Mitochondrion



 

In cell biology, a mitochondrion (plural mitochondria) is a membrane-enclosed organelle found in most eukaryotic cells.[1] The word mitochondrion comes from the Greek μίτος or mitos, thread + χονδρίον or khondrion, granule. Their origin is unclear, but according to the endosymbiotic theory, mitochondria are thought to be descended from ancient bacteria. These organelles range from 1–10 micrometers (μm) in size. Mitochondria are sometimes described as "cellular power plants" because they generate most of the cell's supply of cell death, as well as the control of the cell cycle and cell growth.[2] Finally, mitochondria have been implicated in several human diseases and may play a role in the aging process.

Several characteristics make mitochondria unique. The number of mitochondria in a cell varies widely by organism and tissue type. Many cells have only a single mitochondrion, whereas others can contain several thousand mitochondria.[3][4] The organelle is comprised of compartments that carry out specialized functions. These compartments or regions include the outer membrane, the intermembrane space, the inner membrane, and the genome. Further, its DNA shows substantial similarity to bacterial genomes. These characteristics allow the mitochondrion to play a critical role in cellular processes.

Structure


A mitochondrion contains inner and outer membranes composed of phospholipid bilayers and cristae space (formed by infoldings of the inner membrane), and the matrix (space within the inner membrane).

Outer membrane

Main article: Outer mitochondrial membrane

The outer mitochondrial membrane, which encloses the entire organelle, has a protein-to-multisubunit protein known as TOM (translocase of the outer membrane).[6] Disruption of this "sieve" permits proteins in the intermembrane space to leak into the cytosol, leading to certain cell death.[7]

Intermembrane space

The intermembrane space is the space between the outer membrane and the inner membrane. Because the outer membrane is freely permeable, the intermembrane space is chemically equivalent to the cytosol with respect to small molecules.[3] Because proteins must have a special cytochrome c.[7]

Inner membrane

Main article: Inner mitochondrial membrane

The inner mitochondrial membrane contains proteins with four types of functions:[3]

  1. Those that perform the oxidation reactions of the respiratory chain.
  2. ATP in the matrix.
  3. Specific transport proteins that regulate metabolite passage into and out of the matrix.
  4. Protein import machinery.

It contains more than 100 different electron transport chain.

Cristae

Main article: crista

  The inner mitochondrial membrane is compartmentalized into numerous chemiosmotic function.[9] In typical liver mitochondria, for example, the surface area, including cristae, is about five times that of the outer membrane. Mitochondria of cells that have greater demand for ATP, such as muscle cells, contain more cristae than typical liver mitochondria.[3]

Matrix

Main article: mitochondrial matrix

The matrix is the space enclosed by the inner membrane. It contains about 2/3 of the total protein in a mitochondrion.[3] 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, in addition to the special mitochondrial citric acid cycle.[3]

Mitochondria have their own genetic material, and the machinery to manufacture their own proteins encoded by genes that reside in the host cell's nucleus.

Organization and distribution

Mitochondria are found in nearly all eukaryotes. They vary in number and location according to cell type. Substantial numbers of mitochondria are in the liver, with about 1000–2000 mitochondria per cell making up 1/5th of the cell volume.[3] The mitochondria can be found nestled between myofibrils of muscle or wrapped around the sperm flagellum.[3] Often they form a complex 3D branching network inside the cell with the vimentin, one of the components of the cytoskeleton, is the critical to the association with the cytoskeleton.[12]

Function

The mitochondrion is well known for its ability to produce citric acid cycle. However, the mitochondrion has many other functions in addition to the production of ATP.

Energy conversion

A dominant role for the mitochondria is the production of anaerobic respiration, a process that is independent of the mitochondria.[4] The production of ATP from glucose has an approximately 13-fold higher yield during aerobic respiration compared to anaerobic respiration.[13]

Pyruvate: the citric acid cycle

Main articles: citric acid cycle

Each pyruvate molecule produced by glycolysis is actively transported across the inner mitochondrial membrane, and into the matrix where it is NADH.[4]

The acetyl-CoA is the primary substrate to enter the electron transport chain, and a molecule of GTP (that is readily converted to an ATP).[4]

NADH and FADH2: the electron transport chain

 

The redox energy from NADH and FADH2 is transferred to oxygen (O2) in several steps via the electron transport chain. These energy-rich molecules are produced within the matrix via the citric acid cycle but are also produced in the cytoplasm by oxidative stress in the mitochondria and may contribute to the decline in mitochondrial function associated with the aging process.[15]

As the proton concentration increases in the intermembrane space, a strong John E. Walker for their clarification of the working mechanism of ATP synthase.[18]

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 UCP1.[19] Thermogenin is a 33k Da protein first discovered in 1973.[20] 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.[19]

Storage of calcium ions

The concentrations of free calcium in the cell can regulate an array of reactions and is important for hormones in endocrine cells.

Additional functions

Although it is well-known that the mitochondria convert organic materials into cellular energy in the form of metabolic tasks, such as:

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.

Origin

Main article: Endosymbiotic theory

Mitochondria have many features in common with prokaryotes. They contain ribosomes and DNA and are formed only by the division of other mitochondria. As a result, they are believed to be originally derived from endosymbiotic prokaryotes. Studies of 80S ribosomes found elsewhere in the cell.[34]

A few groups of unicellular eukaryotes lack mitochondria: the microsporidians, metamonads, and archamoebae.[35] These groups appear as the most primitive eukaryotes on phylogenetic trees constructed using rRNA information, suggesting that they appeared before the origin of mitochondria. However, this is now known to be an artifact of long branch attraction – they are apparently derived groups and retain genes or organelles derived from mitochondria (e.g., mitosomes and hydrogenosomes).[1] There are no primitive eukaryotes today that lack mitochondria. The endosymbiosis with mitochondria may have played a critical part in the survival advantage of eukaryotic cells.

Genome

Main article: Mitochondrial DNA

The human mitochondrial genome is a circular rRNA.[36] One mitochondrion can contain 2–10 copies of its DNA.[37]

As in prokaryotes, there is a very high proportion of coding DNA and an absence of repeats. Mitochondrial genes are transcription as multigenic transcripts, which are cleaved and polyadenylated to yield mature mRNAs. Not all proteins necessary for mitochondrial function are encoded by the mitochondrial genome; most are coded by genes in the cell nucleus and imported to the mitochondrion.[38] The exact number of genes encoded by the nucleus and the yeast[41] and protists,[42] including Dictyostelium discoideum.[43]

While slight variations on the standard code had been predicted earlier,[44] none were discovered until 1979 when researchers studying human mitochondrial genes discovered they used an alternative code.[45] Many slight variants have been discovered since,[46] including various alternative mitochondrial codes.[47] Further, the AUA, AUC, and AUU codons are all allowable start codons.

Exceptions to the universal genetic code (UGC) in mitochondria[3]
OrganismCodonStandardNovel
Mammalian AGA, AGG Arginine Stop codon
AUA Isoleucine Methionine
UGA Stop codon Tryptophan
Invertebrates AGA, AGG Arginine Serine
AUA Isoleucine Methionine
UGA Stop codon Tryptophan
Yeast AUA Isoleucine Methionine
UGA Stop codon Tryptophan
CUA Leucine Threonine

Some of these differences should be regarded as pseudo-changes in the genetic code due to the phenomenon of universal genetic code for tryptophan.[48] Of note, the arthropod mitochondrial genetic code has undergone parallel evolution within a phylum, with some organisms uniquely translating AGG to lysine.[49]

Mitochondrial genomes have far fewer genes than the eubacteria from which they are thought to be descended. Although some have been lost altogether, many have been transferred to the nucleus, such as the respiratory complex II protein subunits.[36] This is thought to be relatively common over evolutionary time. A few organisms, such as the Cryptosporidium, actually have mitochondria that lack any DNA, presumably because all their genes have been lost or transferred.[50] In Cryptosporidium, the mitochondria have an altered atovaquone.[50]

Replication and inheritance

See also: mitochondrial genome

Mitochondria replicate their DNA and divide mainly in response to the energy needs of the cell. In other words, their growth and division is not linked to the cell cycle. When the energy needs of a cell are high, mitochondria grow and divide. When the energy use is low, mitochondria are destroyed or become inactive. At cell division, mitochondria are distributed to the daughter cells essentially randomly during the division of the cytoplasm. Mitochondria divide by binary fission similar to bacterial cell division; unlike bacteria, however, mitochondria can also fuse with other mitochondria.[36][51]

Mitochondrial genes are not inherited by the same mechanism as nuclear genes. At fertilization of an egg cell by a sperm, the egg nucleus and sperm nucleus each contribute equally to the genetic makeup of the zygote nucleus. In contrast, the mitochondria, and therefore the mitochondrial DNA, usually comes from the egg only. The sperm's mitochondria enters the egg but does not contribute genetic information to the embryo.[52] Instead, paternal mitochondria are marked with ubiquitin to select them for later destruction inside the embryo.[53] The egg cell contains relatively few mitochondria, but it is these mitochondria that survive and divide to populate the cells of the adult organism. Mitochondria are, therefore, in most cases inherited down the female line, known as maternal inheritance. This mode is seen in most organisms including all animals. However, mitochondria in some species can sometimes be inherited paternally. This is the norm among certain coniferous plants although not in pine trees and yew trees.[54] It has also been suggested to occur at a very low level in humans.[55]

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.[37] For this reason, mitochondrial DNA usually is thought of as reproducing by binary fission. What recombination does place maintains genetic integrity rather than maintaining diversity. However, there are studies showing evidence of recombination in mitochondrial DNA. The enzymes necessary for recombination clearly are present in mammalian cells.[56] Further, evidence suggests that animal mitochondria can undergo recombination.[57] The data are a bit more controversial in humans, although, indirect evidence exists.[58][59] If recombination does not occur, the whole mitochondrial DNA sequence represents a single haplotype, which makes it useful for studying the evolutionary history of populations.

Population genetic studies

Main article: Human mitochondrial genetics

The near-absence of genetic recombination in mitochondrial DNA makes it a useful source of information for scientists involved in population genetics and evolutionary biology.[60] Because all the mitochondrial DNA is inherited as a single unit, or out of Africa.[63] Another human example is the sequencing of mitochondrial DNA from Neanderthal bones. The relatively large evolutionary distance between the mitochondrial DNA sequences of Neanderthals and living humans has been interpreted as evidence for lack of interbreeding between Neanderthals and anatomically modern humans.[64]

However, mitochondrial DNA reflects the history of only females in a population, and so may not represent the history of the population as a whole. This can be partially overcome by the use of patrilineal genetic sequences, such as the non-recombining region of the Y-chromosome.[63] In a broader sense, only studies that also include nuclear DNA can provide a comprehensive evolutionary history of a population.[65] However, genetic recombination means that these studies can be difficult to analyze.

Dysfunction and disease

Mitochondrial diseases

Main article: Mitochondrial disease

With their central place in cell metabolism, damage and dysfunction in mitochondria is an important factor in a wide range of human diseases. Mitochondrial disorders often present as neurological disorders but can manifest as myopathy, diabetes, multiple endocrinopathy, or a variety of other systemic manifestations.[66] Diseases caused by mutation in the mtDNA include Kearns-Sayre syndrome, MELAS syndrome and Leber's hereditary optic neuropathy.[67] In the vast majority of cases, these diseases are transmitted by a female to her children, as the zygote derives its mitochondria and hence its mtDNA from the ovum. Diseases such as Kearns-Sayre syndrome, Pearson's syndrome, and progressive external ophthalmoplegia are thought to be due to large-scale mtDNA rearrangements, while other diseases such as MELAS syndrome, Leber's hereditary optic neuropathy, myoclonic epilepsy with ragged red fibers (MERRF) and others are due to point mutations in mtDNA.[66]

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 pesticide exposure and the later onset of Parkinson's disease.[69][70]

Other diseases not directly linked to mitochondrial enzymes may feature dysfunction of mitochondria. These include schizophrenia, bipolar disorder, dementia, Alzheimer's disease, Parkinson's disease, epilepsy, stroke, cardiovascular disease, reactive oxygen species. These oxidants then damage the mitochondrial DNA, resulting in mitochondrial dysfunction and cell death.[72]

Possible relationships to aging

Given the role of mitochondria as the cell's powerhouse, there may be some leakage of the high-energy oxidative stress and neuronal death in Parkinson's disease.[75] Hypothesized links between aging and oxidative stress are not new and were proposed over 50 years ago;[76] however, there is much debate over whether mitochondrial changes are causes of aging or merely characteristics of aging. One notable study in mice demonstrated no increase in reactive oxygen species despite increasing mitochondrial DNA mutations, suggesting the aging process is not due to oxidative stress.[77] As a result, the exact relationships between of mitochondria, oxidative stress, and aging have not yet been settled.

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See also

This article contains material from the Science Primer published by the NCBI, which, as a U.S. government publication, is in the public domain.

 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Mitochondrion". A list of authors is available in Wikipedia.