Mitochondrion

In cell biology, a mitochondrion (plural mitochondria) (from Greek mitos thread + khondrion granule) is an organelle, variants of which are found in most eukaryotic cells. Mitochondria are sometimes described as "cellular power plants," because their primary function is to convert organic materials into energy in the form of ATP via the process of oxidative phosphorylation. Usually a cell has hundreds or thousands of mitochondria, which can occupy up to 25% of the cell's cytoplasm. Mitochondria have their own DNA and according to Endosymbiotic theory may have descended from free-living prokaryotes that were closely related to rickettsia bacteria.

Mitochondrion structure


A mitochondrion contains outer and inner membranes composed of phospholipid bilayers studded with proteins, much like a typical cell membrane, from which it probably evolved. The two membranes, however, have very different properties.

The outer mitochondrial membrane, which encloses the entire organelle, contains numerous integral proteins called porins, which contain a relatively large internal channel (about 2-3 nm) that is permeable to all molecules of 5000 daltons or less. Larger molecules can only traverse the outer membrane by active transport. The outer mitochondrial membrane is composed of about 50% phospholipids by mass and contains a variety of enzymes involved in such diverse activities as the elongation of fatty acids, oxidation of epinephrine (adrenaline), and the degradation of tryptophan.

The inner membrane contains proteins with three types of functions:
 * 1) those that carry out the oxidation reactions of the respiratory chain
 * 2) ATP synthase, which makes ATP in the matrix
 * 3) specific transport proteins that regulate the passage of metabolites into and out of the matrix.

It contains more than 100 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). Additionally, the inner membrane is rich in an unusual phospholipid, cardiolipin, which is usually characteristic of bacterial plasma membranes. Unlike the outer membrane, the inner membrane does not contain porins, and is highly impermeable; almost all ions and molecules require special membrane transporters to enter or exit the matrix. In addition, there is a membrane potential across the inner membrane.



The mitochondrial matrix
The matrix is the space enclosed by the inner membrane. The matrix contains a highly concentrated mixture of hundreds of enzymes, in addition to the 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.

Thus, mitochondria possess their own genetic material, and the machinery to manufacture their own RNAs and proteins. (See: protein synthesis). This nonchromosomal DNA encodes a small number of mitochondrial peptides (13 in humans) that are integrated into the inner mitochondrial membrane, along with polypeptides encoded by genes that reside in the host cell's nucleus.

The inner mitochondrial membrane is folded into numerous cristae (see diagram above), which expand the surface area of the inner mitochondrial membrane, enhancing its ability to generate ATP. In typical liver mitochondria, for example, the surface area, including cristae, is about five times that of the outer membrane. Mitochondria of cells which have greater demand for ATP, such as muscle cells, contain even more cristae than typical liver mitochondria.

Mitochondrial functions
Although the primary function of mitochondria is to convert organic materials into cellular energy in the form of ATP, mitochondria play an important role in many metabolic tasks, such as:


 * Apoptosis-programmed cell death
 * Glutamate-mediated excitotoxic neuronal injury
 * Cellular proliferation
 * Regulation of the cellular redox state
 * Heme synthesis
 * Steroid synthesis
 * Heat production (enabling the organism to stay warm).

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 a variety of mitochondrial diseases.

Energy conversion
As stated above, the primary function of the mitochondria is the production of ATP. This is done by metabolizing the major products of glycolysis: pyruvate and NADH (glycolysis is performed outside the mitochondria, in the host cell's cytosol). This metabolism can be performed in two very different ways, depending on the type of cell and the presence or absence of oxygen.

Pyruvate: the citric acid cycle
Each pyruvate molecule produced by glycolysis is actively transported across the inner mitochondrial membrane, and into the matrix where it is combined with coenzyme A to form acetyl CoA. Once formed, acetyl CoA is fed into the citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or Krebs cycle. This process creates 3 molecules of NADH and 1 molecule of FADH2, which go on to participate in the electron transport chain.

With the exception of succinate dehydrogenase, which is bound to the inner mitochondrial membrane, all of the enzymes of the citric acid cycle are dissolved in the mitochondrial matrix.

NADH and FADH2: the electron transport chain
This energy from NADH and FADH2 is transferred to oxygen (O2) in several steps via the electron transfer chain. The protein complexes in the inner membrane (NADH dehydrogenase, cytochrome c reductase, cytochrome c oxidase) that perform the transfer use the released energy to pump protons (H+) against a gradient (the concentration of protons in the intermembrane space is higher than that in the matrix). While this process occurs with great efficiency, a small percentage of electrons may leak prematurely to oxygen, forming the toxic free radical superoxide (which is thought to contribute to a wide variety of disease, including, possibly aging).

As the proton concentration increases in the intermembrane space, a strong concentration gradient is built up. The main exit for these protons is through the ATP synthase complex. By transporting protons from the intermembrane space back into the matrix, the ATP synthase complex can make ATP from ADP and inorganic phosphate (Pi). This process is called chemiosmosis and is an example of facilitated diffusion. Peter Mitchell was awarded the 1978 Nobel Prize in Chemistry for his work on chemiosmosis. 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.

Under certain conditions, protons may be allowed to re-enter the mitochondial matrix without contributing to ATP synthesis. This process, known as proton leak or mitochondrial uncoupling, results in the unharnessed energy being released as heat. This mechanism for the metabolic generation of heat is employed primarily in specialized tissues, such as the "brown fat" of newborn or hibernating mammals, brown in colour due to high levels of mitochondria.

Reproduction and gene inheritance
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 more or less 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. Sometimes new mitochondria are synthesized in centers that are rich in proteins and polysomes are needed for their synthesis.

Mitochondrial genes are not inherited by the same mechanism as nuclear genes. At fertilization of an egg 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. During fertilization a single sperm enters the egg along with the mitochondria that it uses to provide the energy needed for its swimming behavior. However, the mitochondria provided by the sperm are targeted for destruction very soon after entry into the egg. The egg itself contains relatively few mitochondria, but it is these mitochondria that survive and divide to populate the cells of the adult organism. This means that mitochondria are, in most cases, inherited down the female line.

This maternal inheritance of mitochondrial DNA is seen in most organisms, including all animals. However, mitochondria in some species can sometimes be inherited through the father. This is the norm amongst certain coniferous plants (although not in pines and yew trees). It has been suggested to occur at a very low level in humans.

Uniparental inheritance means that there is little opportunity for genetic recombination between different lineages of mitochondria. For this reason, mitochondrial DNA is usually thought of as reproducing clonally. However, there are several claims of recombination in mitochondrial DNA, most controversially in humans. 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.

Mitochondrial genomes have many fewer genes than do the related eubacteria from which they are thought to be descended. Although some have been lost altogether, many seem to have been transferred to the nucleus. This is thought to be relatively common over evolutionary time. A few organisms, such as Cryptosporidium, actually have mitochondria which lack any DNA, presumably because all their genes have either been lost or transferred.

The uniparental inheritance of mitochondria is thought to result in intragenomic conflict, such as seen in the petite mutant mitochondria of some yeast species. It is possible that the evolution of separate male and female sexes is a mechanism to resolve this organelle conflict.

Use in population genetic studies
Main article: 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. 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 lack of interbreeding between Neanderthals and anatomically modern humans.

However, mitochondrial DNA only reflects the history of females in a population, and so may not give a representative picture of the history of the population as a whole. For example, if dispersal is primarily undertaken by males, this will not be picked up by mitochondrial studies. This can be partially overcome by the use of patrilineal genetic sequences, if they are available (in mammals the non-recombining region of the Y-chromosome provides such a source). More broadly, only studies that also include nuclear DNA can provide a comprehensive evolutionary history of a population; unfortunately, genetic recombination means that these studies can be difficult to analyse.

Origin
As mitochondria contain ribosomes and DNA, and are only formed by the division of other mitochondria, it is generally accepted that they were originally derived from endosymbiotic prokaryotes. Studies of mitochondrial DNA, which is often circular and employs a variant genetic code, show their ancestor, the so-called proto-mitochondrion, was a member of the Proteobacteria. In particular, the pre-mitochondrion was probably related to the rickettsias, although the exact position of the ancestor of mitochondria among the alpha-proteobacteria remains controversial. The endosymbiotic hypothesis suggests that mitochondria descended from specialized bacteria (probably purple nonsulfur bacteria) that somehow survived endocytosis by another species of prokaryote or some other cell type, and became incorporated into the cytoplasm. The ability of symbiont bacteria to conduct cellular respiration in host cells that had relied on glycolysis and fermentation would have provided a considerable evolutionary advantage. Similarly, host cells with symbiotic bacteria capable of photosynthesis would also have an advantage. In both cases, the number of environments in which the cells could survive would have been greatly expanded.

This relationship developed at least 2 billion years ago and mitochondria still show some signs of their ancient origin. Mitochondrial ribosomes are the 70S (bacterial) type, in contrast to the 80S ribosomes found elsewhere in the cell. 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. Unlike their nuclear cousins, mitochondrial genes are small, generally lacking introns, and many chromosomes are circular, conforming to the bacterial pattern.

A few groups of unicellular eukaryotes lack mitochondria: the microsporidians, metamonads, and archamoebae. On rRNA trees these groups appeared as the most primitive eukaryotes, suggesting they appeared before the origin of mitochondria, but 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). Thus it appears that there are no primitively amitochondriate eukaryotes, and so the origin of mitochondria may have played a critical part in the development of eukaryotic cells.

Fiction

 * The midi-clorians of the Star Wars universe are fictional life-forms inside cells that provide the Force. George Lucas took inspiration from the endosymbiotic theory.
 * A Wind in the Door posits fictional "farandolae" which are to mitochondria what mitochondria are to cells.
 * In the acclaimed novel and video game Parasite Eve, mitochondria are shown to be their own independent organisms, using animals and plants as a form of "transportation," causing a major biological disaster when they decide to set themselves free.