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Electron micrograph of a mitochondrion from mammalian lung tissue showing its matrix and membranes.
Schematic of typical animal cell, showing subcellular components. Organelles:
(1) Nucleolus
(2) Nucleus
(3) Ribosomes
(4) Vesicle
(5) Rough endoplasmic reticulum (ER)
(6) Golgi apparatus
(7) Cytoskeleton
(8) Smooth ER
(9) Mitochondria
(10) Vacuole
(11) Cytoplasm
(12) Lysosome
(13) Centrioles within centrosome

In cell biology, a mitochondrion (plural mitochondria) is a membrane-enclosed organelle found in most eukaryotic cells.[1] These organelles range from 0.5 to 10 micrometers (μm) in diameter. Mitochondria are sometimes described as "cellular power plants" because they generate most of the cell's supply of adenosine triphosphate (ATP), used as a source of chemical energy.[2] In addition to supplying cellular energy, mitochondria are involved in a range of other processes, such as signaling, cellular differentiation, cell death, as well as the control of the cell cycle and cell growth.[3] Mitochondria have been implicated in several human diseases, including mitochondrial disorders[4] and cardiac dysfunction,[5] and may play a role in the aging process. The word mitochondrion comes from the Greek μίτος or mitos, thread + χονδρίον or chondrion, granule.

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.[6][7] The organelle is composed of compartments that carry out specialized functions. These compartments or regions include the outer membrane, the intermembrane space, the inner membrane, and the cristae and matrix. Mitochondrial proteins vary depending on the tissue and the species. In humans, 615 distinct types of proteins have been identified from cardiac mitochondria;[8] whereas in Murinae (rats), 940 proteins encoded by distinct genes have been reported.[9] The mitochondrial proteome is thought to be dynamically regulated.[10] Although most of a cell's DNA is contained in the cell nucleus, the mitochondrion has its own independent genome. Further, its DNA shows substantial similarity to bacterial genomes.[11]

Contents

Structure

Animal mitochondrion diagram en (edit).svg

A mitochondrion contains outer and inner membranes composed of phospholipid bilayers and proteins.[6] The two membranes, however, have different properties. Because of this double-membraned organization, there are five distinct compartments within the mitochondrion. There is the outer mitochondrial membrane, the intermembrane space (the space between the outer and inner membranes), the inner mitochondrial membrane, the crista space (formed by infoldings of the inner membrane), and the matrix (space within the inner membrane).

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Outer membrane

The outer mitochondrial membrane, which encloses the entire organelle, has a protein-to-phospholipid ratio similar to that of the eukaryotic plasma membrane (about 1:1 by weight). It contains large numbers of integral proteins called porins. These porins form channels that allow molecules 5000 Daltons or less in molecular weight to freely diffuse from one side of the membrane to the other.[6] Larger proteins can enter the mitochondrion if a signaling sequence at their N-terminus binds to a large multisubunit protein called translocase of the outer membrane, which then actively moves them across the membrane.[12] Disruption of the outer membrane permits proteins in the intermembrane space to leak into the cytosol, leading to certain cell death.[13] The mitochondrial outer membrane can associate with the ER membrane, in a structure called MAM (mitochondria-associated ER-membrane). This is important in ER-mitochondria calcium signaling and involved in the transfer of lipids between the ER and mitochondria.[14]

Intermembrane space

The intermembrane space is the space between the outer membrane and the inner membrane. Because the outer membrane is freely permeable to small molecules, the concentrations of small molecules such as ions and sugars in the intermembrane space is the same as the cytosol.[6] However, as large proteins must have a specific signaling sequence to be transported across the outer membrane, the protein composition of this space is different than the protein composition of the cytosol. One protein that is localized to the intermembrane space in this way is cytochrome c.[13]

Inner membrane

The inner mitochondrial membrane contains proteins with five types of functions:[6]

  1. Those that perform the redox reactions of oxidative phosphorylation
  2. ATP synthase, which generates ATP in the matrix
  3. Specific transport proteins that regulate metabolite passage into and out of the matrix
  4. Protein import machinery.
  5. Mitochondria fusion and fission protein

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). The inner membrane is home to around 1/5 of the total protein in a mitochondrion.[6] In addition, the inner membrane is rich in an unusual phospholipid, cardiolipin. This phospholipid was originally discovered in beef hearts in 1942, and is usually characteristic of mitochondrial and bacterial plasma membranes.[15] Cardiolipin contains four fatty acids rather than two and may help to make the inner membrane impermeable.[6] 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 Oxa1.[12] In addition, there is a membrane potential across the inner membrane formed by the action of the enzymes of the electron transport chain.

Cristae

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

The inner mitochondrial membrane is compartmentalized into numerous 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 greater than 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. These folds are studded with small round bodies known as F1 particles or oxysomes. These are not simple random folds but rather invaginations of the inner membrane, which can affect overall chemiosmotic function.[16]

Matrix

The matrix is the space enclosed by the inner membrane. It contains about 2/3 of the total protein in a mitochondrion.[6] The matrix is important in the production of ATP with the aid of the ATP synthase contained in the inner membrane. The matrix contains a highly-concentrated mixture of hundreds of enzymes, special mitochondrial ribosomes, tRNA, and several copies of the mitochondrial DNA genome. Of the enzymes, the major functions include oxidation of pyruvate and fatty acids, and the citric acid cycle.[6]

Mitochondria have their own genetic material, and the machinery to manufacture their own RNAs and proteins (see: protein biosynthesis). A published human mitochondrial DNA sequence revealed 16,569 base pairs encoding 37 total genes: 22 tRNA, 2 rRNA, and 13 peptide genes.[17] The 13 mitochondrial peptides in humans are integrated into the inner mitochondrial membrane, along with 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. A single highly branched mitochondrion was described in the unicellular alga "Polytomella agilis".[18] Substantial numbers of mitochondria are in the liver, with about 1000–2000 mitochondria per cell making up 1/5th of the cell volume.[6] The mitochondria can be found nestled between myofibrils of muscle or wrapped around the sperm flagellum.[6] Often they form a complex 3D branching network inside the cell with the cytoskeleton. The association with the cytoskeleton determines mitochondrial shape, which can affect the function as well.[19] Recent evidence suggests vimentin, one of the components of the cytoskeleton, is critical to the association with the cytoskeleton.[20]

Function

The most prominent roles of mitochondria are to produce ATP (i.e., phosphorylation of ADP) through respiration, and to regulate cellular metabolism.[7] The central set of reactions involved in ATP production are collectively known as the citric acid cycle, or the Krebs Cycle. However, the mitochondrion has many other functions in addition to the production of ATP.

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 oxidized and combined with coenzyme A to form CO2, acetyl-CoA, and NADH.[7]

The acetyl-CoA is the primary substrate to enter the citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or Krebs cycle. 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.[21] The citric acid cycle oxidizes the acetyl-CoA to carbon dioxide, and, in the process, produces reduced cofactors (three molecules of NADH and one molecule of FADH2) that are a source of electrons for the electron transport chain, and a molecule of GTP (that is readily converted to an ATP).[7]

NADH and FADH2: the electron transport chain

Diagram of the electron transport chain in the mitonchondrial intermembrane space

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 glycolysis. Reducing equivalents from the cytoplasm can be imported via the malate-aspartate shuttle system of antiporter proteins or feed into the electron transport chain using a glycerol phosphate shuttle.[7] Protein complexes in the inner membrane (NADH dehydrogenase, cytochrome c reductase, and cytochrome c oxidase) perform the transfer and the incremental release of energy is used to pump protons (H+) into the intermembrane space. This process is efficient, but a small percentage of electrons may prematurely reduce oxygen, forming reactive oxygen species such as superoxide.[7] This can cause oxidative stress in the mitochondria and may contribute to the decline in mitochondrial function associated with the aging process.[22]

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 (Pi).[7] This process is called chemiosmosis, and was first described by Peter Mitchell[23][24] 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.[25]

Origin

Mitochondria have many features in common with prokaryotes. As a result, they are believed to be originally derived from endosymbiotic prokaryotes.

A mitochondrion contains DNA, which is organized as several copies of a single, 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 twenty-two tRNAs necessary for the translation of messenger RNAs into protein. The circular structure is also found in prokaryotes, and the similarity is extended by the fact that mitochondrial DNA is organized with a variant genetic code similar to that of Proteobacteria.[26] This suggests that their ancestor, the so-called proto-mitochondrion, was a member of the Proteobacteria.[26] In particular, the proto-mitochondrion was probably related to the rickettsia.[27] However, the exact relationship of the ancestor of mitochondria to the alpha-proteobacteria and whether the mitochondria was formed at the same time or after the nucleus, remains controversial.[28]

The ribosomes coded for by the mitochondrial DNA are similar to those from bacteria in size and structure.[29] 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.[30] The endosymbiotic hypothesis suggests that mitochondria descended from 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. In a similar manner, host cells with symbiotic bacteria capable of photosynthesis would have had an advantage. The incorporation of symbiotes would have increased the number of environments in which the cells could survive. This symbiotic relationship probably developed 1.7[31]-2[32] billion years ago.

A few groups of unicellular eukaryotes lack mitochondria: the microsporidians, metamonads, and archamoebae.[33] 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).[1]

Genome

The human mitochondrial genome is a circular DNA molecule of about 16 kilobases.[34] 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.[34] One mitochondrion can contain two to ten copies of its DNA.[35]

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. Not all proteins necessary for mitochondrial function are encoded by the mitochondrial genome; most are coded by genes in the cell nucleus and the corresponding proteins are imported into the mitochondrion.[36] The exact number of genes encoded by the nucleus and the mitochondrial genome differs between species. In general, mitochondrial genomes are circular, although exceptions have been reported.[37] In general, mitochondrial DNA lacks introns, as is the case in the human mitochondrial genome;[36] however, introns have been observed in some eukaryotic mitochondrial DNA,[38] such as that of yeast[39] and protists,[40] including Dictyostelium discoideum.[41]

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.[42] This pattern is also found in other sucking lice but not in chewing lice. Recombination has been shown to occur between the minichromosomes. The reason for this difference is not known.

While slight variations on the standard code had been predicted earlier,[43] none was discovered until 1979, when researchers studying human mitochondrial genes determined that they used an alternative code.[44] Many slight variants have been discovered since,[45] including various alternative mitochondrial codes.[46] Further, the AUA, AUC, and AUU codons are all allowable start codons.

Exceptions to the universal genetic code (UGC) in mitochondria[6]
Organism Codon Standard Novel
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 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 universal genetic code for tryptophan.[47] Of note, the arthropod mitochondrial genetic code has undergone parallel evolution within a phylum, with some organisms uniquely translating AGG to lysine.[48]

Mitochondrial genomes have far fewer genes than the bacteria 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.[34] 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.[49] 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.[49]

Replication and inheritance

Mitochondria divide by binary fission similar to bacterial cell division; unlike bacteria, however, mitochondria can also fuse with other mitochondria.[34][50]. The regulation of this division differs between eukaryotes. In many single-celled eukaryotes, their growth and division is 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 the energy use is low, mitochondria are destroyed or become inactive. In such examples, and in contrast to the situation in many single celled eukaryotes, mitochondria are apparently randomly distributed to the daughter cells during the division of the cytoplasm.

An individual's 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 enter the egg but do not contribute genetic information to the embryo.[51] Instead, paternal mitochondria are marked with ubiquitin to select them for later destruction inside the embryo.[52] 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.[53] It has been suggested that it occurs at a very low level in humans.[54]


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