16,569 bp human mitochondrial genome encoding 37 genes,
i.e., 28 on the H-strand and 9 on the L-strand Mitochondria contain their own genome. The
human mitochondrial genome is a circular double-stranded
DNA molecule of about 16
kilobases. 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 (12S and 16S rRNA). One of the two mitochondrial DNA (mtDNA) strands has a disproportionately higher ratio of the heavier nucleotides adenine and guanine, and this is termed the heavy strand (or H strand), whereas the other strand is termed the light strand (or L strand). The weight difference allows the two strands to be separated by
centrifugation. mtDNA has one long non-coding stretch known as the non-coding region (NCR), which contains the heavy strand promoter (HSP) and light strand promoter (LSP) for RNA transcription, the origin of replication for the H strand (OriH) localized on the L strand, three conserved sequence boxes (CSBs 1–3), and a termination-associated sequence (TAS). The origin of replication for the L strand (OriL) is localized on the H strand 11,000 bp downstream of OriH, located within a cluster of genes coding for tRNA. 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. 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
introns, as is the case in the human mitochondrial genome; such as that of
yeast and
protists, 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
sucking lice, but not in
chewing lice. Recombination has been shown to occur between the minichromosomes.
Human population genetic studies The near-absence of
genetic recombination in mitochondrial DNA makes it a useful source of information for studying
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 the lack of interbreeding between Neanderthals and modern humans. 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. 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).
Alternative genetic code While slight variations on the standard
genetic code had been predicted earlier, none was discovered until 1979, when researchers studying
human mitochondrial genes determined that they used an alternative code. Nonetheless, the mitochondria of many other eukaryotes, including most plants, use the standard code. Many slight variants have been discovered since, Further, the AUA, AUC, and AUU codons are all allowable start codons. 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.
Replication and inheritance Mitochondria divide by
mitochondrial fission, a form of
binary fission that is also done by bacteria although the process is tightly regulated by the host eukaryotic cell and involves communication between and contact with several other organelles. The regulation of this division differs between eukaryotes. In many single-celled eukaryotes, their growth and division are 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 energy use is low, mitochondria are destroyed or become inactive. In such examples mitochondria are apparently randomly distributed to the daughter cells during the division of the
cytoplasm. Mitochondrial dynamics, the balance between
mitochondrial fusion and
fission, is an important factor in pathologies associated with several disease conditions. 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
egg cell 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. Instead, paternal mitochondria are marked with
ubiquitin to select them for later destruction inside the
embryo. 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
coniferous plants, although not in
pine trees and
yews. For
Mytilids, paternal inheritance only occurs within males of the species. 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. 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
stochastic processes in the cell to increase the cell-to-cell variability in
mutant load 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.
DNA repair Mitochondria can repair oxidative
DNA damage by mechanisms analogous to those occurring in the
cell nucleus. The proteins employed in
mtDNA repair are encoded by nuclear
genes, and are translocated to the mitochondria. The
DNA repair pathways in mammalian mitochondria include
base excision repair, double-strand break repair, direct reversal and
mismatch repair. Alternatively, DNA damage may be bypassed, rather than repaired, by translesion synthesis. Of the several DNA repair process in mitochondria, the base excision repair pathway has been most comprehensively studied. 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. 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. In related species, the mitochondrial genome still has three genes, but in
A. cerati only a single mitochondrial gene — the
cytochrome c oxidase I gene (
cox1) — is found, and it has migrated to the genome of the nucleus. ==Dysfunction and disease==