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.

Mitochondrial functions

• Apoptosis-programmed cell death
• Glutamate-mediated excitotoxic neuronal injury
• Cellular proliferation
• Regulation of the cellular redox state
• Heme synthesis
• Steroid synthesis

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

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 oxidised and combined with coenzyme A to form CO₂, acetyl CoA and NADH.

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. The citric acid cycle oxidises 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.

NADH and FADH₂: the electron transport chain

The redox energy from NADH and FADH₂ is transferred to oxygen (O₂) in several steps via the electron transport chain. 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 efficienct but a small percentage of electrons may leak prematurely to oxygen, forming the toxic free radical superoxide. This can cause oxidative damage in the mitochondria and may contribute to the decline in mitochondrial function associated with the aging process.

As the proton concentration increases in the intermembrane space, a strong electrochemical gradient is built up across the inner membrane. The protons can return to the matrix through the ATP synthase complex and their potential energy is used to synthesis ATP from ADP and inorganic phosphate (P_i). This process is called chemiosmosis and was first described by Peter Mitchell 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.

Heat production

Origin

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.

Reproduction and gene inheritance

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. Sperm cells contain a single spiral mitochondrion that is used to provide the energy needed for its swimming behavior. The sperm's mitochondria enters the egg, but are almost always destroyed and do not contribute their genes to the embryo.Kimball, J.W. (2006) "Sexual Reproduction in Humans: Copulation and Fertilization," Kimball's Biology Pages (based on Biology, 6th ed., 1996)] Paternal sperm mitochondria are marked with ubiquitin to select them for later destruction inside the embryo.}} Discussed in Science News. The egg 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 by binary fission. 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

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.

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.

Cited references