Programmed cell death (PCD) in unicellular organisms is in some instances an altruistic trait. When the beneficiaries are clones or close kin, kin selection theory may be used to explain the evolution of the trait, and when the trait evolves in groups of distantly related individuals, group or multilevel selection theory is invoked. In mixed microbial communities, the benefits are also available to unrelated taxa. But the evolutionary ecology of PCD in communities is poorly understood. Few hypotheses have (...) been offered concerning the community role of PCD despite its far-reaching effects. The hypothesis we consider here is that PCD is a black queen. The Black Queen Hypothesis (BQH) outlines how public goods arising from a leaky function are exploited by other taxa in the community. Black Queen (BQ) traits are essential for community survival, but only some members bear the cost of possessing them, while others lose the trait In addition, BQ traits have been defined in terms of adaptive gene loss, and it is unknown whether this has occurred for PCD. Our conclusion is that PCD fulfils the two most important criteria of a BQ (leakiness and costliness), but that more empirical data are needed for assessing the remaining two criteria. In addition, we hold that for viewing PCD as a BQ, the original BQH needs to include social traits. Thus, despite some empirical and conceptual shortcomings, the BQH provides a helpful avenue for investigating PCD in microbial communities. (shrink)

The cytokine interferon‐γ (IFN‐γ), initiates both cell cycle arrest and cell death in certain cell lines. Through a novel strategy of cell transfection with episomal vectors expressing antisense cDNAs, Deiss et al.(1.2) have demonstrated that it is possible to isolate genes that are required for the initiation of cell death by the cytokine IFN‐γ. This approach, referred to as TKO, for Technical Knock Out, has identified several genes whose activity appears to be essential (...) for the induction of apoptosis by IFN‐γ in HeLa cells. Interestingly, these genes appear to mediate IFN‐γ‐induced apoptosis in HeLa cells, but their inhibition by antisense does not ameliorate the anti‐proliferative effects of IFN‐γ in these cells. The clever strategy employed by these authors holds promise for others who wish to isolate genes required for other differentiative processes in cultured cell lines. (shrink)

Shortly after implantation the embryonic lineage transforms from a coherent ball of cells into polarized cup shaped epithelium. Recently we elucidated a previously unknown apoptosis‐independent morphogenic event that reorganizes the pluripotent lineage. Polarization cues from the surrounding basement membrane rearrange the epiblast into a polarized rosette‐like structure, where subsequently a central lumen is established. Thus, we provided a new model revising the current concept of apoptosis‐dependent epiblast morphogenesis. Cell death however has to be tightly regulated during embryogenesis to (...) ensure developmental success. Here, we follow the stages of early mouse development and take a glimpse at the critical signaling and morphogenic events that determine cells destiny and reshape the embryonic lineage. (shrink)

Systemic autoimmune diseases are characterized by the production of antibodies against a broad range of self-antigens. Recent evidence indicates that the majority of these autoantigens are modified in various ways during cell death. This has led to the hypothesis that the primary immune response in the development of autoimmunity is directed to components of the dying cell. In this article, we summarize data on the modification of autoantigens during cell death and the possible consequences of (...) this for autoimmunity. BioEssays 22:627–636, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Programmed cell death (PCD) or apoptosis is a broadly conserved phenomenon in metazoans, whereby activation of canonical signal pathways induces an ordered dismantling and death of a cell. Paradoxically, the constituent proteins and pathways of PCD (most notably the metacaspase/caspase protease mediated signal pathways) have been demonstrated to retain non‐death functions across all phyla including yeast, nematodes, drosophila, and mammals. The ancient conservation of both death and non‐death functions of PCD proteins raises an (...) interesting evolutionary conundrum: was the primordial intent of these factors to induce cell death or to regulate other cellular adaptations? Here, we propose the hypothesis that apoptotic behavior of PCD proteins evolved or were co‐opted from core non‐death functions. (shrink)

In multicellular organisms, cells are frequently programmed to die. This makes good sense: cells that fail to, or are no longer playing important roles are eliminated. From the cell’s perspective, this also makes sense, since somatic cells in multicellular organisms require the cooperation of clonal relatives. In unicellular organisms, however, programmed cell death poses a difficult and unresolved evolutionary problem. The empirical evidence for PCD in diverse microbial taxa has spurred debates about what precisely PCD means in (...) the case of unicellular organisms. In this article, we survey the concepts of PCD in the literature and the selective pressures associated with its evolution. We show that definitions of PCD have been almost entirely mechanistic and fail to separate questions concerning what PCD fundamentally is from questions about the kinds of mechanisms that realize PCD. We conclude that an evolutionary definition is best able to distinguish PCD from closely related phenomena. Specifically, we define “true” PCD as an adaptation for death triggered by abiotic or biotic environmental stresses. True PCD is thus not only an evolutionary product but must also have been a target of selection. Apparent PCD resulting from pleiotropy, genetic drift, or trade-offs is not true PCD. We call this “ersatz PCD.”. (shrink)

Depletion of mitochondrial endo/exonuclease G‐like (EXOG) in cultured neonatal cardiomyocytes stimulates mitochondrial oxygen consumption rate (OCR) and induces hypertrophy via reactive oxygen species (ROS). Here, we show that neurohormonal stress triggers cell death in endo/exonuclease G‐like‐depleted cells, and this is marked by a decrease in mitochondrial reserve capacity. Neurohormonal stimulation with phenylephrine (PE) did not have an additive effect on the hypertrophic response induced by endo/exonuclease G‐like depletion. Interestingly, PE‐induced atrial natriuretic peptide (ANP) gene expression was completely abolished (...) in endo/exonuclease G‐like‐depleted cells, suggesting a reverse signaling function of endo/exonuclease G‐like. Endo/exonuclease G‐like depletion initially resulted in increased mitochondrial OCR, but this declined upon PE stimulation. In particular, the reserve capacity of the mitochondrial respiratory chain and maximal respiration were the first indicators of perturbations in mitochondrial respiration, and these marked the subsequent decline in mitochondrial function. Although pathological stimulation accelerated these processes, prolonged EXOG depletion also resulted in a decline in mitochondrial function. At early stages of endo/exonuclease G‐like depletion, mitochondrial ROS production was increased, but this did not affect mitochondrial DNA (mtDNA) integrity. After prolonged depletion, ROS levels returned to control values, despite hyperpolarization of the mitochondrial membrane. The mitochondrial dysfunction finally resulted in cell death, which appears to be mainly a form of necrosis. In conclusion, endo/exonuclease G‐like plays an essential role in cardiomyocyte physiology. Loss of endo/exonuclease G‐like results in diminished adaptation to pathological stress. The decline in maximal respiration and reserve capacity is the first sign of mitochondrial dysfunction that determines subsequent cell death. (shrink)

Heterogeneity in mitochondrial content has been previously suggested as a major contributor to cellular noise, with multiple studies indicating its direct involvement in biomedically important cellular phenomena. A recently published dataset explored the connection between mitochondrial functionality and cell physiology, where a non‐linearity between mitochondrial functionality and cell size was found. Using mathematical models, we suggest that a combination of metabolic scaling and a simple model of cell death may account for these observations. However, our findings (...) also suggest the existence of alternative competing hypotheses, such as a non‐linearity between cell death and cell size. While we find that the proposed non‐linear coupling between mitochondrial functionality and cell size provides a compelling alternative to previous attempts to link mitochondrial heterogeneity and cell physiology, we emphasise the need to account for alternative causal variables, including cell cycle, size, mitochondrial density and death, in future studies of mitochondrial physiology. (shrink)

Exploration of immune systems in prokaryotes, such as restriction‐modification or CRISPR‐Cas, shows that both innate and adaptive systems possess programmed cell death (PCD) potential. The key outstanding question is how the immune systems sense and “predict” infection outcomes to “decide” whether to fight the pathogen or induce PCD. There is a striking parallel between this life‐or‐death decision faced by the cell and the decision by temperate viruses to protect or kill their hosts, epitomized by the lysis‐lysogeny (...) switch of bacteriophage Lambda. Immune systems and temperate phages sense the same molecular inputs, primarily, DNA damage, that determine whether the cell lives or dies. Because temperate (pro)phages are themselves components of prokaryotic genomes, their shared “interests” with the hosts result in coregulation of the lysis‐lysogeny switch and immune systems that jointly provide the cell with the decision machinery to probe and predict infection outcomes, answering the life‐or‐death question. (shrink)

The mutations that cause many forms of inherited retinal degenerations have been identified, yet the mechanisms by which these mutations lead to death of photoreceptor cells of the retina are not completely understood. Investigations of the pathways from mutation to retinal degeneration have focused on spontaneous and engineered animal models of disease. Based on the studies performed to date, four major categories of degeneration mechanism can be identified. These include disruption of photoreceptor outer segment morphogenesis, metabolic overload, dysfunction of (...) retinal pigment epithelial cells, and chronic activation of phototransduction. Future investigations will likely identify additional mechanisms of photoreceptor damage. This review will summarize what has been learned from studying animal models of non-syndromic inherited retinal degenerations. BioEssays 23:605–618, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

During development, large numbers of cells die by a process known as programmed cell death. This loss of cells plays a number of important roles, including the sculpting of the body form and the removal of vestigial tissues. Data obtained from a variety of organisms has suggested that a cell's ‘decision’ to die is a differentiative event, requiring the activation of specific sets of genes. Several putative ‘cell death’ genes have recently been cloned, and one (...) has been identified as the product of the polyubiquitin gene. Accumulation of ubiquitin has been observed not only during programmed cell death, but also in several neurodegenerative disorders, including Alzheimer's Disease. (shrink)

Programmed cell death (PCD) is a process aimed at the removal of redundant, misplaced, or damaged cells and it is essential to the development and maintenance of multicellular organisms. In contrast to the relatively well‐described cell death pathway in animals, often referred to as apoptosis, mechanisms and regulation of plant PCD are still ill‐defined. Several morphological and biochemical similarities between apoptosis and plant PCD have been described, including DNA laddering, caspase‐like proteolytic activity, and cytochrome c release (...) from mitochondria. Reactive oxygen species (ROS) have emerged as important signals in the activation of plant PCD. In addition, several plant hormones may exert their respective effects on plant PCD through the regulation of ROS accumulation. The possible plant PCD regulators discussed in this review are integrated in a model that combines plant‐specific regulators with mechanisms functionally conserved between animals and plants. BioEssays 25:47–57, 2003. © 2002 Wiley Periodicals, Inc. (shrink)

Apoptosis (programmed cell death) is an evolutionarily conserved cellular process, important for development and homeostasis(1). Most apoptotic cells share a common set of morphological and physiological characteristics that distinguish them from necrotic deaths(2). While genetic studies have indicated that these characteristic changes result from the activation of an endogenous ‘suicide program’(3), little is known about the nature of this program and the molecular events underlying these changes. Two recent papers(4,5) describing cell‐free extracts that reproduce several of the (...) characteristic changes observed in apoptotic cells promise to make these phenomena accessible to biochemical analysis. (shrink)

A marked feature of eukaryotic programmed cell death is an early drop in mitochondrial transmembrane potential. This results from the opening of permeability transition pores, which are composed of adenine nucleotide translocators and mitochondrial porins. The latter share striking similarites with bacterial porins, (including down‐regulation of their pore size by purine nucleotides), suggesting a common origin. The porins of some invasive bacteria play a crucial role during their accommodation inside the host cell and this co‐existence resembles the (...) endosymbiotic origin of mitochondria. The above observations suggest that early in eukaryotic evolution, former invaders may have used porin‐type channels to enter their host and to induce its death when the levels of its cytoplasmic purine nucleotides were dropped. The appearance of adenosine nucleotide translocators in the primitive eukaryotes, which permitted usage of the oxidative metabolism of the invaders, provided the basis for the permeability transition phenomena, now linked to the apoptotic process. Bcl‐2‐type molecules, being able to modulate the permeability transition pores by interaction with adenosine nucleotide translocators, may have played an essential role in conferring a means of controlling apoptosis. (shrink)

A distinct group of receptors including DCC, UNC5, RET and Ptc1 is known to function in ligand‐dependent neuronal growth and differentiation or axon guidance. Acting as “dependence receptors”, they may also regulate neuronal cell survival by inducing apoptosis in the absence of cognate ligand. Receptor‐initiated apoptosis requires proteolytic (caspase) cleavage and exposure of a pro‐apoptotic region in the cytoplasmic domains of the receptors. In contrast, classical apoptosis induced by growth factor or cytokine deprivation involves loss of survival signaling without (...) receptor cleavage. DCC, UNC5, RET and Ptc1 are downregulated or mutated in diverse cancers, and show properties characteristic of tumor suppressors, consistent with their ability to promote neuronal cell death. Dysfunctional dependence receptors have been linked to the loss of specific neurons in certain inherited and neurodegenerative diseases. Dependence receptor‐initiated apoptosis represents a novel paradigm for the controlled removal of specific cells during neural development and elimination of malignant cells that have strayed beyond regions of ligand availability. BioEssays 26:656–664, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Recently it has been hypothesized that apoptotic cell death is involved in several neuropathological conditions including Parkinson's disease (PD). Initial morphological studies assessing the presence of apoptosis in Parkinsonian brain tissues yielded mixed results. Based on more recent studies in human PD brains as well in animal and cell culture models of the disease, a picture is emerging, however, that strongly suggests that many of the molecular players thought to participate in this type of neuronal cell (...) death are active in the disease. The task of researchers in the field is now to deduce how these players may be interacting with one another to bring about cell death in PD and to design effective therapies to interfere with these processes. BioEssays 23:640–646, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The bcl‐2 gene product, a 25 kDa membrane protein residing at mitochondrial, microsomal and nuclear membrane sites within many cell types, is a broad and potent inhibitor of cell death by apoptosis. A family of bcl‐2‐related genes with death‐inhibiting or ‐promoting activities has recently been described, indicating a potentially quite complex cell death regulatory network at the level of gene expression and protein‐protein interactions. The function of bcl‐2 may be to regulate a final common (...) pathway in apoptosis. Current hypotheses suggest that oxidative stress, specific proteolytic activity or cell cycle control may be common elements in apoptosis through which bcl‐2 exerts its survival function. Based on the extent to which elements of apoptotic pathways overlap with non‐apoptotic cellular functions, the physiological role of bcl‐2 may also extend to other cellular processes such as differentiation and proliferation. (shrink)

Although the Bcl‐2 family members and p53 are involved in the regulation of apoptosis, the status of apoptotic machinery (eg caspases) plays a major role in determining the mode and timing of cell death. If the apoptotic machinery is lost, inhibited, or intrinsically inactivated, the “death stars”, Bcl‐2 and p53, may become irrelevant to cell death. In this light, high levels of Bcl‐2 may indicate that downstream apoptotic pathways are still functional. This explains why Bcl‐2 (...) overexpression can be a marker of chemosensitivity and favorable prognosis in certain cancers and why retention of wild‐type p53 may manifest inactivation of caspases in aggressive cancers. BioEssays 23:947–953, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Extracellular ATP released from necrotic cells in inflamed tissues activates the P2X7 receptor, stimulates the exposure of phosphatidylserine, and causes cell lysis. Recent findings indicated that XK, a paralogue of XKR8 lipid scramblase, forms a complex with VPS13A at the plasma membrane of T cells. Upon engagement by ATP, an unidentified signal(s) from the P2X7 receptor activates the XK‐VPS13A complex to scramble phospholipids, followed by necrotic cell death. P2X7 is expressed highly in CD25+CD4+ T cells but weakly (...) in CD8+ T cells, suggesting a role of this system in the activation of the immune system to prevent infection. On the other hand, a loss‐of‐function mutation in XK or VPS13A causes neuroacanthocytosis, indicating the crucial involvement of XK‐VPS13A‐mediated phospholipid scrambling at plasma membranes in the maintenance of homeostasis in the nervous and red blood cell systems. (shrink)

Genetic abnormalities of three factors related to the photoreceptor mechanism have been reported in both animal models and humans. Apoptotic mechanism has also been suggested as a final common pathway of photoreceptor cell death. Our findings of increased level of glutamate in photoreceptor cells in rds mice suggest that amino acid might mediate between these two pathological mechanisms.

Endo‐exonucleases from E. coli to man, although very different proteins, are multifunctional enzymes with similar enzymatic activities. They probably have two common but opposing biological roles. On the one hand, they promote survival of the organism by acting in recombination and recombinational DNA repair to diversify and help preserve the genome intact. On the other hand, they degrade the genomic DNA when it is damaged beyond repair. This ensures elimination of heavily mutagenized cells from the population.

The tricarboxylic acid (TCA) or Krebs cycle, which takes place in prokaryotic cells and in the mitochondria of eukaryotic cells, is central to life on Earth and participates in key events such as energy production and anabolic processes. Despite its relevance, it is not perceived as tightly regulated compared to other key metabolisms such as glycolysis/gluconeogenesis. A better understanding of the functioning of the TCA cycle is crucial due to mitochondrial function impairment in several diseases, especially those that occur with (...) neurodegeneration. This article revisits what is known about the regulation of the Krebs cycle and hypothesizes the need for large‐scale, rapid regulation of TCA cycle enzyme activity. Evidence of mitochondrial enzyme activity regulation by activation/deactivation of protein kinases and phosphatases exists in the literature. Apart from indirect regulation via G protein‐coupled receptors (GPCRs) at the cell surface, signaling upon activation of GPCRs in mitochondrial membranes may lead to a direct regulation of the enzymes of the Krebs cycle. Hormonal‐like regulation by posttranscriptional events mediated by activable kinases and phosphatases deserve proper assessment using isolated mitochondria. Also see the video abstract here: https://youtu.be/aBpDSWiMQyI. (shrink)

Mild and massive DNA damage are differentially integrated into the cellular signaling networks and, in consequence, provoke different cell fate decisions. After mild damage, the tumor suppressor p53 directs the cellular response to cell cycle arrest, DNA repair, and cell survival, whereas upon severe damage, p53 drives the cell death response. One posttranslational modification of p53, phosphorylation at Serine 46, selectively occurs after severe DNA damage and is envisioned as a marker of the cell (...) death response. However, the molecular mechanism of action of the p53 Ser46 phospho‐isomer, the molecular timing of this phosphorylation event, and its activating effects on apoptosis and ferroptosis still await exploration. In this essay, the current body of evidence on the molecular function of this deadly p53 mark, its evolutionary conservation, and the regulation of the key players of this response, the p53 Serine 46 kinases, are reviewed and dissected. (shrink)

Ischemic stroke involves numerous and complex pathophysiological mechanisms including blood flow reduction, ionic exchanges, spreading depressions and cell death through necrosis or apoptosis. We used a mathematical model based on these phenomena to study the influences of intensity and duration of ischemia on the final size of the infarcted area. This model relies on a set of ordinary and partial differential equations. After a sensibility study, the model was used to carry out in silico experiments in various ischemic (...) conditions. The simulation results show that the proportion of apoptotic cells increases when the intensity of ischemia decreases, which contributes to the model validation. The simulation results also show that the influence of ischemia duration on the infarct size is more complicated. They suggest that reperfusion is beneficial when performed in the early stroke but may be either inefficacious or even deleterious when performed later after the stroke onset. This aggravation could be explained by the depolarisation waves which might continue to spread ischemic damage and by the speeding up of the apoptotic process leading to cell death. The effect of reperfusion on cell death through these two phenomena needs to be further studied in order to develop new therapeutic strategies for stroke patients. (shrink)

A class of maize mutants, collectively known as disease lesion mimics, display discrete disease‐like symptoms in the absence of pathogens. It is intriguing that a majority of these lesion mimics behave as dominant gain‐of‐function mutations. The production of lesions is strongly influenced by light, temperature, developmental state and genetic background. Presently, the biological significance of this lesion mimicry is not clear, although suggestions have been made that they may represent defects in the plants' recognition of, or response to, pathogens. One (...) feature that is common to all lesion mimics is their association with cell death. In plants, as in animals, a number of developmental and pathological processes exist where controlled cell death, whether programmed or triggered in response to physiological or environmental stimuli, constitutes the normal aspect of life. Might disease lesion mimic mutations represent variants where regulation of desirable cell death has gone awry? In this paper we argue that this might be the case, and further conjecture that these mutants offer a unique opportunity for studying the genetic and cellular mechanisms of cell death in plants. (shrink)

Reactive oxygen species (ROS) are known as toxic metabolic products in plants and other aerobic organisms. An elaborate and highly redundant plant ROS network, composed of antioxidant enzymes, antioxidants and ROS-producing enzymes, is responsible for maintaining ROS levels under tight control. This allows ROS to serve as signaling molecules that coordinate an astonishing range of diverse plant processes. The specificity of the biological response to ROS depends on the chemical identity of ROS, intensity of the signal, sites of production, plant (...) developmental stage, previous stresses encountered and interactions with other signaling molecules such as nitric oxide, lipid messengers and plant hormones. Although many components of the ROS signaling network have recently been identified, the challenge remains to understand how ROS-derived signals are integrated to eventually regulate such biological processes as plant growth, development, stress adaptation and programmed cell death. (shrink)

Bacteria are able to induce defense and DNA repair systems that specifically counteract the toxic effects of some important natural agents. «Adaptive responses» to alkylation and oxidation damage have revealed novel strategies for escape from certain kinds of genetic damage.

Host‐pathogen arms race is a universal, central aspect of the evolution of life. Most organisms evolved several distinct yet interacting strategies of anti‐pathogen defense including resistance to parasite invasion, innate and adaptive immunity, and programmed cell death (PCD). The PCD is the means of last resort, a suicidal response to infection that is activated when resistance and immunity fail. An infected cell faces a decision between active defense and altruistic suicide or dormancy induction, depending on whether immunity (...) is “deemed” capable of preventing parasite reproduction and consequent infection of other cells. In bacteria and archaea, immunity genes typically colocalize with PCD modules, such as toxins‐antitoxins, suggestive of immunity‐PCD coupling, likely mediated by shared proteins that sense damage and “predict” the outcome of infections. In type VI CRISPR‐Cas systems, the same enzyme that inactivates the target RNA might execute cell suicide, in a case of ultimate integration of immunity and PCD. (shrink)

The word soul in the cell-soul pathway does not have a scientific definition but has been hypothesized to be an indefinite, non-structured, massless energy made up of electromagnetic radiations that is confined in the cytoskeletal network of a living cell. It is a coherent, imperceptible, uncontainable and recyclable support pathway, which uses energy to promulgate consciousness in the cell supporting its functions. The pathway currently provides a mechanistic explanation of the flow of consciousness within the body, but (...) the intent of this paper is to provide an arduous explanation of non-local consciousness or disembodiment observed in near-death experiences. The paper hypothetically subsets the cell-soul pathway with the presence of two forms of consciousness, consistent with a recently developed model by Reddy : bodily consciousness, which manages functions only at cellular level, and functional consciousness, which is present in the body but can get disembodied and perform non-locally; the two forms of consciousness represent the overall state of consciousness. The non-locality of subjective experiences observed in near-death cases can be related to the realm of quantum physics – quantum entanglement between the two forms of consciousness that can demonstrate the capability of storing information holographically within the void or vacuum with the ability to create memories beyond the limitations of the brain and body. (shrink)

Upon starvation and growth arrest, Escherichia coli cells gradually lose their ability to reproduce. These apparently sterile/nonculturable cells initially remain intact and metabolically active and the underlying molecular mechanism behind this sterility is something of an enigma in bacteriology. Three different models have been proposed to explain this phenomenon. The first theory suggests that starving cells become nonculturable due to cellular deterioration, are moribund, and show some of the same signs of senescence as aging organisms. The two other theories suggest (...) that genetically programmed pathways, rather than stochastic deterioration, trigger nonculturability. One “program” theory suggests that nonculturability is the culmination of an adaptive pathway generating dormant survival forms, similar to spore formation in differentiating bacteria. The other “program” theory states that starved cells lose viability due to activation of genetic modules mediating programmed cell death. The different models will be reviewed and evaluated in light of recent data on the physiology and molecular biology of growth‐arrested E. coli cells. BioEssays 25:204–211, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Theoretical frameworks concerning cell fate typically center on proximate causes to explain how cells know what type they are meant to become. While major advances in cell fate theory have been achieved by these mechanism-focused frameworks, there are some aspects of cell decision-making that require an evolutionary interpretation. While mechanistic biologists sometimes turn to evolutionary theory to gain insights about cell fate (cancer is a good example), it is not entirely clear in cell fate theory (...) what insights evolutionary theory can add, and why in some cases it is required for understanding cell fate. In this perspective we draw on our work on cellular mortality to illustrate how evolutionary theory provides an explanation for death being selected as one of the potential cell fates. Using our hypothesis for why some microbes in a community choose death as their fate, we suggest that some insights in cell fate theory are inaccessible to a theoretical framework that focuses solely on proximate causes. (shrink)

Apoptosis‐inducing factor (AIF) is expelled from mitochondria after some apoptotic stimuli and translocates to the nucleus, which may contribute to DNA and nuclear fragmentation in some non‐physiological mammalian cell deaths. Conversely, the requirement for mitochondrial AIF in oxidative phosphorylation and energy generation provides a plausible explanation for the embryonic lethality or neurodegeneration that has been found in different AIF‐deficient mouse models. These findings may help illuminate the ability of mitochondrial AIF to suppress cytoplasmic stress granule formation and to promote (...) the tumorigenic growth of cancer cells. AIF is ideally located in the mitochondrion to perform a vital normal function in energy production. Once it translocates to the nucleus, however, the cell might die either of energy failure or nuclear fragmentation (or both). We propose that the main function of AIF is to support energy production in both normal and transformed cell physiology, whereas nuclear‐translocated AIF might contribute to stress‐induced or pathological cell death in certain scenarios. BioEssays 28: 834–843, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Interleukin 1β‐converting enzyme (ICE)‐like proteases (caspases) play an important role in programmed cell death (apoptosis), and elucidating the consequences of their proteolytic activity is central to our understanding of the molecular mechanisms of cell death. Diverse structural and regulatory proteins and enzymes, including protein kinase Cδ, the retinoblastoma protein (a protein involved in cell survival), the DNA repair enzyme DNA‐dependent protein kinase and the nuclear lamins, undergo specific and limited endoproteolytic cleavage by various caspases during (...) apoptosis. Since individual caspases can cleave multiple substrates, the consequences of cleavage of only a single substrate are still poorly understood. Nevertheless, proteolytic activation of protein kinase Cδ may be an important early step in the cell death pathway, and cleavage of the retinoblastoma protein could suppress its cell survival function, whereas proteolytic inactivation of DNA repair enzymes might compromise the ability of the cell to reverse DNA fragmentation. On the other hand, cleavages of nuclear and cytoplasmic structural proteins (e.g. the lamins and Gas2) appear to be required for or contribute to the dramatic rearrangements in cellular architecture that are necessary for the completion of the cell death process. An emerging theme is that parallel and sequential proteolytic activation and inactivation of key protein substrates occurs during the multiple steps of apoptosis. (shrink)

As life extended into eukaryota, a great host of strategies emerged in the pursuit of cellular life. Some cells have been successful in solitude, some moved into cooperatives (i.e., multicellular organisms), but one additional strategy emerged. Throughout eukaryotes, many of the diverse multicellular cooperatives took life in partnership one step further. These cells came together and lost their singularity in the expanse of syncytial life. Recently in our search for this elusive “how”, we discovered the intriguing peculiarity of a nuclear, (...) RNA‐binding protein living a second life as a fusion manager at the surface of developing osteoclasts, ushering them into syncytia 1. It is from here that we will develop several thoughts about the advantages of multinucleated cells and discuss how these fusing cells pass through several hallmarks of cell death. We will propose that cell fusion shares much with cell death because cell fusion is a death of sorts for the cells that undergo it – a death of the life that was and the beginning of new life in a community without borders. (shrink)