Митохондрии: Энергетические станции клетки.

Organelle in eukaryotic cells responsible for respiration

A mitochondrion (,/m//aɪ//t//ə/'/k//ɒ//n//d//r//i//ə//n/; : 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. The term mitochondrion was coined by Carl Benda in 1898. The mitochondrion is popularly nicknamed the "powerhouse of the cell", a phrase coined by Philip Siekevitz in a 1957 article of the same name. 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. 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. 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.

Mitochondria may have a number of different shapes. A mitochondrion contains outer and inner membranes composed of phospholipid bilayers and proteins. 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. 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, 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.

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 F particles or oxysomes.

The matrix is the space enclosed by the inner membrane. It contains about 2/3 of the total proteins in a mitochondrion.

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. 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.

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. 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. 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. 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, 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. Ca 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.

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. 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. 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.

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

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 Ca channels localized to the outer mitochondrial membrane seemed to contradict this organelle's purported responsiveness to changes in intracellular Ca flux. But the presence of the MAM resolves this apparent contradiction: the close physical association between the two organelles results in Ca microdomains at contact points that facilitate efficient Ca transmission from the ER to the mitochondria. This Ca tunneling occurs through the low affinity Ca 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 Ca sink is a result of the electrochemical gradient generated during oxidative phosphorylation, which makes tunneling of the cation an exergonic process. However, once Ca 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.

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.

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. 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. 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 rRNA information, which once suggested that they appeared before the origin of mitochondria. However, this is now known to be an artifact of long branch attraction: They are derived groups and retain genes or organelles derived from mitochondria (e. g., mitosomes and hydrogenosomes). 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.

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 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; 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.

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. 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 per base per generation).

Mitochondria divide by mitochondrial fission, a form of binary fission that is also done by bacteria 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. 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. 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.

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. 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. 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. 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.

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. 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. 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. 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.

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.

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. 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 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.