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A mitochondrion () is an organelle found in the cells of most , such as , and fungi. Mitochondria have a double lipid bilayer 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, meaning a thread-like granule, 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, and , have reduced or transformed their mitochondria into other structures, e.g. and . The Monocercomonoides, Streblomastix, and Blattamonas completely lost their mitochondria.
Mitochondria are commonly between 0.75 and 3 micrometre in cross section, but vary considerably in size and structure. Unless specifically Staining, they are not visible. The mitochondrion is composed of compartments that carry out specialized functions. These compartments or regions include the outer membrane, intermembrane space, inner membrane, , and matrix.
In addition to supplying cellular energy, mitochondria are involved in other tasks, such as cell signaling, cellular differentiation, and apoptosis, as well as maintaining control of the cell cycle and cell growth. Mitochondrial biogenesis is in turn temporally coordinated with these cellular processes.
Mitochondria are implicated in human disorders and conditions such as mitochondrial diseases, Heart failure, heart failure, and autism.
The number of mitochondria in a cell vary widely by organism, tissue, and cell type. A mature red blood cell has no mitochondria, whereas a hepatocyte can have more than 2000. (2025). 9780815341055, Garland Publishing Inc.. ISBN 9780815341055
Although most of a eukaryotic cell's DNA is contained in the cell nucleus, the mitochondrion has its own genome ("mitogenome") that is similar to genomes. This finding has led to general acceptance of the Symbiogenesis - 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 respire to generate cellular energy.
The outer membrane also contains involved in such diverse activities as the elongation of , oxidation of epinephrine, and the Biodegradation 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.
It contains more than 151 different , 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 Bos taurus 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 of the electron transport chain. Inner membrane fusion is mediated by the inner membrane protein OPA1.
In the citric acid cycle, all the intermediates (e.g. citrate, Isocitric acid, alpha-ketoglutarate, succinate, Fumaric acid, Malic acid 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 CO and water, with the energy thus released captured in the form of ATP.
In the liver, the carboxylation of pyruvate into intra-mitochondrial oxaloacetate is an early step in the gluconeogenesis pathway, which converts lactic acid 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 FADH) that are a source of electrons for the electron transport chain, and a molecule of GTP (which is readily converted to an ATP).
The major energy-releasing reactions (2025). 9780471193500, Wiley. ISBN 9780471193500 (2025). 9780716787594, Freeman. ISBN 9780716787594 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:
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):
The ubiquinone (Q) generated reacts, in complex I, with NADH:
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 Hydrogen ion (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). 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.
(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.
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 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 Symbiogenesis 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 . 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 site methylation and can be detected by Toll-like receptor 9 and cGAS. DsRNA (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.
Researchers cultured human mitochondria-free lung cancer cells with stem cells. The stem cells ejected mitochondria, which were absorbed by the lung cells. The lung cells then recovered their ability to divide and metabolize glucose. Mitochondria were then detected moving among lung, heart, brain, fat, bone, and other cells. Research has not identified how a cell indicates that it needs mitochondrial assistance or how other cells read those indicators.
Various purposes have been observed to explain such donations. These include:
Extracellular mitochondria use multiple modes of transport:
Some mitochondrial functions are performed only in specific types of cells. For example, mitochondria in 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 heart mitochondria, whereas in Murinae, 940 proteins have been reported. The mitochondrial proteome is thought to be dynamically regulated.
Purified MAM from subcellular fractionation is enriched in enzymes involved in phospholipid exchange, in addition to channels associated with Ca 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.
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 Protein complex 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.
The fate of these puffs—in particular, whether they remain restricted to isolated locales or integrated into Ca waves for propagation throughout the cell—is determined in large part by MAM dynamics. Although reuptake of Ca by the ER (concomitant with its release) modulates the intensity of the puffs, thus insulating mitochondria to a certain degree from high Ca exposure, the MAM often serves as a firewall that essentially buffers Ca puffs by acting as a sink into which free ions released into the cytosol can be funneled. 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. Normal, mild calcium influx from cytosol into the mitochondrial matrix causes transient depolarization that is corrected by pumping out protons.
But transmission of Ca is not unidirectional; rather, it is a two-way street. The properties of the Ca pump SERCA and the channel IP3R present on the ER membrane facilitate feedback regulation coordinated by MAM function. In particular, the clearance of Ca by the MAM allows for spatio-temporal patterning of Ca signaling because Ca alters IP3R activity in a biphasic manner. SERCA is likewise affected by mitochondrial feedback: uptake of Ca by the MAM stimulates ATP production, thus providing energy that enables SERCA to reload the ER with Ca for continued Ca efflux at the MAM. Thus, the MAM is not a passive buffer for Ca puffs; rather it helps modulate further Ca signaling through feedback loops that affect ER dynamics.
Regulating ER release of Ca at the MAM is especially critical because only a certain window of Ca uptake sustains the mitochondria, and consequently the cell, at homeostasis. Sufficient intraorganelle Ca signaling is required to stimulate metabolism by activating dehydrogenase enzymes critical to flux through the citric acid cycle. 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. 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 Ca 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 Ca signaling, it is perhaps unsurprising that dysregulated mitochondrial Ca has been implicated in several neurodegenerative diseases, while the catalogue of tumor suppressors includes a few that are enriched at the MAM.
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 of , and the 22 necessary for the translation of into protein. The circular structure is also found in prokaryotes. The proto-mitochondrion was probably closely related to genus Rickettsia, which is in class Alphaproteobactera of phylum Pseudomonadota. 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 ribosomes, which are coded for by Cell nucleus 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 , , 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., and ). 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 appear to have lost their mitochondria completely and at least some of the mitochondrial functions seem to be carried out by cytoplasmic proteins now.
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 Polyadenylation to yield mature . 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 , 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 , 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 Anoplura, but not in Mallophaga. Recombination has been shown to occur between the minichromosomes.
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 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).
| +Exceptions to the standard genetic code in mitochondria | |||
| AGA, AGG | Arginine | Stop codon | |
| AGA, AGG | Arginine | Serine | |
| Fungus | CUA | Leucine | Threonine |
| All of the above | AUA | Isoleucine | Methionine |
| UGA | Stop codon | Tryptophan |
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. Of note, the arthropod mitochondrial genetic code has undergone parallel evolution within a phylum, with some organisms uniquely translating AGG to lysine.
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 ovum 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.Kimball, J.W. (2006) "Sexual Reproduction in Humans: Copulation and Fertilization" , Kimball's Biology Pages (based on Biology, 6th ed., 1996) Instead, paternal mitochondria are marked with ubiquitin to select them for later destruction inside the embryo. Discussed in Science News . 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 plants, although not in and taxus. For Mytilidae, paternal inheritance only occurs within males of the species. Male and Female Mitochondrial DNA Lineages in the Blue Mussel (Mytilus edulis) Species Group by Donald T. Stewart, Carlos Saavedra, Rebecca R. Stanwood, Amy 0. Ball, and Eleftherios Zouros 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 cellular noise to increase the cell-to-cell variability in heteroplasmy 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.
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.
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 uncoupler 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.
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.
In 1939, experiments using minced muscle cells demonstrated that cellular respiration using one Oxygen 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. In November 2024, Researchers from the United States have discovered that mitochondria divide into two distinct forms when cells are starved, this could help explain and describe how cancers thrive in hostile conditions.
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