Covalent bond

From Wikipedia, the free encyclopedia

A covalent bond forming H₂ (right) where two hydrogen atoms share the two electrons

 

A covalent bond, also called a molecular bond, is a chemical bond that involves the sharing of electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs, and the stable balance of attractive and repulsive forces between atoms, when they share electrons, is known as covalent bonding. For many molecules, the sharing of electrons allows each atom to attain the equivalent of a full outer shell, corresponding to a stable electronic configuration. 

Covalent bonding includes many kinds of interactions, including σ-bonding, π-bonding, metal-to-metal bonding, agostic interactions, bent bonds, and three-center two-electron bonds. The term covalent bond dates from 1939. The prefix co- means jointly, associated in action, partnered to a lesser degree, etc.; thus a "co-valent bond", in essence, means that the atoms share "valence", such as is discussed in valence bond theory. 

In the molecule H
₂, the hydrogen atoms share the two electrons via covalent bonding. Covalency is greatest between atoms of similar electronegativities. Thus, covalent bonding does not necessarily require that the two atoms be of the same elements, only that they be of comparable electronegativity. Covalent bonding that entails sharing of electrons over more than two atoms is said to be delocalized.

History

Early concepts in covalent bonding arose from this kind of image of the molecule of methane. Covalent bonding is implied in the Lewis structure by indicating electrons shared between atoms.

 

The term covalence in regard to bonding was first used in 1919 by Irving Langmuir in a Journal of the American Chemical Society article entitled "The Arrangement of Electrons in Atoms and Molecules". Langmuir wrote that "we shall denote by the term covalence the number of pairs of electrons that a given atom shares with its neighbors."

The idea of covalent bonding can be traced several years before 1919 to Gilbert N. Lewis, who in 1916 described the sharing of electron pairs between atoms. He introduced the Lewis notation or electron dot notation or Lewis dot structure, in which valence electrons (those in the outer shell) are represented as dots around the atomic symbols. Pairs of electrons located between atoms represent covalent bonds. Multiple pairs represent multiple bonds, such as double bonds and triple bonds. An alternative form of representation, not shown here, has bond-forming electron pairs represented as solid lines.

Lewis proposed that an atom forms enough covalent bonds to form a full (or closed) outer electron shell. In the diagram of methane shown here, the carbon atom has a valence of four and is, therefore, surrounded by eight electrons (the octet rule), four from the carbon itself and four from the hydrogens bonded to it. Each hydrogen has a valence of one and is surrounded by two electrons (a duet rule) – its own one electron plus one from the carbon. The numbers of electrons correspond to full shells in the quantum theory of the atom; the outer shell of a carbon atom is the n = 2 shell, which can hold eight electrons, whereas the outer (and only) shell of a hydrogen atom is the n = 1 shell, which can hold only two.

While the idea of shared electron pairs provides an effective qualitative picture of covalent bonding, quantum mechanics is needed to understand the nature of these bonds and predict the structures and properties of simple molecules. Walter Heitler and Fritz London are credited with the first successful quantum mechanical explanation of a chemical bond (molecular hydrogen) in 1927. Their work was based on the valence bond model, which assumes that a chemical bond is formed when there is good overlap between the atomic orbitals of participating atoms.

Types of covalent bonds

Atomic orbitals (except for s orbitals) have specific directional properties leading to different types of covalent bonds. Sigma (σ) bonds are the strongest covalent bonds and are due to head-on overlapping of orbitals on two different atoms. A single bond is usually a σ bond. Pi (π) bonds are weaker and are due to lateral overlap between p (or d) orbitals. A double bond between two given atoms consists of one σ and one π bond, and a triple bond is one σ and two π bonds. 

Covalent bonds are also affected by the electronegativity of the connected atoms which determines the chemical polarity of the bond. Two atoms with equal electronegativity will make nonpolar covalent bonds such as H–H. An unequal relationship creates a polar covalent bond such as with H−Cl. However polarity also requires geometric asymmetry, or else dipoles may cancel out resulting in a non-polar molecule.

Covalent structures

There are several types of structures for covalent substances, including individual molecules, molecular structures, macromolecular structures and giant covalent structures. Individual molecules have strong bonds that hold the atoms together, but there are negligible forces of attraction between molecules. Such covalent substances are usually gases, for example, HCl, SO₂, CO₂, and CH₄. In molecular structures, there are weak forces of attraction. Such covalent substances are low-boiling-temperature liquids (such as ethanol), and low-melting-temperature solids (such as iodine and solid CO₂). Macromolecular structures have large numbers of atoms linked by covalent bonds in chains, including synthetic polymers such as polyethylene and nylon, and biopolymers such as proteins and starch. Network covalent structures (or giant covalent structures) contain large numbers of atoms linked in sheets (such as graphite), or 3-dimensional structures (such as diamond and quartz). These substances have high melting and boiling points, are frequently brittle, and tend to have high electrical resistivity. Elements that have high electronegativity, and the ability to form three or four electron pair bonds, often form such large macromolecular structures.

One- and three-electron bonds

Lewis and MO diagrams of an individual 2e bond and 3e bond

 

Bonds with one or three electrons can be found in radical species, which have an odd number of electrons. The simplest example of a 1-electron bond is found in the dihydrogen cation, H⁺
₂. One-electron bonds often have about half the bond energy of a 2-electron bond, and are therefore called "half bonds". However, there are exceptions: in the case of dilithium, the bond is actually stronger for the 1-electron Li⁺
₂ than for the 2-electron Li₂. This exception can be explained in terms of hybridization and inner-shell effects.

The simplest example of three-electron bonding can be found in the helium dimer cation, He⁺
₂. It is considered a "half bond" because it consists of only one shared electron (rather than two); in molecular orbital terms, the third electron is in an anti-bonding orbital which cancels out half of the bond formed by the other two electrons. Another example of a molecule containing a 3-electron bond, in addition to two 2-electron bonds, is nitric oxide, NO. The oxygen molecule, O₂ can also be regarded as having two 3-electron bonds and one 2-electron bond, which accounts for its paramagnetism and its formal bond order of 2. Chlorine dioxide and its heavier analogues bromine dioxide and iodine dioxide also contain three-electron bonds.

Molecules with odd-electron bonds are usually highly reactive. These types of bond are only stable between atoms with similar electronegativities.

Modified Lewis structures with 3e bonds:

 

Nitric oxide

 

Dioxygen

Resonance

There are situations whereby a single Lewis structure is insufficient to explain the electron configuration in a molecule, hence a superposition of structures are needed. The same two atoms in such molecules can be bonded differently in different structures (a single bond in one, a double bond in another, or even none at all), resulting in a non-integer bond order. The nitrate ion is one such example with three equivalent structures. The bond between the nitrogen and each oxygen is a double bond in one structure and a single bond in the other two, so that the average bond order for each N–O interaction is 2 + 1 + 1/3 = 4/3. 

Aromaticity

In organic chemistry, when a molecule with a planar ring obeys Hückel's rule, where the number of π electrons fit the formula 4n + 2 (where n is an integer), it attains extra stability and symmetry. In benzene, the prototypical aromatic compound, there are 6 π bonding electrons (n = 1, 4n + 2 = 6). These occupy three delocalized π molecular orbitals (molecular orbital theory) or form conjugate π bonds in two resonance structures that linearly combine (valence bond theory), creating a regular hexagon exhibiting a greater stabilization than the hypothetical 1,3,5-cyclohexatriene.

In the case of heterocyclic aromatics and substituted benzenes, the electronegativity differences between different parts of the ring may dominate the chemical behaviour of aromatic ring bonds, which otherwise are equivalent.

Hypervalence

Certain molecules such as xenon difluoride and sulfur hexafluoride have higher co-ordination numbers than would be possible due to strictly covalent bonding according to the octet rule. This is explained by the three-center four-electron bond ("3c–4e") model which interprets the molecular wavefunction in terms of non-bonding highest occupied molecular orbitals in molecular orbital theory and resonance of sigma bonds in valence bond theory.

Electron deficiency

In three-center two-electron bonds ("3c–2e") three atoms share two electrons in bonding. This type of bonding occurs in electron deficient compounds like diborane. Each such bond (2 per molecule in diborane) contains a pair of electrons which connect the boron atoms to each other in a banana shape, with a proton (nucleus of a hydrogen atom) in the middle of the bond, sharing electrons with both boron atoms. In certain cluster compounds, so-called four-center two-electron bonds also have been postulated.

Quantum mechanical description

After the development of quantum mechanics, two basic theories were proposed to provide a quantum description of chemical bonding: valence bond (VB) theory and molecular orbital (MO) theory. A more recent quantum description is given in terms of atomic contributions to the electronic density of states.

Comparison of VB and MO theories

The two theories represent two ways to build up the electron configuration of the molecule. For valence bond theory, the atomic hybrid orbitals are filled with electrons first to produce a fully bonded valence configuration, followed by performing a linear combination of contributing structures (resonance) if there are several of them. In contrast, for molecular orbital theory a linear combination of atomic orbitals is performed first, followed by filling of the resulting molecular orbitals with electrons. 

The two approaches are regarded as complementary, and each provides its own insights into the problem of chemical bonding. As valence bond theory builds the molecular wavefunction out of localized bonds, it is more suited for the calculation of bond energies and the understanding of reaction mechanisms. As molecular orbital theory builds the molecular wavefunction out of delocalized orbitals, it is more suited for the calculation of ionization energies and the understanding of spectral absorption bands.

At the qualitative level, both theories contain incorrect predictions. Simple (Heitler–London) valence bond theory correctly predicts the dissociation of homonuclear diatomic molecules into separate atoms, while simple (Hartree–Fock) molecular orbital theory incorrectly predicts dissociation into a mixture of atoms and ions. On the other hand, simple molecular orbital theory correctly predicts Hückel's rule of aromaticity, while simple valence bond theory incorrectly predicts that cyclobutadiene has a larger resonance energy than benzene. 

Although the wavefunctions generated by both theories at the qualitative level do not agree and do not match the stabilization energy by experiment, they can be corrected by configuration interaction. This is done by combining the valence bond covalent function with the functions describing all possible ionic structures or by combining the molecular orbital ground state function with the functions describing all possible excited states using unoccupied orbitals. It can then be seen that the simple molecular orbital approach overestimates the weight of the ionic structures while the simple valence bond approach neglects them. This can also be described as saying that the simple molecular orbital approach neglects electron correlation while the simple valence bond approach overestimates it.

Modern calculations in quantum chemistry usually start from (but ultimately go far beyond) a molecular orbital rather than a valence bond approach, not because of any intrinsic superiority in the former but rather because the MO approach is more readily adapted to numerical computations. Molecular orbitals are orthogonal, which significantly increases feasibility and speed of computer calculations compared to nonorthogonal valence bond orbitals. However, better valence bond programs are now available.

Covalency from atomic contribution to the electronic density of states

In COOP, COHP and BCOOP, evaluation of bond covalency is dependent on the basis set. To overcome this issue, an alternative formulation of the bond covalency can be provided in this way. 

The center mass cm(n,l,m_l,m_s) of an atomic orbital |n,l,m_l,m_s⟩, with quantum numbers n, l, m_l, m_s, for atom A is defined as

${\displaystyle cm^{\mathrm {A} }(n,l,m_{l},m_{s})={\frac {\int \limits _{E_{0}}\limits ^{E_{1}}Eg_{|n,l,m_{l},m_{s}\rangle }^{\mathrm {A} }\left(E\right)dE}{\int \limits _{E_{0}}\limits ^{E_{1}}g_{|n,l,m_{l},m_{s}\rangle }^{\mathrm {A} }\left(E\right)dE}}}$

where g^A
_{|n,l,ml,ms⟩}(E) is the contribution of the atomic orbital |n,l,m_l,m_s⟩ of the atom A to the total electronic density of states g(E) of the solid

${\displaystyle g\left(E\right)=\sum _{\mathrm {A} }\sum _{n,l}\sum _{m_{l},m_{s}}{g_{|n,l,m_{l},m_{s}\rangle }^{\mathrm {A} }\left(E\right)}}$

where the outer sum runs over all atoms A of the unit cell. The energy window [E₀,E₁] is chosen in such a way that it encompasses all relevant bands participating in the bond. If the range to select is unclear, it can be identified in practice by examining the molecular orbitals that describe the electron density along the considered bond. 

The relative position C_nAlA,nBlB of the center mass of |n_A,l_A⟩ levels of atom A with respect to the center mass of |n_B,l_B⟩ levels of atom B is given as

${\displaystyle C_{n_{\mathrm {A} }l_{\mathrm {A} },n_{\mathrm {B} }l_{\mathrm {B} }}=-\left|cm^{\mathrm {A} }(n_{\mathrm {A} },l_{\mathrm {A} })-cm^{\mathrm {B} }(n_{\mathrm {B} },l_{\mathrm {B} })\right|}$

where the contributions of the magnetic and spin quantum numbers are summed. According to this definition, the relative position of the A levels with respect to the B levels is

${\displaystyle C_{\mathrm {A,B} }=-\left|cm^{\mathrm {A} }-cm^{\mathrm {B} }\right|}$

where, for simplicity, we may omit the dependence from the principal quantum number n in the notation referring to C_nAlA,nBlB.

In this formalism, the greater the value of C_A,B, the higher the overlap of the selected atomic bands, and thus the electron density described by those orbitals gives a more covalent A–B bond. The quantity C_A,B is denoted as the covalency of the A–B bond, which is specified in the same units of the energy E.

Programmed cell death

From Wikipedia, the free encyclopedia

Programmed cell death (or PCD) is the death of a cell in any form, mediated by an intracellular program, and is also referred to as Cellular Suicide. PCD is carried out in a biological process, which usually confers advantage during an organism's life-cycle. For example, the differentiation of fingers and toes in a developing human embryo occurs because cells between the fingers apoptose; the result is that the digits are separate. PCD serves fundamental functions during both plant and animal tissue development. Apoptosis and autophagy, both are the forms of programmed cell death, but necrosis was long seen as a non-physiological process that occurs as a result of infection or injury.

 

Necrosis is the death of a cell caused by external factors such as trauma or infection and occurs in several different forms. Recently a form of programmed necrosis, called necroptosis, has been recognized as an alternative form of programmed cell death. It is hypothesized that necroptosis can serve as a cell-death backup to apoptosis when the apoptosis signaling is blocked by endogenous or exogenous factors such as viruses or mutations. Most recently, other types of regulated necrosis have been discovered as well, which share several signaling events with necroptosis and apoptosis.

History

The concept of "programmed cell-death" was used by Lockshin & Williams in 1964 in relation to insect tissue development, around eight years before "apoptosis" was coined. Since then, PCD has become the more general of these two terms. 

The first insight into the mechanism came from studying BCL2, the product of a putative oncogene activated by chromosome translocations often found in follicular lymphoma. Unlike other cancer genes, which promote cancer by stimulating cell proliferation, BCL2 promoted cancer by stopping lymphoma cells from being able to kill themselves.

PCD has been the subject of increasing attention and research efforts. This trend has been highlighted with the award of the 2002 Nobel Prize in Physiology or Medicine to Sydney Brenner (United Kingdom), H. Robert Horvitz (US) and John E. Sulston (UK).

Types

Overview of signal transduction pathways involved in apoptosis.

• Apoptosis or Type I cell-death.
• Autophagic or Type II cell-death. (Cytoplasmic: characterized by the formation of large vacuoles that eat away organelles in a specific sequence prior to the destruction of the nucleus.)

Apoptosis

Apoptosis is the process of programmed cell death (PCD) that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation. It is now thought that- in a developmental context- cells are induced to positively commit suicide whilst in a homeostatic context; the absence of certain survival factors may provide the impetus for suicide. There appears to be some variation in the morphology and indeed the biochemistry of these suicide pathways; some treading the path of "apoptosis", others following a more generalized pathway to deletion, but both usually being genetically and synthetically motivated. There is some evidence that certain symptoms of "apoptosis" such as endonuclease activation can be spuriously induced without engaging a genetic cascade, however, presumably true apoptosis and programmed cell death must be genetically mediated. It is also becoming clear that mitosis and apoptosis are toggled or linked in some way and that the balance achieved depends on signals received from appropriate growth or survival factors.

Autophagy

Macroautophagy, often referred to as autophagy, is a catabolic process that results in the autophagosomic-lysosomal degradation of bulk cytoplasmic contents, abnormal protein aggregates, and excess or damaged organelles. 

Autophagy is generally activated by conditions of nutrient deprivation but has also been associated with physiological as well as pathological processes such as development, differentiation, neurodegenerative diseases, stress, infection and cancer.

Mechanism

A critical regulator of autophagy induction is the kinase mTOR, which when activated, suppresses autophagy and when not activated promotes it. Three related serine/threonine kinases, UNC-51-like kinase -1, -2, and -3 (ULK1, ULK2, UKL3), which play a similar role as the yeast Atg1, act downstream of the mTOR complex. ULK1 and ULK2 form a large complex with the mammalian homolog of an autophagy-related (Atg) gene product (mAtg13) and the scaffold protein FIP200. Class III PI3K complex, containing hVps34, Beclin-1, p150 and Atg14-like protein or ultraviolet irradiation resistance-associated gene (UVRAG), is required for the induction of autophagy. 

The ATG genes control the autophagosome formation through ATG12-ATG5 and LC3-II (ATG8-II) complexes. ATG12 is conjugated to ATG5 in a ubiquitin-like reaction that requires ATG7 and ATG10. The Atg12–Atg5 conjugate then interacts non-covalently with ATG16 to form a large complex. LC3/ATG8 is cleaved at its C terminus by ATG4 protease to generate the cytosolic LC3-I. LC3-I is conjugated to phosphatidylethanolamine (PE) also in a ubiquitin-like reaction that requires Atg7 and Atg3. The lipidated form of LC3, known as LC3-II, is attached to the autophagosome membrane.

Autophagy and apoptosis are connected both positively and negatively, and extensive crosstalk exists between the two. During nutrient deficiency, autophagy functions as a pro-survival mechanism, however, excessive autophagy may lead to cell death, a process morphologically distinct from apoptosis. Several pro-apoptotic signals, such as TNF, TRAIL, and FADD, also induce autophagy. Additionally, Bcl-2 inhibits Beclin-1-dependent autophagy, thereby functioning both as a pro-survival and as an anti-autophagic regulator.

Other types

Besides the above two types of PCD, other pathways have been discovered. Called "non-apoptotic programmed cell-death" (or "caspase-independent programmed cell-death" or "necroptosis"), these alternative routes to death are as efficient as apoptosis and can function as either backup mechanisms or the main type of PCD. 

Other forms of programmed cell death include anoikis, almost identical to apoptosis except in its induction; cornification, a form of cell death exclusive to the eyes; excitotoxicity; ferroptosis, an iron-dependent form of cell death and Wallerian degeneration.

Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis.

Eryptosis is a form of suicidal erythrocyte death.

Aponecrosis is a hybrid of apoptosis and necrosis and refers to an incomplete apoptotic process that is completed by necrosis.

NETosis is the process of cell-death generated by NETs.

Paraptosis is another type of nonapoptotic cell death that is mediated by MAPK through the activation of IGF-1. It's characterized by the intracellular formation of vacuoles and swelling of mitochondria.

Pyroptosis, an inflammatory type of cell death, is uniquely mediated by caspase 1, an enzyme not involved in apoptosis, in response to infection by certain microorganisms.

Plant cells undergo particular processes of PCD similar to autophagic cell death. However, some common features of PCD are highly conserved in both plants and metazoa.

Atrophic factors

An atrophic factor is a force that causes a cell to die. Only natural forces on the cell are considered to be atrophic factors, whereas, for example, agents of mechanical or chemical abuse or lysis of the cell are considered not to be atrophic factors. Common types of atrophic factors are:

1. Decreased workload
2. Loss of innervation
3. Diminished blood supply
4. Inadequate nutrition
5. Loss of endocrine stimulation
6. Senility
7. Compression

Role in the development of the nervous system

Dying cells in the proliferate zone

 

The initial expansion of the developing nervous system is counterbalanced by the removal of neurons and their processes. During the development of the nervous system almost 50% of developing neurons are naturally removed by programmed cell death (PCD). PCD in the nervous system was first recognized in 1896 by John Beard. Since then several theories were proposed to understand its biological significance during neural development.

Role in neural development

PCD in the developing nervous system has been observed in proliferating as well as post-mitotic cells. One theory suggests that PCD is an adaptive mechanism to regulate the number of progenitor cells. In humans, PCD in progenitor cells starts at gestational week 7 and remains until the first trimester. This process of cell death has been identified in the germinal areas of the cerebral cortex, cerebellum, thalamus, brainstem, and spinal cord among other regions. At gestational weeks 19-23, PCD is observed in post-mitotic cells. The prevailing theory explaining this observation is the neurotrophic theory which states that PCD is required to optimize the connection between neurons and their afferent inputs and efferent targets. Another theory proposes that developmental PCD in the nervous system occurs in order to correct for errors in neurons that have migrated ectopically, innervated incorrect targets, or have axons that have gone awry during path finding. It is possible that PCD during the development of the nervous system serves different functions determined by the developmental stage, cell type, and even species.

The neurotrophic theory

The neurotrophic theory is the leading hypothesis used to explain the role of programmed cell death in the developing nervous system. It postulates that in order to ensure optimal innervation of targets, a surplus of neurons is first produced which then compete for limited quantities of protective neurotrophic factors and only a fraction survive while others die by programmed cell death. Furthermore, the theory states that predetermined factors regulate the amount of neurons that survive and the size of the innervating neuronal population directly correlates to the influence of their target field.

The underlying idea that target cells secrete attractive or inducing factors and that their growth cones have a chemotactic sensitivity was first put forth by Santiago Ramon y Cajal in 1892. Cajal presented the idea as an explanation for the “intelligent force” axons appear to take when finding their target but admitted that he had no empirical data. The theory gained more attraction when experimental manipulation of axon targets yielded death of all innervating neurons. This developed the concept of target derived regulation which became the main tenet in the neurotrophic theory. Experiments that further supported this theory led to the identification of the first neurotrophic factor, nerve growth factor (NGF).

Peripheral versus central nervous system

Cell death in the peripheral vs central nervous system

 

Different mechanisms regulate PCD in the peripheral nervous system (PNS) versus the central nervous system (CNS). In the PNS, innervation of the target is proportional to the amount of the target-released neurotrophic factors NGF and NT3. Expression of neurotrophin receptors, TrkA and TrkC, is sufficient to induce apoptosis in the absence of their ligands. Therefore, it is speculated that PCD in the PNS is dependent on the release of neurotrophic factors and thus follows the concept of the neurotrophic theory.

Programmed cell death in the CNS is not dependent on external growth factors but instead relies on intrinsically derived cues. In the neocortex, a 4:1 ratio of excitatory to inhibitory interneurons is maintained by apoptotic machinery that appears to be independent of the environment. Supporting evidence came from an experiment where interneuron progenitors were either transplanted into the mouse neocortex or cultured in vitro. Transplanted cells died at the age of two weeks, the same age at which endogenous interneurons undergo apoptosis. Regardless of the size of the transplant, the fraction of cells undergoing apoptosis remained constant. Furthermore, disruption of TrkB, a receptor for brain derived neurotrophic factor (Bdnf), did not affect cell death. It has also been shown that in mice null for the proapoptotic factor Bax (Bcl-2-associated X protein) a larger percentage of interneurons survived compared to wild type mice. Together these findings indicate that programmed cell death in the CNS partly exploits Bax-mediated signaling and is independent of BDNF and the environment. Apoptotic mechanisms in the CNS are still not well understood, yet it is thought that apoptosis of interneurons is a self-autonomous process.

Nervous system development in its absence

Programmed cell death can be reduced or eliminated in the developing nervous system by the targeted deletion of pro-apoptotic genes or by the overexpression of anti-apoptotic genes. The absence or reduction of PCD can cause serious anatomical malformations but can also result in minimal consequences depending on the gene targeted, neuronal population, and stage of development. Excess progenitor cell proliferation that leads to gross brain abnormalities is often lethal, as seen in caspase-3 or caspase-9 knockout mice which develop exencephaly in the forebrain. The brainstem, spinal cord, and peripheral ganglia of these mice develop normally, however, suggesting that the involvement of caspases in PCD during development depends on the brain region and cell type. Knockout or inhibition of apoptotic protease activating factor 1 (APAF1), also results in malformations and increased embryonic lethality. Manipulation of apoptosis regulator proteins Bcl-2 and Bax (overexpression of Bcl-2 or deletion of Bax) produces an increase in the number of neurons in certain regions of the nervous system such as the retina, trigeminal nucleus, cerebellum, and spinal cord. However, PCD of neurons due to Bax deletion or Bcl-2 overexpression does not result in prominent morphological or behavioral abnormalities in mice. For example, mice overexpressing Bcl-2 have generally normal motor skills and vision and only show impairment in complex behaviors such as learning and anxiety. The normal behavioral phenotypes of these mice suggest that an adaptive mechanism may be involved to compensate for the excess neurons.

Invertebrates and vertebrates

A conserved apoptotic pathway in nematodes, mammals and fruitflies

 

Learning about PCD in various species is essential in understanding the evolutionary basis and reason for apoptosis in development of the nervous system. During the development of the invertebrate nervous system, PCD plays different roles in different species. The similarity of the asymmetric cell death mechanism in the nematode and the leech indicates that PCD may have an evolutionary significance in the development of the nervous system. In the nematode, PCD occurs in the first hour of development leading to the elimination of 12% of non-gonadal cells including neuronal lineages. Cell death in arthropods occurs first in the nervous system when ectoderm cells differentiate and one daughter cell becomes a neuroblast and the other undergoes apoptosis. Furthermore, sex targeted cell death leads to different neuronal innervation of specific organs in males and females. In Drosophila, PCD is essential in segmentation and specification during development. 

In contrast to invertebrates, the mechanism of programmed cell death is found to be more conserved in vertebrates. Extensive studies performed on various vertebrates show that PCD of neurons and glia occurs in most parts of the nervous system during development. It has been observed before and during synaptogenesis in the central nervous system as well as the peripheral nervous system. However, there are a few differences between vertebrate species. For example, mammals exhibit extensive arborization followed by PCD in the retina while birds do not. Although synaptic refinement in vertebrate systems is largely dependent on PCD, other evolutionary mechanisms also play a role.

In plant tissue

Programmed cell death in plants has a number of molecular similarities to animal apoptosis, but it also has differences, the most obvious being the presence of a cell wall and the lack of an immune system that removes the pieces of the dead cell. Instead of an immune response, the dying cell synthesizes substances to break itself down and places them in a vacuole that ruptures as the cell dies.

In "APL regulates vascular tissue identity in Arabidopsis", Martin Bonke and his colleagues had stated that one of the two long-distance transport systems in vascular plants, xylem, consists of several cell-types "the differentiation of which involves deposition of elaborate cell-wall thickenings and programmed cell-death." The authors emphasize that the products of plant PCD play an important structural role. 

Basic morphological and biochemical features of PCD have been conserved in both plant and animal kingdoms. Specific types of plant cells carry out unique cell-death programs. These have common features with animal apoptosis—for instance, nuclear DNA degradation—but they also have their own peculiarities, such as nuclear degradation triggered by the collapse of the vacuole in tracheary elements of the xylem.

Janneke Balk and Christopher J. Leaver, of the Department of Plant Sciences, University of Oxford, carried out research on mutations in the mitochondrial genome of sun-flower cells. Results of this research suggest that mitochondria play the same key role in vascular plant PCD as in other eukaryotic cells.

PCD in pollen prevents inbreeding

During pollination, plants enforce self-incompatibility (SI) as an important means to prevent self-fertilization. Research on the corn poppy (Papaver rhoeas) has revealed that proteins in the pistil on which the pollen lands, interact with pollen and trigger PCD in incompatible (i.e., self) pollen. The researchers, Steven G. Thomas and Veronica E. Franklin-Tong, also found that the response involves rapid inhibition of pollen-tube growth, followed by PCD.

In slime molds

The social slime mold Dictyostelium discoideum has the peculiarity of either adopting a predatory amoeba-like behavior in its unicellular form or coalescing into a mobile slug-like form when dispersing the spores that will give birth to the next generation.

The stalk is composed of dead cells that have undergone a type of PCD that shares many features of an autophagic cell-death: massive vacuoles forming inside cells, a degree of chromatin condensation, but no DNA fragmentation. The structural role of the residues left by the dead cells is reminiscent of the products of PCD in plant tissue.

D. discoideum is a slime mold, part of a branch that might have emerged from eukaryotic ancestors about a billion years before the present. It seems that they emerged after the ancestors of green plants and the ancestors of fungi and animals had differentiated. But, in addition to their place in the evolutionary tree, the fact that PCD has been observed in the humble, simple, six-chromosome D. discoideum has additional significance: It permits the study of a developmental PCD path that does not depend on caspases characteristic of apoptosis.

Evolutionary origin of mitochondrial apoptosis

The occurrence of programmed cell death in protists is possible, but it remains controversial. Some categorize death in those organisms as unregulated apoptosis-like cell death.

Biologists had long suspected that mitochondria originated from bacteria that had been incorporated as endosymbionts ("living together inside") of larger eukaryotic cells. It was Lynn Margulis who from 1967 on championed this theory, which has since become widely accepted. The most convincing evidence for this theory is the fact that mitochondria possess their own DNA and are equipped with genes and replication apparatus. 

This evolutionary step would have been risky for the primitive eukaryotic cells, which began to engulf the energy-producing bacteria, as well as a perilous step for the ancestors of mitochondria, which began to invade their proto-eukaryotic hosts. This process is still evident today, between human white blood cells and bacteria. Most of the time, invading bacteria are destroyed by the white blood cells; however, it is not uncommon for the chemical warfare waged by prokaryotes to succeed, with the consequence known as infection by its resulting damage.

One of these rare evolutionary events, about two billion years before the present, made it possible for certain eukaryotes and energy-producing prokaryotes to coexist and mutually benefit from their symbiosis.

Mitochondriate eukaryotic cells live poised between life and death, because mitochondria still retain their repertoire of molecules that can trigger cell suicide. It is not clear why apoptotic machinery is maintained in the extant unicellular organisms. This process has now been evolved to happen only when programmed. to cells (such as feedback from neighbors, stress or DNA damage), mitochondria release caspase activators that trigger the cell-death-inducing biochemical cascade. As such, the cell suicide mechanism is now crucial to all of our lives.

Programmed death of entire organisms

Clinical significance

ABL

The BCR-ABL oncogene has been found to be involved in the development of cancer in humans.

c-Myc

c-Myc is involved in the regulation of apoptosis via its role in downregulating the Bcl-2 gene. Its role the disordered growth of tissue.

Metastasis

A molecular characteristic of metastatic cells is their altered expression of several apoptotic genes.