Why is programmed cell death important

In other cases, they may have lost their function, or they may have competed and lost out to other cells. In some organisms, especially lower species, there are cells that die off very soon after they are born. There is no clear reason why they ever existed. These cells are probably evolutionary relics that were useful in the past, but no longer serve any valuable function. For an example of cells that lose their function, consider the cells in the tail of the tadpole, which become superfluous when the animal develops into a frog.

The brain makes many more neurons than we need, probably because the body does not 'know' how many neurons will suffice and because wiring together an intricate structure such as the brain is not easy. For example, many neurons will fail to reach their targets--their axons may take a wrong turn or may terminate prematurely. These strays that fail to establish a proper connection will die. Death here functions as a built-in error-correcting mechanism. Cell division forms the clay, whereas cell death sculpts the clay into the desired form.

Consider human hands, which start out as paddlelike structures. Fingers develop in the paddles, but then the cells in the tissue between the fingers must die for a proper hand to form. One might say that the cells kill themselves for the greater good.

Additionally, enzyme activation assay is another assay which is solely base on the buffer or salt composition, optimal pH, ionic strength for effective results. Luminometric caspase activity assay also employ a number of substrates with luciferase enzymes upon cleavage, caspase activity is determined as light emission. Apoptotic pathways: paper wraps stone blunts scissors. Apoptosis being a programmed cell death will have to do with the approaches on how cell get proliferated and with a detailed study of the elements and signals involved will help to provide an in-depth knowledge for further development of cancer related drugs.

Apoptosis can therefore be said to be a significant condition which help in the normal development and growth of cells.

This review seeks to enlighten us on the recent conditions occurring in the processes of apoptosis together with its signals, triggering, inhibition elements and methods of detection. Further studies will seek to help in the curtailing of some conditions that results in abnormal proliferation of cell in cancer related cases. LY17C for their support. Open menu Brazil. Brazilian Journal of Biology.

Open menu. Abstract Resumo English Resumo Portuguese. Text EN Text English. Abstract Apoptosis is a sequential order of cell death occurring regularly to ensure a homeostatic balance between the rate of cell formation and cell death.

Introduction Apoptosis is a process of sequential order of cell death thus referred to as a programmed cell death that first emerge in prior to the idea that the cell death does not occur accidentally Lockshin and Williams, LOCKSHIN, R.

Morphological conditions in apoptosis Morphologically the presence of apoptosis renders the cell with shrinkage and pyknosis, this is characterized by DNA fragmentation, chromatin condensation and the compacting of the cytoplasm. Biochemical process in apoptosis From the aforementioned conditions such as protein cleavage, DNA breakdown followed by the phagocytic degradation can all be considered to occur through a biochemical process.

Intrinsic mitochondrial pathway This pathway involves series of intracellular event occurring within the mitochondria. Figure1 The various pathways of Apoptosis. With 1 figure. BAI, L. Journal of molecular Cancer , vol. Apoptotic chromatin changes Dordrecht: Springer; Apoptotic chromatin changes, pp. Journal of Molecular and Cellular Cardiology , vol. Cancer Cell , vol. Biochemical and Biophysical Research Communications , vol. The Journal of Biological Chemistry , vol.

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Annual Review of Biochemistry , vol. Mechanisms of p53 -dependent apoptosis. Biochemical Society Transactions , vol. Cold Spring Harbor Perspectives in Biology , vol. Journal of Electron Microscopy Technique , vol. SONI, S. American Journal of Reproductive Immunology , vol. Too much apoptosis in an otherwise normal human being will result in a number of so-called neurodegenerative diseases where cells die when they're not supposed to die.

And they get messages from some place, most of which we don't understand, to tell them to die, so in a certain part of the lower part of the brain, that's what causes Parkinson's disease. This also characterizes Huntington's disease, and Alzheimer's disease, and Lou Gehrig's disease, and a number of other neurodegenerative diseases. Christopher P. Austin, M. This leads to the development of a multicellular body made of a stalk of dead cells that support the long-lived, metabolically quiescent spores that will give rise to a new colony of cycling single cells once the environment becomes appropriate.

The identification of a regulated cell death program inducing an apoptotic phenotype in nine different single-celled eukaryote organisms that belong to four diverging branches of the eukaryote phylogenic tree provides a paradigm for a widespread role for programmed cell death in the control of cell survival, and raises the question of the origin and nature of the genes that may be involved in the execution and regulation of such a process. In such a context, it is important to realize that the frontiers between multicellular organisms and single-celled organisms may not be as stringent as usually believed.

Indeed, the slime mold Dictyostelium discoideum can build multicellular bodies, and the kinetoplastid parasites have evolved a lifestyle that requires their permanent cohabitation with multicellular animal bodies. Thus, the emergence of what we call multicellularity may have only represented an extreme and irreversible manifestation of an ancestral feature on which single-celled eukaryotes have realized countless variations: the social control of cell fates through intercellular signaling at the level of a colony.

Particular usage of programmed cell death may involve intercellular interactions even more closely related to multicellularity. Interestingly, the finding that a cell suicide program is operational in several unicellular eukaryote lineages explored to date support the seemingly paradoxical view that genetic mutations that would allow cells to escape environmental regulation of their suicide machinery may have become counterselected at the level of the colonies of these single-celled eukaryotes.

It may be interesting to reflect, for a moment, on how influential a paradigm such as that of the obligate emergence of programmed cell death in multicellular organisms can be in preventing interpretation of already existing, and sometimes quite ancient, experimental results. Indeed, there have been several experimental findings, some reported more than forty years ago, that could have been interpreted as suggestions that programmed cell death may be operational in single-celled organisms.

The first concerns developmental programs that lead to the concomitant formation of dead cells and spores, in the context of transient multicellular aggregated bodies. All these programs are triggered by changes in environmental conditions, involve intercellular signaling, and are considered as an integral part of the organism life cycle.

During several decades, however, questions about the mechanism, role and genetic control of developmentally regulated cell death programs have remained solely addressed in multicellular organisms. Ten years ago, it was reported that a machinery similar to that inducing the nuclear features of apoptosis in cells from multicellular organisms the nuclear chromatin condensation and the DNA fragmentation into multiples of oligonucleosome length fragments was present and operational in the unicellular ciliated eukaryote Tetrahymena.

This finding led to the proposal that programmed cell death, in multicellular organisms evolved from genetic programs that were originally involved, in single-celled eukaryote organisms, in the elimination of supernumerary macronuclei.

In other words, the identification in a single-celled organism of part of the machinery allowing self-destruction did not provide a rationale for the investigation of self-destruction in such organisms, but reinforced the paradigm that self-destruction emerged with multicellularity.

In cells from multicellular organisms, restricted usage of the apoptotic self-destruction machinery can also achieve means other than cell death and allow particular forms of cell differentiation: in mammals for example, a process of selective induction of apoptotic chromatin and DNA fragmentation, that eliminates the nucleus while allowing the cell to survive is involved in the differentiation of the lens cell in the eye.

If one attempts to briefly recapitulate the history of the successive views of programmed cell death during the last hundred and fifty years, self-destruction was first considered as an unlikely process; this view was progressively replaced by the idea that programmed cell death may play an essential role in embryonic development, but only in given cell populations, at given time points and at given locations. In other words, programmed cell death became considered, during a very long period, as a price to pay for the complexity of the problems that have to be resolved during embryonic development.

More recently, it was proposed that programmed cell death may also be operational, and play an essential role, in adult cells; that dysregulation of physiological cell death programs may play a central role in the pathogenesis of several diseases; and finally that most, if not all, cells from the bodies of multicellular animals are constantly programmed to self-destruct unless signaled by other cells to repress induction of self-destruction.

Such a regulation of cell survival was, however, once again considered as an exceptional price to pay for complexity; complexity being in this case the complexity of the multicellular organisms. If one has to consider programmed cell death as a price to pay for the emergence of complexity during evolution, the ultimate, and simplest, level of complexity that we are now addressing is that of single-celled organisms. What are the effector pathways involved in the execution of programmed cell death in single-celled eukaryotes?

How many different molecular pathways may induce programmed cell death with a phenotype resembling apoptosis? Do unicellular eukaryotes share effectors and regulators of self-destruction with multicellular animals? Oligonucleosomal-like DNA degradation, an apoptotic feature that depends in mammalian cells on caspase-mediated activation of the CAD endonuclease, 86 and maybe also on mitochondrial release of endonuclease G, 85 has been reported as a feature of programmed death in all single-celled eukaryotes mentioned above, , , , , , , , , except Dictyostelium discoideum.

Caspase inhibitors have been reported to interfere with the development of a multicellular Dictyostelium body, but do not inhibit the developmentally-regulated induction of programmed cell death, consistent with the lack of chromatin and DNA fragmentation during programmed cell death of this organism.

In the dinoflagellate Peridinium gatunense , however, an inhibitor of mammalian cystein proteinases was reported to prevent cell death, and to favor the alternative differentiation into cyst, but the nature of the protease involved was not identified.

In the kinetoplastids, inhibitors of cystein proteinases have been reported to prevent cell death in Trypanosoma cruzi and in Leishmania donovani , , or to prevent the nuclear features of apoptosis when failing to inhibit cell death induction in Leishmania major. While these yet unidentified cystein proteinases and this AIF homologue participate in the respective nuclear modifications and DNA degradation associated with cell death in these two organisms, their potential role in the induction or execution of cell death remains to be assessed.

Finally, reactive oxygen species ROS induce cell death in the kinetoplastid Trypanosoma brucei brucei , the yeast Saccharomyces cerevisiae and the dinoflagellate Peridinium gatunense , but only in the latter has death been reported to be prevented by an inhibitor of ROS, catalase. The sequencing of the whole yeast genome, however, has provided a surprising result: no gene encoding a protease with a caspase-related catalytic cleavage site has been identified.

A possible implication is that Ced-4 has more ways to induce self-destruction than we yet know, for example by forming aggregates or by sequestering ATP. Experiments involving cell death induction by heterologous gene over-expression need, however, to be interpreted with caution. Therefore, it is possible that over-expression of nematode or mammalian pro-apoptotic genes in yeast induces death in ways entirely unrelated, and irrelevant, to their physiological effect in their original species.

It should be noted, however, that a protein with Bcllike anti-apoptotic properties, that prevents human cell programmed death by controlling mitochondria permeabilization, but has no sequence homology with any known member of the Bcl-2 family, nor any other known programmed cell death repressor, has been recently identified in a human virus, cytomegalovirus , suggesting that there may exist other protein families with Bcllike functional activities that remain to be identified.

Also, the mitochondrial flavoprotein AIF, that has caspase-independent pro-apoptotic activity in mammalian cells, is broadly conserved in single-celled eukaryotes. Their potential role in single-celled eukaryote death, however, has not yet been assessed, and mitochondrial executioners other than AIF may exist. Indeed, while a homologue of AIF is present in Saccharomyces pombe , but lacking in Saccharomyces cerevisiae , Bax has been reported to induce death in both the Saccharomyces cerevisiae and Saccharomyces pombe yeast species.

In summary, we still do not know the molecular nature of the effectors of self-destruction that operate in single-celled eukaryotes. And we do not know whether similar or different effectors operate in divergent branches of these organisms. Any attempt to travel into the past raises intrinsic problems and limitations, due to the fact that all the single-celled organisms that surround us, however ancient their phylogenic divergence may be, are not ancestors but contemporaries that have been subjected to numerous and lengthy evolutionary pressures.

Currently, there are several possible explanations for the existence of programmed cell death in at least nine single-celled eukaryote organisms belonging to four different lineages that diverged during a still elusive time-frame ranging between two and one billion years ago.

The first possible explanation is that programmed cell death is an ancient and conserved feature in most, if not all, single-celled eukaryote organisms, and that programmed cell death emerged at the time — or prior to the time — of the emergence of the first eukaryotes. If this were true, programmed cell death should be found to be present and operational in most, if not all, the branches of the eukaryote phylogenic tree.

Accordingly, one way to attempt exploring such possibility is to investigate how many single-celled eukaryotes are endowed with the capacity to self-destruct. But the interpretation of such findings may still remain elusive. If some single-celled eukaryote organisms are found to be devoid of the capacity to self-destruct, this will not allow excluding the possibility of a form of reductive evolution, namely a secondary loss of an ancient evolutionary shared feature. Conversely, if all single-celled eukaryote organisms are found to have operational physiological self-destruction programs, this will not exclude the possibility of strong selective pressures leading to recent parallel acquisitions of programmed cell death.

In this context, the kinetoplastid parasites provide an interesting example. Kinetoplastids emerged before the first multicellular animals, but the ancestors of present day trypanosomes and leishmania have subsequently evolved into obligate parasites of both invertebrate and vertebrate hosts. This important question as to whether the emergence of an apoptotic death program in a kinetoplastid may be related to its obligate parasite nature may be addressed by investigating the closely related kinetoplastid Bodonids that include both parasites and free-living non-parasite single-celled organisms.

In summary, it is possible that the ancestors of the nine present day single-celled eukaryotes that are endowed with the capacity to undergo programmed cell death were initially devoid of the ability to self-destruct, and that programmed cell death became selected in different branches of the phylogenic tree in response to selective pressures that may have involved competition, interaction and cooperation with more recently diverging eukaryotes. Such a process of parallel evolution leading to a somehow recent acquisition of programmed cell death may have happened either through horizontal gene transfer, through the building of similar cell death machinery by using a common molecular framework of conserved proteins of shared ancestry, or through the building of different cell death machinery by using diverse proteins through a process of convergent evolution.

But, whatever the molecular nature of such effectors may be, how did unicellular organisms select for the complex genetic programs allowing self-destruction, as well as for the coupling of cell survival to the repression of self-destruction? This is the question that I will now try to address. I will now argue that there are ways to look at the nature and role of programmed cell death that are very different from those we have been accustomed to by thinking in the context of multicellular organisms.

The first example that I will discuss concerns various forms of regulated cell death that have been described in various bacterial species for several decades, but that were not considered, until recently, , , , , as potential examples of programmed cell death.

Such primitive forms of programmed cell death had been described not only, as mentioned above, in circumstances that include the terminal differentiation of Myxobacteria , Streptomyces and Bacillus subtilis , but also, in several circumstances that involve competitions between bacterial colonies from different species, as well as competitions between plasmids or viruses and bacteria within a given bacterial colony.

When competing for the control of environmental resources, several bacterial species use strategies based on the killing of other bacterial species. They do this by secreting toxins antibiotics that induce the death of other bacteria. Such toxins include colicin E1, colicin E7, microcin Mcc B17, and streptomycin, and act either by inserting pores in the bacterial membrane, or by damaging bacterial DNA through direct or indirect mechanisms, involving the modulation of the activity of enzymes that participate in the modification of DNA topology, such as DNA gyrases.

These genetic modules bear surprising resemblance to the basic core of the genetic modules that allow, in cells from multicellular organisms, the regulation of programmed cell death.

In other words, the ability to self-destruct may have simply evolved as a consequence of a capacity to kill others. But there are other important aspects of an evolutionary arms race in bacteria that also pertain to the potential evolutionary origin of programmed cell death. In the prokaryote world, competition for environmental resources is not restricted to competition between different bacterial species.

Infectious agents, such as plasmids and bacteriophage viruses, also compete with bacteria: in this case, it is the bacteria itself that is the resource, and the evolutionary arms race involves the spreading of the heterogeneous mobile genetic elements in the bacterial colony. Strategies allowing plasmids and bacteriophages to propagate in the bacterial colony involves various mechanisms that allow spreading from one bacteria to another.

Thus, the first targets of the toxins are the uninfected neighboring bacteria from the colony. This strategy allows a dramatic propagation of the plasmid in the colony, since it couples infection with survival, and induces the elimination of all uninfected bacteria. Such strategy not only enforces efficient propagation, it also induces some level of irreversibility. But there are still more extreme forms of plasmid-mediated addiction strategies.

Several plasmids achieve this by encoding both a toxin and an antidote. There are various forms of toxins and antidotes involved, but they all share two similar features: firstly, neither the toxin nor the antidote are secreted by the infected cell; secondly, the toxins are stable and long-lived, the antidotes are unstable and short-lived. The usual view of symbiosis is that of a cooperation process, whereby the merging provides mutual benefits to the partners.

Here we see that a symbiosis can be achieved in a different and more radical way, by coupling separation with obligate death. What is the nature of the toxins and antidotes encoded by the addiction modules, and how is their respective half-life determined? All toxins are long-lived proteins; antidotes come in two kinds. Surprisingly, in all the known models, the protease is not encoded by the plasmid, but the plasmid addiction module relies on constitutively expressed bacterial chromosomal-encoded proteases, which include the Lon- or the ClpP-ATP-dependent serine proteases.

The reason why these bacterial serine proteases are constitutively expressed in the bacterial targets of the plasmid is that they appear to perform essential roles in bacterial survival, that will lead to the counterselection of protease loss of function mutants that may have otherwise escaped plasmid addiction.

In some bacterial species, some of these essential roles performed by the Lon and ClpP proteases have been uncovered. In both instances, they enforce the propagation of these genetic modules by inducing the elimination of the bacterial cells that do not express them.

Natural selection can favor the propagation of given genes for the sole reason that they are successful at propagating themselves, while being of no advantage, or sometimes while even being detrimental, to the fitness of the organisms that carry them. A bacterial chromosome-encoded addiction module has been discovered in Escherichia coli. The MazE protein antidote is short-lived because it is constantly cleaved by the constitutively expressed bacterial ClpP ATP-dependent serine protease.

In appropriate environmental conditions, the MazF toxin, the MazE antidote and the ClpP proteins are constitutively expressed, leading to a constant de novo synthesis of the toxin, and to a constant de novo synthesis and cleavage of the antidote, a dynamic equilibrium that allows bacterial survival.

The ClpP protease continues to be expressed, the residual MazE antidote continues to be cleaved, and bacterial self-destruction occurs, as a consequence of MazF toxin-mediated irreversible DNA damage. Such a self-destruction process does not only provide the surviving cells with a greater share in the available external resources, but also with the additional nutrients represented by the dying cells.

Because the bacterial cells constitutively express the executioner protein allowing induction of cell suicide, cell survival constantly depends on the expression of a dominant but short-lived antidote protein that prevents activation of the executioner. Accordingly, a surprising view of programmed cell death emerges when one fully realizes that it is not the expression of the programmed cell death module that induces cell suicide, but its repression; self-destruction in Escherichia coli is a phenotype that results from the regulated repression in response to environmental signals of a self-addiction genetic module encoding a toxin and an antidote.

But the coupling of such a repression of the addiction module to given exogenous signals could have become selected only if it allowed the concomitant survival of at least some members of the colony.

In other words, such a program has to be socially regulated at the level of the colony population in order not to lead to the indiscriminate self-destruction of all the bacterial cells in response to adverse environmental conditions.

How may such a decision become integrated at the level of the bacterial colony? How may bacteria decide, at a single-cell level, when to die and when to survive? Although this is often neglected, the ability to differentiate is a feature of most, if not all, single-celled organisms, including prokaryotes.

In bacteria, as in single-celled eukaryotes, coordinated changes in gene expression lead to changes in cell cycle regulation, in morphology, and in intercellular signaling. Several other forms of differentiation have been described in bacteria, including the SOS stress and repair response, and the formation of biofilms that constitute complex multicellular communities. Upon nutrient shortage, a developmental program is triggered in most bacteria species, that leads to the concomitant induction of cell differentiation in a part of the population, and of cell death in the rest of the colony.

In Myxobacteria , Streptomyces and Bacilli , nutrient shortage induces the terminal differentiation, followed by the death, of a part of the cells from the colony; these terminally differentiated cells helping the other part of the cells from the colony to differentiate into long-lived non-cycling and highly resistant spores.

Although environmental changes represent the initial and necessary trigger for the complex set of modifications that will lead to this process of alternate and complementary differentiation, the environmental signals by themselves are not sufficient: an additional step of intercellular signaling is required, that will lead to a coordinated set of changes in gene expression. Quorum factor binding induces gene expression only when a threshold concentration of quorum factor is reached, that greatly exceeds the quantity of quorum factor that can be synthesized by any given cell.

Such a process provides an interesting model for understanding how important changes that will affect the future of the whole colony are not taken at the level of any individual cell, but integrated at the level of the colony. I will now argue that there is a striking example that illustrates how such a complex process can be achieved.

A cell suicide program will become counterselected unless it is regulated in such a way that the sacrifice of some individuals in a unicellular colony will benefit or at least will not prevent the survival of other members of the colony.

As mentioned above, a coupling of programmed cell death regulation to that of cell differentiation and of intercellular signaling represents one of the essential steps towards such a solution. But how is this solution achieved?

Bacillus subtilis provides a spectacular and extreme example of how such a major theoretical problem concerning the evolution of programmed cell death in unicellular organisms can be solved. In favorable environmental conditions, Bacillus subtilis undergoes vegetative growth through symmetrical cell division.

In adverse environmental conditions, such as nutrient shortage, Bacillus subtilis undergoes a complex developmental program whose initiation depends, as mentioned above, on cell density and on the concentration of released quorum factors.

The septum cannot anymore be positioned at the middle of the cell as during vegetative growth but only closer to one pole of the developing cell. Cell division, however, is not completed: the polar septum separates the cells in two different territories, and the two asymmetric future cells remain attached one to the other. In other words, the initiation of a process of asymmetric cell division allows Bacillus subtilis , at the level of each single cell, to undergo a developmental program leading to the emergence of the simplest possible form of a transient multicellular organism, made up of two cells that have respectively differentiated into the equivalent of a somatic cell the mother cell and into the equivalent of a germ cell the spore.

Because each single cell in the colony becomes the coupling unit, differentiation will obligatorily lead in the colony to an equal number of self-destructing cells and of surviving cells.

Such a sophisticated temporal and spatial regulation of gene expression provides a spectacular example of how the coupling of programmed cell death to intercellular communication can avoid the death of the whole colony in adverse environmental conditions, by ensuring that the sacrifice of one half of the progeny will be coupled to the survival of the other half of the progeny.

Sporulation occurs only in some bacterial species, but as previously mentioned, cell differentiation associated with cell death is a usual response of most bacterial species to adverse environmental conditions. The view that I have proposed is that Bacillus subtilis represents an example rather than an exception of the intercellular communication that may operate maybe in a more stochastic manner in most single-celled organisms, and may allow the breaking of symmetry required for the coupling of programmed cell death to survival at the level of the colony.

While asymmetric cell division is an important and conserved mechanism involved in cell differentiation in bacteria , and single-celled eukaryotes, , it is not the sole mechanism allowing the breaking of symmetry at the level of a colony.

In the single-celled eukaryote Dictyostelium discoideum , for example, independently of the numbers of the cells that have initially aggregated in response to adverse environmental changes and will develop a multicellular body, the respective proportions of cells that will become surviving spores and dying stalk will be conserved.

In contrast to Bacillus subtilis , however, the numbers of cells that will survive is not equal to the number of cells that will die, the former representing two-thirds of the cells, and the latter one-third. It seems that each cell of the Dictyostelium colony, at the moment it begins to join the others, has the same initial stochastic probability to become a dying or a surviving cell.

During a few hours, intercellular signaling, acting on initially random differentiation choices, seems to achieve a fine tuning of the respective proportion of future spore and stalk cells, through the release of molecules that, upon reaching threshold, influence the differentiation process in neighboring cells. In summary, the evolutionary scenario that I have outlined above suggests a multi-step process for the emergence of programmed cell death in bacteria.

Most eukaryote cells — from single-celled eukaryote organisms to multicellular animals and plants — harbor at least two genomes: the nuclear genome, that contains most of the cellular genes, and the cytoplasmic organelle genomes, that are small circular DNAs present in the mitochondria single-celled plants and multicellular plants contain an additional organelle genome, the plastid chloroplast circular DNA. Numbers of mitochondria per cell also greatly vary depending on the organism, ranging from a giant unique mitochondrion kinetoplast in the kinetoplastid protozoan single-celled eukaryotes, such as the trypanosomes, to several hundred mitochondria per cell in several single-celled eukaryotes and in multicellular animals.

Mitochondria play an essential role in eukaryote cells from single-celled and multicellular organisms: they perform aerobic metabolism, that allows energy production through ATP synthesis by a respiratory process that involves an electron transport chain and a chemiosmotic process. Loss of mitochondrial function forces cells to rely only on anaerobic metabolism, which may be lethal in most cells from multicellular animals but mature human erythrocytes, that lack mitochondria, represent an interesting exception and, probably, from most single-celled eukaryote but Giardia and Microsporidia , that lack mitochondria, represent interesting exceptions.

Each mitochondrion is bound by two highly specialized membranes that create two separate compartments, the internal matrix space and the intermembrane space. All these features strongly suggest that mitochondria are of ancient bacterial origin, and support the hypothesis that mitochondria arose from symbiosis between bacteria able to perform aerobic metabolism and ancestors of eukaryote cells.

Present day mitochondria and eukaryotic cells are condemned to live together, and this symbiotic equilibrium is usually viewed as a consequence of a mutual cooperation process between the ancestors of the eukaryotic cells and the aerobic bacteria they captured. This is true of some of the pathogenic bacteria,such as Ricketsia , Listeria and Schigella , that invade mammals and replicate in their cells by subverting host cell signaling processes.

First, the amoebae palomyxa palustris , one of the rare single-celled eukaryotes that lack mitochondria, is a symbiont that contains aerobic bacteria in its cytoplasm; and it is these bacteria that perform the respiratory activity required for the aerobic metabolism of the amoebae.

If these situations are to be considered as examples of intermediate evolutionary steps towards endosymbiosis, they strongly suggest that the evolution of the present day eukaryote cell may have resulted as much from an initial bacterial manipulation of their host, than from the opposite situation.

In present day mitochondriated eukaryotes, most of the genes encoding mitochondrial proteins are located in the cell nucleus and seem therefore to have been progressively transferred from the mitochondrial genome to the nuclear genome.

These proteins are synthesized on cytoplasmic ribosomes, and are then imported into the organelle. Once they have been synthesized and imported into the mitochondria, these proteins are believed never to leave the mitochondria, at least as long as the cell survives.