BBA - Molecular Cell Research (v.1783, #7)
Editorial Board (ii).
Preface to the special issue: Apoptosis in yeast by Frank Madeo; Kai-Uwe Fröhlich (1271).
Mitochondrial death pathways in yeast and mammalian cells by Wen-Chih Cheng; Kelly M. Leach; J. Marie Hardwick (1272-1279).
In mammals, mitochondria are important mediators of programmed cell death, and this process is often regulated by Bcl-2 family proteins. However, a role for mitochondria-mediated cell death in non-mammalian species is more controversial. New evidence from a variety of sources suggests that mammalian mitochondrial fission/division proteins also have the capacity to promote programmed cell death, which may involve interactions with Bcl-2 family proteins. Homologues of these fission factors and several additional mammalian cell death regulators are conserved in flies, worms and yeast, and have been suggested to regulate programmed cell death in these species as well. However, the molecular mechanisms by which these phylogenetically conserved proteins contribute to cell death are not known for any species. Some have taken the conserved pro-death activity of mitochondrial fission factors to mean that mitochondrial fission per se, or failed attempts to undergo fission, are directly involved in cell death. Other evidence suggests that the fission function and the cell death function of these factors are separable. Here we consider the evidence for these arguments and their implications regarding the origins of programmed cell death.
Keywords: Yeast apoptosis; Mitochondria; Fission; Fusion; Drp1; Dnm1; Caspase; Metacaspase">; Fragmentation; Cytochrome c;
Chronological aging-induced apoptosis in yeast by Paola Fabrizio; Valter D. Longo (1280-1285).
Saccharomyces cerevisiae is the simplest among the major eukaryotic model organisms for aging and diseases. Longevity in the chronological life span paradigm is measured as the mean and maximum survival period of populations of non-dividing yeast. This paradigm has been used successfully to identify several life-regulatory genes and three evolutionary conserved pro-aging pathways. More recently, Schizosaccharomyces pombe has been shown to age chronologically in a manner that resembles that of S. cerevisiae and that depends on the activity of the homologues of two pro-aging proteins previously identified in the budding yeast. Both yeast show features of apoptotic death during chronological aging. Here, we review some fundamental aspects of the genetics of chronological aging and the overlap between yeast aging and apoptotic processes with particular emphasis on the identification of an aging/death program that favors the dedifferentiation and regrowth of a few better adapted mutants generated within populations of aging S. cerevisiae. We also describe the use of a genome-wide screening technique to gain further insights into the mechanisms of programmed death in populations of chronologically aging S. cerevisiae.
Keywords: Programmed death; Chronological aging; Superoxide; Adaptive regrowth; Mitochondria;
Mitochondria-dependent apoptosis in yeast by C. Pereira; R.D. Silva; L. Saraiva; B. Johansson; M.J. Sousa; M. Côrte-Real (1286-1302).
Mitochondrial involvement in yeast apoptosis is probably the most unifying feature in the field. Reports proposing a role for mitochondria in yeast apoptosis present evidence ranging from the simple observation of ROS accumulation in the cell to the identification of mitochondrial proteins mediating cell death. Although yeast is unarguably a simple model it reveals an elaborate regulation of the death process involving distinct proteins and most likely different pathways, depending on the insult, growth conditions and cell metabolism. This complexity may be due to the interplay between the death pathways and the major signalling routes in the cell, contributing to a whole integrated response. The elucidation of these pathways in yeast has been a valuable help in understanding the intricate mechanisms of cell death in higher eukaryotes, and of severe human diseases associated with mitochondria-dependent apoptosis. In addition, the absence of obvious orthologues of mammalian apoptotic regulators, namely of the Bcl-2 family, favours the use of yeast to assess the function of such proteins. In conclusion, yeast with its distinctive ability to survive without respiration-competent mitochondria is a powerful model to study the involvement of mitochondria and mitochondria interacting proteins in cell death.
Keywords: Yeast apoptosis; Apoptotic regulators; Mitochondrial outer membrane permeabilization; Permeability transition pore; Bcl-2 family; Mitochondrial fragmentation;
Negative regulation of apoptosis in yeast by Esther Owsianowski; David Walter; Birthe Fahrenkrog (1303-1310).
In recent years, yeast has been proven to be a useful model organism for studying programmed cell death. It not only exhibits characteristic markers of apoptotic cell death when heterologous inducers of apoptosis are expressed or when treated with apoptosis inducing drugs such as hydrogen peroxide (H2O2) or acetic acid, but contains homologues of several components of the apoptotic machinery identified in mammals, flies and nematodes, such as caspases, apoptosis inducing factor (AIF), Omi/HtrA2 and inhibitor-of-apoptosis proteins (IAPs). In this review, we focus on the role of negative regulators of apoptosis in yeasts. Bir1p is the only IAP protein in Saccharomyces cerevisiae and has long been known to play a role in cell cycle progression by acting as kinetochore and chromosomal passenger protein. Recent data established Bir1p's protective function against programmed cell death induced by H2O2 treatment and in chronological ageing. Other factors that have a direct or indirect influence on intracellular levels of reactive oxygen species (ROS) and thus lead to apoptosis if they are misregulated or non-functional will be discussed.
Keywords: Apoptosis; BIR; IAP; ROS; Yeast;
Caspase-independent apoptosis in yeast by Qiuli Liang; Wei Li; Bing Zhou (1311-1319).
Apoptosis is a highly regulated cellular suicide program crucial for metazoan development. Yeast counterparts of central metazoan apoptotic regulators, such as metacaspase Yca1p, have been identified. In spite of the importance of Yca1p in yeast apoptotic process, many other factors such as Aif1p, orthologs of EndoG, AMID and cyclophilin D play important roles in caspase-independent apoptotic pathways. This review summarized recent progress about studies of various intrinsic and extrinsic apoptotic stimuli that may induce yeast cell death via caspase-independent apoptosis.
Keywords: Apoptosis; AIF1; EndoG; AMID; MPTP;
Caspase-dependent apoptosis in yeast by Cristina Mazzoni; Claudio Falcone (1320-1327).
Damaging environment, certain intracellular defects or heterologous expression of pro-apoptotic genes induce death in yeast cells exhibiting typical markers of apoptosis. In mammals, apoptosis can be directed by the activation of groups of proteases, called caspases, that cleave specific substrates and trigger cell death. In addition, in plants, fungi, Dictyostelium and metazoa, paracaspases and metacaspases have been identified that share some homologies with caspases but showing different substrate specificity. In the yeast Saccharomyces cerevisiae, a gene (MCA1/YCA1) has been identified coding for a metacaspase involved in the induction of cell death. Metacaspases are not biochemical, but sequence and functional homologes of caspases, as deletion of them rescues entirely different death scenarios. In this review we will summarize the current knowledge in S. cerevisiae on apoptotic processes, induced by internal and external triggers, which are dependent on the metacaspase gene YCA1.
Keywords: Yeast; Caspase; Apoptosis;
Senescence and apoptosis in yeast mother cell-specific aging and in higher cells: A short review by Peter Laun; Gino Heeren; Mark Rinnerthaler; Raphaela Rid; Sonja Kössler; Lore Koller; Michael Breitenbach (1328-1334).
It is our intention to give the reader a short overview of the relationship between apoptosis and senescence in yeast mother cell-specific aging. We are studying yeast as an aging model because we want to learn something of the basic biology of senescence and apoptosis even from a unicellular eukaryotic model system, using its unrivalled ease of genetic analysis. Consequently, we will discuss also some aspects of apoptosis in metazoa and the relevance of yeast apoptosis and aging research for cellular (Hayflick type) and organismic aging of multicellular higher organisms. In particular, we will discuss the occurrence and relevance of apoptotic phenotypes for the aging process. We want to ask the question whether apoptosis (or parts of the apoptotic process) are a possible cause of aging or vice versa and want to investigate the role of the cellular stress response system in both of these processes. Studying the current literature, it appears that little is known for sure in this field and our review will therefore be, for a large part, more like a memorandum or a program for future research.
Keywords: Yeast apoptosis; Replicative lifespan; Chronological lifespan; S. cerevisiae; Translational control; Eukaryotic ribosome; AIF; YCA1; NUC1; NMA111;
Programmed cell death in fission yeast Schizosaccharomyces pombe by Choon Pei Low; Hongyuan Yang (1335-1349).
Yeasts have proven to be invaluable, genetically tractable systems to study various fundamental biological processes including programmed cell death. Recent advances in the elucidation of the molecular pathways underlying apoptotic cell death in yeasts have revealed remarkable similarities to mammalian apoptosis at cellular, organelle and macromolecular levels, thus making a strong case for the relevance of yeast models of regulated cell death. Programmed cell death has been reported in fission yeast Schizosaccharomyces pombe, primarily in the contexts of perturbed intracellular lipid metabolism, defective DNA replication, improper mitotic entry, chronological and replicative aging. Here we review the current understanding of the programmed cell death in fission yeast, paying particular attention to lipid-induced cell death. We discuss our recent findings that fission yeast exhibits plasticity of apoptotic and non-apoptotic modes of cell death in response to different lipid stimuli and growth conditions, and that mitochondria, reactive oxygen species and novel cell death mediators including metacaspase Pca1, SpRad9 and Pck1 are involved in the lipotoxic cell death. We also present perspectives on how various aspects of the cell and molecular biology of this organism can be explored to shed light on the governing principles underlying lipid-mediated signaling and cell demise.
Keywords: Fission yeast; Schizosaccharomyces pombe; Programmed cell death; Apoptosis; Lipoapoptosis; Lipotoxicity; Triacylglycerol; Diacylglycerol; Ceramide; Metacaspase; Pca1; Rad9; Mitochondria; Reactive oxygen species; Protein kinase C; Pck1; Bzz1; Chronological aging; Replicative aging; Replication defect; Cell cycle checkpoint;
Natural causes of programmed death of yeast Saccharomyces cerevisiae by Fedor F. Severin; Margarita V. Meer; Ekaterina A. Smirnova; Dmitry A. Knorre; Vladimir P. Skulachev (1350-1353).
The existence of cell death program in unicellular organisms has been reported for a number of species. Nevertheless, the question why the ability to commit suicide has been maintained throughout evolution is far from being solved. While it is believed that altruistic death of individual yeast cells could be beneficial for the population, it is generally not known (i) what is wrong with the individuals destined for elimination, (ii) what is the critical value of the parameter that makes a cell unfit and (iii) how the cell monitors this parameter. Studies performed on yeast Saccharomyces cerevisiae allow us to hypothesize on ways of possible solutions of these problems. Here we argue that (a) the main parameter for life-or-death decision measured by the cell is the degree of damage to the genetic material, (b) its critical value is dictated by quorum sensing machinery, and (c) it is measured by monitoring delays in cell division.
Keywords: Yeast; Programmed death; yca1; Altruistic; Group selection;
Reactive oxygen species and yeast apoptosis by Gabriel G. Perrone; Shi-Xiong Tan; Ian W. Dawes (1354-1368).
Apoptosis is associated in many cases with the generation of reactive oxygen species (ROS) in cells across a wide range of organisms including lower eukaryotes such as the yeast Saccharomyces cerevisiae. Currently there are many unresolved questions concerning the relationship between apoptosis and the generation of ROS. These include which ROS are involved in apoptosis, what mechanisms and targets are important and whether apoptosis is triggered by ROS damage or ROS are generated as a consequence or part of the cellular disruption that occurs during cell death. Here we review the nature of the ROS involved, the damage they cause to cells, summarise the responses of S. cerevisiae to ROS and discuss those aspects in which ROS affect cell integrity that may be relevant to the apoptotic process.
Keywords: Saccharomyces cerevisiae; Yeast; Apoptosis; Programmed cell death; Reactive oxygen species; Oxidative stress; Mitochondria; Endoplasmic reticulum; Actin; Stress responses;
Programmed cell death in pathogenic fungi by Mark Ramsdale (1369-1380).
Greater understanding of programmed cell death (PCD) responses in pathogenic fungi may offer a chance of exploiting the fungal molecular death machinery to control fungal infections. Clearly identifiable differences between the death machineries of pathogens and their hosts, make this a feasible target. Evidence for PCD in a range of pathogenic fungi is discussed alongside an evaluation of the capacity of existing antifungal agents to promote apoptosis and other forms of cell death. Information about death related signalling pathways that have been examined in pathogens as diverse as Candida albicans, Aspergillus fumigatus, Magnaporthe grisea and Colletotrichum trifolii are discussed.
Keywords: Antifungal drug; Candida albicans; Apoptosis; Necrosis;
Protein folding diseases and neurodegeneration: Lessons learned from yeast by Joris Winderickx; Charlotte Delay; Ann De Vos; Harald Klinger; Klaartje Pellens; Thomas Vanhelmont; Fred Van Leuven; Piotr Zabrocki (1381-1395).
Budding yeast Saccharomyces cerevisiae has proven to be a valuable model organism for studying fundamental cellular processes across the eukaryotic kingdom including man. In this respect, complementation assays, in which the yeast protein is replaced by a homologous protein from another organism, have been very instructive. A newer trend is to use the yeast cell factory as a toolbox to understand cellular processes controlled by proteins for which the yeast lacks functional counterparts. An increasing number of studies have indicated that S. cerevisiae is a suitable model system to decipher molecular mechanisms involved in a variety of neurodegenerative disorders caused by aberrant protein folding. Here we review the current knowledge gained by the use of so-called humanized yeasts in the field of Huntington's, Parkinson's and Alzheimer's diseases.
Keywords: Neurodegenerative disease; Huntington; Parkinson; Alzheimer; Yeast; Protein folding;
Programmed cell death in protists by Marcel Deponte (1396-1405).
Programmed cell death in protists does not seem to make sense at first sight. However, apoptotic markers in unicellular organisms have been observed in all but one of the six/eight major groups of eukaryotes suggesting an ancient evolutionary origin of this regulated process. This review summarizes the available data on apoptotic markers in non-opisthokonts and elucidates potential functions and evolution of programmed cell death. A newly discovered family of caspase-like proteases, the metacaspases, is considered to exert the function of caspases in unicellular organisms. Important results on metacaspases, however, showed that they cannot be always correlated to the measured proteolytic activity during protist cell death. Thus, a major challenge for apoptosis research in a variety of protists remains the identification of the molecular cell death machinery.
Keywords: Protist; Unicellular organism; Programmed cell death; Autophagic cell death; Metacaspase; Evolution;
Cytoskeletal induced apoptosis in yeast by Jane E. Leadsham; Campbell W. Gourlay (1406-1412).
The influence of the cytoskeleton reaches into almost every aspect of eukaryotic cell function. It is a little surprise therefore that links between the regulation of the cytoskeleton and apoptosis have been found in a variety of eukaryotic systems. Studies from yeast have made a significant contribution to this new field of research and have highlighted the importance of interactions between the cytoskeleton and mitochondria in determining cell fate. In yeast both the actin and microtubular cytoskeletons have been shown to influence mitochondrial function and the commitment to apoptosis. In this review we discuss the recent advances and speculate that apoptotic mechanisms that feed off the ability of the cytoskeleton to respond to environmental signals may represent a useful mechanism to remove weak or damaged individuals from a population.
Keywords: Actin; Mitochondria; Yeast; Apoptosis; ROS; Ras; Aging; Cell death; cAMP;
Viral induced yeast apoptosis by Manfred J. Schmitt; Jochen Reiter (1413-1417).
In an analogous system to mammals, induction of an apoptotic cell death programme (PCD) in yeast is not only restricted to various exogenous factors and stimuli, but can also be triggered by viral killer toxins and viral pathogens. In yeast, toxin secreting killer strains are frequently infected with double-stranded (ds)RNA viruses that are responsible for killer phenotype expression and toxin secretion in the infected host. In most cases, the viral toxins are either pore-forming proteins (such as K1, K2, and zygocin) that kill non-infected and sensitive yeast cells by disrupting cytoplasmic membrane function, or protein toxins (such as K28) that act in the nucleus by blocking DNA synthesis and subsequently causing a G1/S cell cycle arrest. Interestingly, while all these virus toxins cause necrotic cell death at high concentration, they trigger caspase- and ROS-mediated apoptosis at low-to-moderate concentration, indicating that even low toxin doses are deadly by triggering PCD in enemy cells. Remarkably, viral toxins are not solely responsible for cell death induction in vivo, as killer viruses themselves were shown to trigger apoptosis in non-infected yeast. Thus, as killer virus-infected and toxin secreting yeasts are effectively protected and immune to their own toxin, killer yeasts bear the intrinsic potential to dominate over time in their natural habitat.
Keywords: Yeast; Apoptosis; Killer toxin; dsRNA virus;
Mechanisms of Cdc48/VCP-mediated cell death — from yeast apoptosis to human disease by Ralf J. Braun; Hans Zischka (1418-1435).
The evolutionary conserved protein Cdc48/VCP is involved in various cellular processes, such as protein degradation, membrane fusion and chaperone activity. Increased levels of Cdc48/VCP correlate with cancer, whereas Cdc48/VCP at endogenous levels has been proposed to be a pathological effector in protein deposition diseases. Upon mutation Cdc48/VCP triggers the multisystem disorder ‘inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia’ (IBMPFD). The roles of Cdc48/VCP under these diverse pathological conditions, especially its function in decreased and increased incidences of cell death underlying these diseases, are poorly understood. Mutation of yeast CDC48 (cdc48 S565G) results in yeast cells demonstrating morphological markers of apoptotic cell death. In other species it has been confirmed that mutations and depletion of Cdc48/VCP cause apoptosis, whereas increased levels of this protein provide an anti-apoptotic effect. This review critically compares mechanisms of Cdc48/VCP-mediated apoptosis observed in yeast and other species. Cdc48/VCP plays a triple role in cell death. At first, loss-of-function of Cdc48/VCP due to mutation or depletion causes ER stress and oxidative stress, triggering apoptosis. Secondly, upon exogenously applied ER stress functional Cdc48/VCP is important in the processing of caspases and plays therewith a pro-apoptotic role. Finally, Cdc48/VCP protects cells from apoptosis through mediating and activating pro-survival signaling pathways, namely Akt and NFκB signaling. This complex role in cell death pathways could correspond with the various pathophysiological conditions Cdc48/VCP is involved in.
Keywords: CDC48; VCP; p97; Mitochondria; Oxidative stress; ER stress; Apoptosis; Cell survival;
Drug-induced apoptosis in yeast by B. Almeida; A. Silva; A. Mesquita; B. Sampaio-Marques; F. Rodrigues; P. Ludovico (1436-1448).
In order to alter the impact of diseases on human society, drug development has been one of the most invested research fields. Nowadays, cancer and infectious diseases are leading targets for the design of effective drugs, in which the primary mechanism of action relies on the modulation of programmed cell death (PCD). Due to the high degree of conservation of basic cellular processes between yeast and higher eukaryotes, and to the existence of an ancestral PCD machinery in yeast, yeasts are an attractive tool for the study of affected pathways that give insights into the mode of action of both antitumour and antifungal drugs. Therefore, we covered some of the leading reports on drug-induced apoptosis in yeast, revealing that in common with mammalian cells, antitumour drugs induce apoptosis through reactive oxygen species (ROS) generation and altered mitochondrial functions. The evidence presented suggests that yeasts may be a powerful model for the screening/development of PCD-directed drugs, overcoming the problem of cellular specificity in the design of antitumour drugs, but also enabling the design of efficient antifungal drugs, targeted to fungal-specific apoptotic regulators that do not have major consequences for human cells.
Keywords: Antifungal drug; Antitumour drug; Drug targets; Mitochondria; Reactive oxygen species; Yeast apoptosis;
The pleiotropic effects of heterologous Bax expression in yeast by Chamel M. Khoury; Michael T. Greenwood (1449-1465).
The finding that the heterologous expression of Bcl-2 proteins in yeast elicits effects that resemble their roles in metazoan apoptosis has contributed to the increasing use of this organism as a model for the study of apoptotic regulation. The pro-apoptotic Bax protein, for example, localizes to the yeast mitochondria, where it acts to promote alterations in mitochondrial physiology and cell death, similar to its ascribed mode of action in higher organisms. These observations lead to the hypothesis that the heterologous Bcl-2 proteins impinge on conserved elements of the apoptotic machinery in yeast. We herein provide a retrospective of the studies aimed at both testing this general hypothesis and investigating the mechanisms of the Bcl-2 proteins using yeast, with a particular emphasis on Bax. We also discuss the evidence for pleiotropic roles of Bax in yeast apoptosis.
Keywords: Bax; Bcl-2 protein; Yeast apoptosis;