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. recent measurements of the molecular clock for mitochondrial dna 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 (10−8 per base per generation). alternative genetic code exceptions to the standard genetic code in mitochondria organismcodonstandardmitochondria mammals aga, agg arginine stop codon invertebrates aga, agg arginine serine fungi cua leucine threonine all of the above aua isoleucine methionine uga stop codon tryptophan 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, including various alternative mitochondrial codes. 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. what recombination does take place maintains genetic integrity rather than maintaining diversity. however, there are studies showing evidence of recombination in mitochondrial dna. it is clear that the enzymes necessary for recombination are present in mammalian cells. 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. base excision repair is carried out by a sequence of enzyme-catalyzed steps that include recognition and excision of a damaged dna base, removal of the resulting abasic site, end processing, gap filling and ligation. a common damage in mtdna that is repaired by base excision repair is 8-oxoguanine produced by oxidation of guanine. 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. lack of mitochondrial dna some organisms have lost mitochondrial dna altogether. in these cases, genes encoded by the mitochondrial dna have been lost or transferred to the nucleus. cryptosporidium have mitochondria that lack any dna, presumably because all their genes have been lost or transferred. 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. mitochondria that lack their own dna have been found in a marine parasitic dinoflagellate from the genus amoebophyra. this microorganism, a. cerati, has functional mitochondria that lack a genome. 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 mitochondrial diseases main article: mitochondrial disease damage and subsequent dysfunction in mitochondria is an important factor in a range of human diseases due to their influence in cell metabolism. mitochondrial disorders often present as neurological disorders, including autism. they can also manifest as myopathy, diabetes, multiple endocrinopathy, and a variety of other systemic disorders. diseases caused by mutation in the mtdna include kearns–sayre syndrome, melas syndrome and leber's hereditary optic neuropathy. 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 syndrome, and progressive external ophthalmoplegia are thought to be due to large-scale mtdna rearrangements, whereas other diseases such as melas syndrome, leber's hereditary optic neuropathy, merrf syndrome, and others are due to point mutations in mtdna. it has also been reported that drug tolerant cancer cells have an increased number and size of mitochondria which suggested an increase in mitochondrial biogenesis. a 2022 study in nature nanotechnology has reported that cancer cells can hijack the mitochondria from immune cells via physical tunneling nanotubes. 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 wilson's disease. these diseases are inherited in a dominance relationship, as applies to most other genetic diseases. a variety of disorders can be caused by nuclear mutations of oxidative phosphorylation enzymes, such as coenzyme q10 deficiency and barth syndrome. environmental influences may interact with hereditary predispositions and cause mitochondrial disease. for example, there may be a link between pesticide exposure and the later onset of parkinson's disease. other pathologies with etiology involving mitochondrial dysfunction include schizophrenia, bipolar disorder, dementia, alzheimer's disease, parkinson's disease, epilepsy, stroke, cardiovascular disease, chronic fatigue syndrome, retinitis pigmentosa, and diabetes mellitus. mitochondria-mediated oxidative stress plays a role in cardiomyopathy in type 2 diabetics. increased fatty acid delivery to the heart increases fatty acid uptake by cardiomyocytes, resulting in increased fatty acid oxidation in these cells. this process increases the reducing equivalents available to the electron transport chain of the mitochondria, ultimately increasing reactive oxygen species (ros) production. ros increases uncoupling proteins (ucps) and potentiate proton leakage through the adenine nucleotide translocator (ant), the combination of which uncouples the mitochondria. uncoupling then increases oxygen consumption by the mitochondria, compounding the increase in fatty acid oxidation. this creates a vicious cycle of uncoupling; furthermore, even though oxygen consumption increases, atp synthesis does not increase proportionally because the mitochondria are uncoupled. less atp availability ultimately results in an energy deficit presenting as reduced cardiac efficiency and contractile dysfunction. to compound the problem, impaired sarcoplasmic reticulum calcium release and reduced mitochondrial reuptake limits peak cytosolic levels of the important signaling ion during muscle contraction. decreased intra-mitochondrial calcium concentration increases dehydrogenase activation and atp synthesis. so in addition to lower atp synthesis due to fatty acid oxidation, atp synthesis is impaired by poor calcium signaling as well, causing cardiac problems for diabetics. relationships to aging there may be some leakage of the electrons transferred in the respiratory chain to form reactive oxygen species. this was thought to result in significant oxidative stress in the mitochondria with high mutation rates of mitochondrial dna. hypothesized links between aging and oxidative stress are not new and were proposed in 1956, which was later refined into the mitochondrial free radical theory of aging. a vicious cycle was thought to occur, as oxidative stress leads to mitochondrial dna mutations, which can lead to enzymatic abnormalities and further oxidative stress. a number of changes can occur to mitochondria during the aging process. tissues from elderly humans show a decrease in enzymatic activity of the proteins of the respiratory chain. however, mutated mtdna can only be found in about 0.2% of very old cells. large deletions in the mitochondrial genome have been hypothesized to lead to high levels of oxidative stress and neuronal death in parkinson's disease. mitochondrial dysfunction has also been shown to occur in amyotrophic lateral sclerosis. since mitochondria cover a pivotal role in the ovarian function, by providing atp necessary for the development from germinal vesicle to mature oocyte, a decreased mitochondria function can lead to inflammation, resulting in premature ovarian failure and accelerated ovarian aging. the resulting dysfunction