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Biological: Behavioural genetics · Evolutionary psychology · Neuroanatomy · Neurochemistry · Neuroendocrinology · Neuroscience · Psychoneuroimmunology · Physiological Psychology · Psychopharmacology (Index, Outline)
Mitochondrial genetics are the genetics of the DNA contained in mitochondria, eukaryotic cell organelles that generate adenosine triphosphate from pyruvic acid and are hence referred to as the "powerhouses" of the cell. Mitochondrial DNA (mtDNA) is not transmitted through nuclear DNA, and in most multicellular organisms, virtually all mitochondria are inherited from the mother's ovum.
Mitochondrial inheritance is therefore non-Mendelian, as Mendelian inheritance presumes that half the genetic material of a zygote derives from each parent.
Eighty percent of mitochondrial DNA codes for functional mitochondrial proteins, and therefore most mitochondrial DNA mutations lead to functional problems, which may be manifested as myopathies (muscle disorders).
Understanding the genetic mutations that affect mitochondria can help us to understand the inner workings of cells and organisms, as well as helping to suggest methods for successful therapeutic tissue and organ cloning, and to treatments or possibly cures for many devastating muscular disorders.
Mitochondrial function and genome[]
Because they provide 36 molecules of ATP per glucose molecule in contrast to the 2 ATP molecules produced by glycolysis, mitochondria are essential to all higher organisms for sustaining life. The mitochondrial diseases are genetic disorders carried specifically in mitochondrial DNA; slight problems with any one of the numerous enzymes used by the mitochondria can be devastating to the cell, and in turn, to the organism.
Membrane complexes[]
The processes carried out by the electron transport chain are mediated by protein complexes (named Complexes I-V, DHO-QO, ETF-QO, and ANT). Complex I, or NADH : coenzyme Q oxidoreductase, uses the energy in NADH to pump protons into the intermembrane space of the mitochondrion, pumping 2 protons per electron and passing 2 eletrons via coenzyme Q to complex III or coenzyme Q : cytochrome c oxidoreductase. Complex II or succinate : coenzyme Q oxidoreductase accepts energy from succinate produced in the citric acid cycle and passes it via coenzyme Q to complex III. Complex III pumps 1 protons per electron and passes 1 electron via cytochrome c to complex IV. Complex IV pumps 1 protons into the space between the mitochondrion’s two membranes before passing the electron to O2 which reacts to form water. Complex V (ATP synthase) is a rotary complex which allows approximately (determining the actual number is very difficult) 10 protons to enter the mitochondrial matrix along their concentration gradients. It uses the energy from the gradient to form the bond between ADP and the phosphate group to create ATP. The electron transfer flavoprotein : coenzyme Q oxidoreductase is also an electron-transporting molecule and is involved in the breakdown of fatty acids and amino acids. ANT (adenine nucleotide translocator) is also involved in oxidative phosphorylation as an energy carrying molecule. Each of these eight complexes plays a vital role in the health of the cell and any slight mutation in any one of the proteins that make up these complexes can lead to cell death or stress, which can both in turn lead to a number of diseases.
Genome[]
- Further information: Mitochondrial DNA
Mitochondrial DNA (mtDNA) is present in mitochondria as a circular molecule and in most species codes for 13 or 14 proteins involved in the electron transfer chain, 2 rRNA subunits and 22 tRNA molecules (all necessary for protein synthesis). The number of proteins involved in the electron transfer chain is much larger than 13 or 14, but the remainder is in fact coded by the nuclear DNA.
In total, the mitochondrion hosts about 3000 proteins, but only about 37 of them are coded on the mitochondrial DNA. Most of the 3000 genes are involved in a variety of processes other than ATP production, such as porphyrin synthesis. Only about 3% of them code for ATP production proteins. This means most of the genetic information coding for the protein makeup of mitochondria is in chromosomal DNA and is involved in processes other than ATP synthesis. This increases the chances that a mutation that will affect a mitochondrion will occur in chromosomal DNA, which is inherited in a Mendelian pattern. Another result is that a chromosomal mutation will affect a specific tissue due to its specific needs, whether those may be high energy requirements or a need for the catabolism or anabolism of a specific neurotransmitter or nucleic acid. Because several copies of the mitochondrial genome are carried by each mitochondrion (2-10 in humans), mitochondrial mutations can be inherited maternally by mtDNA mutations which are present in mitochondria inside the oocyte before fertilization, or (as stated above) through mutations in the chromosomes.
In humans, the heavy strand of mtDNA carries 28 genes and the light strand of mtDNA carries only 9 genes. Eight of the 9 genes on the light strand code for mitochondrial tRNA molecules. Human mtDNA consists of 16,569 nucleotide pairs. The entire molecule is regulated by only one regulatory region which contains the origins of replication of both heavy and light strands. The entire human mitochondrial DNA molecule has been mapped[1][2]. The rate of mutation in mtDNA is calculated to be about ten times greater than that of nuclear DNA, possibly due to a paucity of DNA repair mechanisms. This high mutation rate leads to a high variation between mitochondria, not only among different species but even within the same species. It is calculated that if two humans are chosen randomly and their mtDNA is tested, they will have an average of between fifty and seventy different nucleotides. This may not seem like much, but when compared to the total number of nucleotides of a human mitochondrial DNA molecule (16,569), as much as .42% of the mtDNA varies between two people.
Genetic code variants[]
The genetic code is, for the most part, universal, with few exceptions: mitochondrial genetics includes some of these. For most organisms the "stop codons" are “UAA”, “UAG”, and “UGA”. In vertebrate mitochondria “AGA” and “AGG” are also stop codons, but not “UGA”, which codes for tryptophan instead. “AUA” codes for isoleucine in most organisms but for methionine in vertebrate mitochondrial mRNA/tRNA.
There are many other variations among the codes used by other mitochondrial m/tRNA, which happened not to be harmful to their organisms, and which can be used as a tool (along with other mutations among the mtDNA/RNA of different species) to determine relative proximity of common ancestry of related species. (The more related two species are, the more mtDNA/RNA mutations will be the same in their mitochondrial genome).
Using these techniques, it is estimated that the first mitochondrion evolved, was consumed, or developed around 1.5 billion years ago, as an aerobic prokaryote in a symbiotic relationship within an anaerobic eukaryote.
Inheritance patterns[]
Because mitochondrial diseases (diseases due to malfunction of mitochondria) can be inherited both maternally and through chromosomal inheritance, the way in which they are passed on from generation to generation can vary greatly depending on the disease. Mitochondrial genetic mutations that occur in the nuclear DNA can occur in any of the chromosomes (depending on the species). Mutations inherited through the chromosomes can be autosomal dominant or recessive and can also be sex-linked dominant or recessive. Chromosomal inheritance follows normal Mendelian laws, despite the fact that the phenotype of the disease may be masked. Because of the complex ways in which mitochondrial and nuclear DNA "communicate" and interact, even seemingly simple inheritance is hard to diagnose. A mutation in chromosomal DNA may change a protein that regulates (an increase or decrease) the production of another certain protein in the mitochondria or the cytoplasm and may lead to slight, if any, noticeable symptoms. On the other hand, there are some devastating mtDNA mutations that are easy to diagnose because of their widespread damage to muscular, neural, and/or hepatic (among other high energy and metabolism dependent) tissues and due to the fact that they are present in the mother and all the offspring. Mitochondrial genome mutations are passed on 100% of the time from mother to all her offspring. Because the mitochondria within the fertilized oocyte is what the new life will have to begin with (in terms of mtDNA), and because the number of affected mitochondria varies from cell (in this case, the fertilized oocyte) to cell depending both on the number it inherited from its mother cell and environmental factors which may favor mutant or wildtype mitochondrial DNA, and because the number of mtDNA molecules in the mitochondria varies from around two to ten, the number of affected mtDNA molecules inherited to a specific offspring can vary greatly. It is possible, even in twin births, for one baby to receive more than half mutant mtDNA molecules while the other twin may receive only a tiny fraction of mutant mtDNA molecules with respect to wildtype (depending on how the twins divide from each other and how many mutant mitochondria happen to be on each side of the division). In a few cases, some mitochondria or a mitochondrion from the sperm cell enters the oocyte but paternal mitochondria are actively decomposed.
Replication, Repair, Transcription, and Translation[]
Mitochondrial replication is controlled by nuclear genes and is specifically suited to make as many mitochondria as that particular cell needs at the time. Human mitochondrial DNA (mtDNA) has three promoters, H1, H2, and L (heavy strand 1, heavy strand 2, and light strand promoters). The H1 promoter transcribes the entire heavy strand and the L promoter transcribes the entire light strand. The H2 promoter causes the transcription of the two mitochondrial rRNA molecules. When transcription takes place on the heavy strand a polycistronic transcript is created. The light strand produces either small transcripts, which can be used as primers, or one long transcript. The production of primers occurs by processing of light strand transcripts with the Mitochondrial RNase MRP (Mitochondrial RNA Processing). The requirement of transcription to produce primers links the process of transcription to mtDNA replication. Full length transcripts are cut into functional tRNA, rRNA, and mRNA molecules. The process of transcription initiation in mitochondria involves three types of proteins: the mitochondrial RNA polymerase (POLRMT), mitochondrial transcription factor A (TFAM), and mitochondrial transcription factors B1 and B2 (TFB1M, TFB2M). POLRMT, TFAM, and TFB1M or TFB2M assemble at the mitochondrial promoters and begin transcription. The actual molecular events that are involved in initiation are unknown, but these factors make up the basal transcription machinery and have been shown to function in vitro. Mitochondrial translation is still not very well understood. In vitro translations have still not been successful, probably due to the difficulty of isolating sufficient mt mRNA, functional mt rRNA, and possibly because of the complicated changes that the mRNA undergoes before it is translated.
Mitochondrial DNA Polymerase[]
The Mitochondrial DNA Polymerase (Pol gamma) is used in the copying of mtDNA during replication. Because the two (heavy and light) strands on the circular mtDNA molecule have different origins of replication, it replicates in a D-loop (displacement) configuration. One strand begins to replicate first, displacing the other strand. This continues until replication reaches the origin of replication on the other strand, at which point the other strand beings replicating in the opposite direction. This results in two new mtDNA molecules. Each mitochondria has several copies of the mtDNA molecule and the number of mtDNA molecules is a limiting factor in mitochondrial fission. After the mitochondrion has enough mtDNA, membrane area, and membrane proteins, it can undergo fission (very similar to that which bacteria use) to become two mitochondria. Evidence suggests that mitochondria can also undergo fusion and exchange (in a form of crossover) genetic material among each other. Mitochondria sometimes form large matrices in which fusion, fission, and protein exchanges are constantly occurring. mtDNA shared among mitochondria (despite the fact that they can undergo fusion).
Damage and transcription error[]
Mitochondrial DNA is prone to damage from free oxygen radicals from mistakes that occur during the production of ATP through the electron transport chain. These mistakes can be caused by genetic disorders, cancer, and temperature variations. These radicals can damage mtDNA molecules or change them, making it hard for mitochondrial polymerase to replicate them. Both cases can lead to deletions, rearrangements, and other mutations. Recent evidence has suggested that mitochondria have enzymes that proofread mtDNA and fix mutations that may occur due to free radicals. It is believed that a DNA recombinase found in mammalian cells is also involved in a repairing recombination process. Deletions and mutations due to free radicals have been associated with the aging process. It is believed that radicals cause mutations which lead to mutant proteins, which in turn lead to more radicals. This process takes many years and is associated with some aging processes involved in oxygen-dependent tissues such as brain, heart, muscle, and kidney. Auto-enhancing processes such as these are possible causes of degenerative diseases including Parkinson’s, Alzheimer’s, and coronary artery disease.
Chromosomally Mediated mtDNA Replication Errors[]
Because mitochondrial growth and fission are mediated by the nuclear DNA, mutations in nuclear DNA can have a wide array of effects on mtDNA replication. Despite the fact that the loci for some of these mutations have been found on human chromosomes, specific genes and proteins involved have not yet been isolated. Mitochondria need a certain protein to undergo fission. If this protein (made by the nucleus) is not present, the mitochondria grow but they do not divide. This leads to giant, inefficient mitochondria. Mistakes in chromosomal genes or their products can also affect mitochondrial replication more directly by inhibiting mitochondrial polymerase and can even cause mutations in the mtDNA directly and indirectly. Indirect mutations are most often caused by radicals created by defective proteins made from nuclear DNA.
Mitochondrial Diseases[]
Mitochondrial diseases range in severity from almost not diagnosable to fatal. They also range in cause from inherited to acquired mutations (although acquired mutations that cause disease are very rare). A certain mutation can cause several different diseases depending on the severity of the problem in the mitochondria and the tissue the affected mitochondria are in. Conversely, several different mutations may present themselves as the same disease. This almost patient-specific characterization of mitochondrial diseases makes them very hard to accurately diagnose and trace. Some diseases are observable at or even before birth (most causing death) while others do not show themselves until late adulthood. This is because the number of mutant versus wildtype mitochondria varies from cell to cell and tissue to tissue, and is always changing. Because cells have multiple mitochondria, different mitochondria in the same cell can have different variations of the mtDNA genome. This condition is referred to as heteroplasmy. When a certain tissue reaches a certain ration of mutant versus wildtype mitochondria, a disease will present itself. The ration varies from person to person and tissue to tissue (depending on its specific energy, oxygen, and metabolism requirements, and the effects of the specific mutation). Mitochondrial diseases are very numerous and different. Apart from diseases definitely caused by abnormalities in mitochondrial DNA, many diseases are suspected to be caused in part by dysfunction of mitochondria, such as diabetes mellitus, forms of cancer and cardiovascular disease, lactic acidosis, specific forms of myopathy, osteoporosis, Alzheimer's disease, Parkinsons's disease, stroke, and many more. Furthermore, mtDNA mutations are believed to play a role in the aging process.
Notes[]
- ^ Societat Catalana de Neurologia. URL accessed on December 5, 2005.
- ^ http://www.mitomap.org/mitomap/mitomapgenome.pdf. URL accessed on December 5, 2005.
See also[]
- Human mitochondrial DNA haplogroups
- Cambridge Reference Sequence
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