chloroquine
• Critical illness myopathy
• Metabolic myopathies
• Paraneoplastic myopathy

Treatments

Because different types of myopathies are caused by many different pathways, there is no single treatment for myopathy. Treatments range from treatment of the symptoms to very specific cause-targeting treatments. Drug therapy, physical therapy, bracing for support, surgery, and massage are all current treatments for a variety of myopathies.