Abstract
A cell's decision to die is controlled by a sophisticated network whose deregulation contributes to the pathogenesis of multiple diseases including neoplastic and neurodegenerative disorders. The finding, more than a decade ago, that baker's yeast (Saccharomyces cerevisiae) can undergo apoptosis uncovered the possibility to investigate this mode of programmed cell death (PCD) in a model organism that combines both technical advantages and a eukaryotic ‘cell room.’ Since then, numerous exogenous and endogenous triggers have been found to induce yeast apoptosis and multiple yeast orthologs of crucial metazoan apoptotic regulators have been identified and characterized at the molecular level. Such apoptosis-relevant orthologs include proteases such as the yeast caspase as well as several mitochondrial and nuclear proteins that contribute to the execution of apoptosis in a caspase-independent manner. Additionally, physiological scenarios such as aging and failed mating have been discovered to trigger apoptosis in yeast, providing a teleological interpretation of PCD affecting a unicellular organism. Due to its methodological and logistic simplicity, yeast constitutes an ideal model organism that is efficiently helping to decipher the cell death regulatory network of higher organisms, including the switches between apoptotic, autophagic, and necrotic pathways of cellular catabolism. Here, we provide an overview of the current knowledge about the apoptotic subroutine of yeast PCD and its regulation.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- PCD:
-
programmed cell death
- ROS:
-
reactive oxygen species
- PTP:
-
permeability transition pore
- HDAC:
-
histone deacetylase
- α-syn:
-
α-synuclein
- PKA:
-
protein kinase-A
- ATG:
-
autophagy-related gene
- GAPDH:
-
glyceraldehyde-3-phosphate dehydrogenase
- UPR:
-
unfolded protein response
- ERAD:
-
endoplasmic reticulum-associated protein degradation
- EndoG:
-
endonuclease-G
- AIF:
-
apoptosis-inducing factor
- TUNEL:
-
terminal dUTP nick-end labeling
References
Madeo F, Frohlich E, Frohlich KU . A yeast mutant showing diagnostic markers of early and late apoptosis. J Cell Biol 1997; 139: 729–734.
Carmona-Gutierrez D, Madeo F . Tracing the roots of death: apoptosis in Saccharomyces cerevisiae. In: Dong Z, Yin X-M (eds). Essentials of Apoptosis – A Guide for Basic and Clinical Research. Humana Press, 2009, pp 325–354.
Ribeiro GF, Corte-Real M, Johansson B . Characterization of DNA damage in yeast apoptosis induced by hydrogen peroxide, acetic acid, and hyperosmotic shock. Mol Biol Cell 2006; 17: 4584–4591.
Vachova L, Palkova Z . Physiological regulation of yeast cell death in multicellular colonies is triggered by ammonia. J Cell Biol 2005; 169: 711–717.
Buttner S, Eisenberg T, Carmona-Gutierrez D, Ruli D, Knauer H, Ruckenstuhl C et al. Endonuclease G regulates budding yeast life and death. Mol Cell 2007; 25: 233–246.
Wissing S, Ludovico P, Herker E, Buttner S, Engelhardt SM, Decker T et al. An AIF orthologue regulates apoptosis in yeast. J Cell Biol 2004; 166: 969–974.
Eisenberg T, Knauer H, Schauer A, Buttner S, Ruckenstuhl C, Carmona-Gutierrez D et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol 2009; 11: 1305–1314.
Buttner S, Eisenberg T, Herker E, Carmona-Gutierrez D, Kroemer G, Madeo F . Why yeast cells can undergo apoptosis: death in times of peace, love, and war. J Cell Biol 2006; 175: 521–525.
Fabrizio P, Battistella L, Vardavas R, Gattazzo C, Liou LL, Diaspro A et al. Superoxide is a mediator of an altruistic aging program in Saccharomyces cerevisiae. J Cell Biol 2004; 166: 1055–1067.
Herker E, Jungwirth H, Lehmann KA, Maldener C, Frohlich KU, Wissing S et al. Chronological aging leads to apoptosis in yeast. J Cell Biol 2004; 164: 501–507.
Laun P, Pichova A, Madeo F, Fuchs J, Ellinger A, Kohlwein S et al. Aged mother cells of Saccharomyces cerevisiae show markers of oxidative stress and apoptosis. Mol Microbiol 2001; 39: 1166–1173.
Severin FF, Hyman AA . Pheromone induces programmed cell death in S. cerevisiae. Curr Biol 2002; 12: R233–R235.
Ahn SH, Henderson KA, Keeney S, Allis CD . H2B (Ser10) phosphorylation is induced during apoptosis and meiosis in S. cerevisiae. Cell Cycle 2005; 4: 780–783.
Knorre DA, Smirnova EA, Severin FF . Natural conditions inducing programmed cell death in the yeast Saccharomyces cerevisiae. Biochemistry (Moscow) 2005; 70: 264–266.
Yuan JY, Horvitz HR . The Caenorhabditis elegans genes ced-3 and ced-4 act cell autonomously to cause programmed cell death. Dev Biol 1990; 138: 33–41.
Lam E . Controlled cell death, plant survival and development. Nat Rev Mol Cell Biol 2004; 5: 305–315.
Ameisen JC . Looking for death at the core of life in the light of evolution. Cell Death Differ 2004; 11: 4–10.
Reiter J, Herker E, Madeo F, Schmitt MJ . Viral killer toxins induce caspase-mediated apoptosis in yeast. J Cell Biol 2005; 168: 353–358.
Morton CO, Dos Santos SC, Coote P . An amphibian-derived, cationic, alpha-helical antimicrobial peptide kills yeast by caspase-independent but AIF-dependent programmed cell death. Mol Microbiol 2007; 65: 494–507.
Narasimhan ML, Coca MA, Jin J, Yamauchi T, Ito Y, Kadowaki T et al. Osmotin is a homolog of mammalian adiponectin and controls apoptosis in yeast through a homolog of mammalian adiponectin receptor. Mol Cell 2005; 17: 171–180.
Madeo F, Frohlich E, Ligr M, Grey M, Sigrist SJ, Wolf DH et al. Oxygen stress: a regulator of apoptosis in yeast. J Cell Biol 1999; 145: 757–767.
Madeo F, Herker E, Maldener C, Wissing S, Lachelt S, Herlan M et al. A caspase-related protease regulates apoptosis in yeast. Mol Cell 2002; 9: 911–917.
Singh K, Kang PJ, Park HO . The Rho5 GTPase is necessary for oxidant-induced cell death in budding yeast. Proc Natl Acad Sci USA 2008; 105: 1522–1527.
Ludovico P, Sousa MJ, Silva MT, Leao C, Corte-Real M . Saccharomyces cerevisiae commits to a programmed cell death process in response to acetic acid. Microbiology 2001; 147 (Pt 9): 2409–2415.
Fannjiang Y, Cheng WC, Lee SJ, Qi B, Pevsner J, McCaffery JM et al. Mitochondrial fission proteins regulate programmed cell death in yeast. Genes Dev 2004; 18: 2785–2797.
Ludovico P, Rodrigues F, Almeida A, Silva MT, Barrientos A, Corte-Real M . Cytochrome c release and mitochondria involvement in programmed cell death induced by acetic acid in Saccharomyces cerevisiae. Mol Biol Cell 2002; 13: 2598–2606.
Pereira C, Camougrand N, Manon S, Sousa MJ, Corte-Real M . ADP/ATP carrier is required for mitochondrial outer membrane permeabilization and cytochrome c release in yeast apoptosis. Mol Microbiol 2007; 66: 571–582.
Valenti D, Vacca RA, Guaragnella N, Passarella S, Marra E, Giannattasio S . A transient proteasome activation is needed for acetic acid-induced programmed cell death to occur in Saccharomyces cerevisiae. FEMS Yeast Res 2008; 8: 400–404.
Burtner CR, Murakami CJ, Kennedy BK, Kaeberlein M . A molecular mechanism of chronological aging in yeast. Cell Cycle 2009; 8: 1256–1270.
Almeida B, Ohlmeier S, Almeida AJ, Madeo F, Leao C, Rodrigues F et al. Yeast protein expression profile during acetic acid-induced apoptosis indicates causal involvement of the TOR pathway. Proteomics 2009; 9: 720–732.
Almeida T, Marques M, Mojzita D, Amorim MA, Silva RD, Almeida B et al. Isc1p plays a key role in hydrogen peroxide resistance and chronological lifespan through modulation of iron levels and apoptosis. Mol Biol Cell 2008; 19: 865–876.
Aerts AM, Zabrocki P, Francois IE, Carmona-Gutierrez D, Govaert G, Mao C et al. Ydc1p ceramidase triggers organelle fragmentation, apoptosis and accelerated ageing in yeast. Cell Mol Life Sci 2008; 65: 1933–1942.
Low CP, Shui G, Liew LP, Buttner S, Madeo F, Dawes IW et al. Caspase-dependent and -independent lipotoxic cell-death pathways in fission yeast. J Cell Sci 2008; 121 (Pt 16): 2671–2684.
Garbarino J, Padamsee M, Wilcox L, Oelkers PM, D’Ambrosio D, Ruggles KV et al. Sterol and diacylglycerol acyltransferase deficiency triggers fatty acid-mediated cell death. J Biol Chem 2009; 284: 30994–31005.
Madeo F, Carmona-Gutierrez D, Ring J, Buttner S, Eisenberg T, Kroemer G . Caspase-dependent and caspase-independent cell death pathways in yeast. Biochem Biophys Res Commun 2009; 382: 227–231.
Pozniakovsky AI, Knorre DA, Markova OV, Hyman AA, Skulachev VP, Severin FF . Role of mitochondria in the pheromone- and amiodarone-induced programmed death of yeast. J Cell Biol 2005; 168: 257–269.
Madeo F, Durchschlag M, Kepp O, Panaretakis T, Zitvogel L, Frohlich KU et al. Phylogenetic conservation of the preapoptotic calreticulin exposure pathway from yeast to mammals. Cell Cycle 2009; 8: 639–642.
Gourlay CW, Du W, Ayscough KR . Apoptosis in yeast – mechanisms and benefits to a unicellular organism. Mol Microbiol 2006; 62: 1515–1521.
Almeida B, Silva A, Mesquita A, Sampaio-Marques B, Rodrigues F, Ludovico P . Drug-induced apoptosis in yeast. Biochim Biophys Acta 2008; 1783: 1436–1448.
Sun Q, Bi L, Su X, Tsurugi K, Mitsui K . Valproate induces apoptosis by inducing accumulation of neutral lipids which was prevented by disruption of the SIR2 gene in Saccharomyces cerevisiae. FEBS Lett 2007; 581: 3991–3995.
Zhang YQ, Rao R . Global disruption of cell cycle progression and nutrient response by the antifungal agent amiodarone. J Biol Chem 2007; 282: 37844–37853.
Zhang NN, Dudgeon DD, Paliwal S, Levchenko A, Grote E, Cunningham KW . Multiple signaling pathways regulate yeast cell death during the response to mating pheromones. Mol Biol Cell 2006; 17: 3409–3422.
Eisenberg T, Buttner S, Kroemer G, Madeo F . The mitochondrial pathway in yeast apoptosis. Apoptosis 2007; 12: 1011–1023.
Longo VD, Ellerby LM, Bredesen DE, Valentine JS, Gralla EB . Human Bcl-2 reverses survival defects in yeast lacking superoxide dismutase and delays death of wild-type yeast. J Cell Biol 1997; 137: 1581–1588.
Outeiro TF, Lindquist S . Yeast cells provide insight into alpha-synuclein biology and pathobiology. Science 2003; 302: 1772–1775.
Buttner S, Bitto A, Ring J, Augsten M, Zabrocki P, Eisenberg T et al. Functional mitochondria are required for alpha-synuclein toxicity in aging yeast. J Biol Chem 2008; 283: 7554–7560.
Braun RJ, Buttner S, Ring J, Kroemer G, Madeo F . Nervous yeast: modeling neurotoxic cell death. Trends Biochem Sci 2009; doi:10.1016/j.tibs.2009.10.005.
Winderickx J, Delay C, De Vos A, Klinger H, Pellens K, Vanhelmont T et al. Protein folding diseases and neurodegeneration: lessons learned from yeast. Biochim Biophys Acta 2008; 1783: 1381–1395.
Hauptmann P, Riel C, Kunz-Schughart LA, Frohlich KU, Madeo F, Lehle L . Defects in N-glycosylation induce apoptosis in yeast. Mol Microbiol 2006; 59: 765–778.
Mazzoni C, Herker E, Palermo V, Jungwirth H, Eisenberg T, Madeo F et al. Yeast caspase 1 links messenger RNA stability to apoptosis in yeast. EMBO Rep 2005; 6: 1076–1081.
Yang H, Ren Q, Zhang Z . Cleavage of Mcd1 by caspase-like protease Esp1 promotes apoptosis in budding yeast. Mol Biol Cell 2008; 19: 2127–2134.
Weinberger M, Ramachandran L, Feng L, Sharma K, Sun X, Marchetti M et al. Apoptosis in budding yeast caused by defects in initiation of DNA replication. J Cell Sci 2005; 118 (Pt 15): 3543–3553.
Begley U, Dyavaiah M, Patil A, Rooney JP, DiRenzo D, Young CM et al. Trm9-catalyzed tRNA modifications link translation to the DNA damage response. Mol Cell 2007; 28: 860–870.
Iraqui I, Kienda G, Soeur J, Faye G, Baldacci G, Kolodner RD et al. Peroxiredoxin Tsa1 is the key peroxidase suppressing genome instability and protecting against cell death in Saccharomyces cerevisiae. PLoS Genet 2009; 5: e1000524.
Fabrizio P, Liou LL, Moy VN, Diaspro A, Valentine JS, Gralla EB et al. SOD2 functions downstream of Sch9 to extend longevity in yeast. Genetics 2003; 163: 35–46.
Rockenfeller P, Madeo F . Apoptotic death of ageing yeast. Exp Gerontol 2008; 43: 876–881.
Longo VD . Ras: the other pro-aging pathway. Sci Aging Knowledge Environ 2004; 2004: pe36.
Levine B, Kroemer G . Autophagy in the pathogenesis of disease. Cell 2008; 132: 27–42.
Yorimitsu T, Zaman S, Broach JR, Klionsky DJ . Protein kinase A and Sch9 cooperatively regulate induction of autophagy in Saccharomyces cerevisiae. Mol Biol Cell 2007; 18: 4180–4189.
Leadsham JE, Miller K, Ayscough KR, Colombo S, Martegani E, Sudbery P et al. Whi2p links nutritional sensing to actin-dependent Ras–cAMP–PKA regulation and apoptosis in yeast. J Cell Sci 2009; 122 (Pt 5): 706–715.
Kourtis N, Tavernarakis N . Autophagy and cell death in model organisms. Cell Death Differ 2009; 16: 21–30.
Camougrand N, Kissova I, Velours G, Manon S . Uth1p: a yeast mitochondrial protein at the crossroads of stress, degradation and cell death. FEMS Yeast Res 2004; 5: 133–140.
Almeida B, Buttner S, Ohlmeier S, Silva A, Mesquita A, Sampaio-Marques B et al. NO-mediated apoptosis in yeast. J Cell Sci 2007; 120 (Pt 18): 3279–3288.
Magherini F, Tani C, Gamberi T, Caselli A, Bianchi L, Bini L et al. Protein expression profiles in Saccharomyces cerevisiae during apoptosis induced by H2O2 . Proteomics 2007; 7: 1434–1445.
Tarze A, Deniaud A, Le Bras M, Maillier E, Molle D, Larochette N et al. GAPDH, a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization. Oncogene 2007; 26: 2606–2620.
Braun RJ, Zischka H . Mechanisms of Cdc48/VCP-mediated cell death: from yeast apoptosis to human disease. Biochim Biophys Acta 2008; 1783: 1418–1435.
Haynes CM, Titus EA, Cooper AA . Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death. Mol Cell 2004; 15: 767–776.
Khan MA, Chock PB, Stadtman ER . Knockout of caspase-like gene, YCA1, abrogates apoptosis and elevates oxidized proteins in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 2005; 102: 17326–17331.
Sundstrom JF, Vaculova A, Smertenko AP, Savenkov EI, Golovko A, Minina E et al. Tudor staphylococcal nuclease is an evolutionarily conserved component of the programmed cell death degradome. Nat Cell Biol 2009; 11: 1347–1354.
Lee RE, Puente LG, Kaern M, Megeney LA . A non-death role of the yeast metacaspase: Yca1p alters cell cycle dynamics. PLoS One 2008; 3: e2956.
Fahrenkrog B, Sauder U, Aebi U . The S. cerevisiae HtrA-like protein Nma111p is a nuclear serine protease that mediates yeast apoptosis. J Cell Sci 2004; 117 (Pt 1): 115–126.
Walter D, Wissing S, Madeo F, Fahrenkrog B . The inhibitor-of-apoptosis protein Bir1p protects against apoptosis in S. cerevisiae and is a substrate for the yeast homologue of Omi/HtrA2. J Cell Sci 2006; 119 (Pt 9): 1843–1851.
Qiu J, Yoon JH, Shen B . Search for apoptotic nucleases in yeast: role of Tat-D nuclease in apoptotic DNA degradation. J Biol Chem 2005; 280: 15370–15379.
Ahn SH, Diaz RL, Grunstein M, Allis CD . Histone H2B deacetylation at lysine 11 is required for yeast apoptosis induced by phosphorylation of H2B at serine 10. Mol Cell 2006; 24: 211–220.
Carmona-Gutierrez D, Madeo F . Yeast unravels epigenetic apoptosis control: deadly chat within a histone tail. Mol Cell 2006; 24: 167–169.
Modjtahedi N, Giordanetto F, Madeo F, Kroemer G . Apoptosis-inducing factor: vital and lethal. Trends Cell Biol 2006; 16: 264–272.
Li W, Sun L, Liang Q, Wang J, Mo W, Zhou B . Yeast AMID homologue Ndi1p displays respiration-restricted apoptotic activity and is involved in chronological aging. Mol Biol Cell 2006; 17: 1802–1811.
Buttner S, Carmona-Gutierrez D, Vitale I, Castedo M, Ruli D, Eisenberg T et al. Depletion of endonuclease G selectively kills polyploid cells. Cell Cycle 2007; 6: 1072–1076.
Scheckhuber CQ, Erjavec N, Tinazli A, Hamann A, Nystrom T, Osiewacz HD . Reducing mitochondrial fission results in increased life span and fitness of two fungal ageing models. Nat Cell Biol 2007; 9: 99–105.
Cheng WC, Teng X, Park HK, Tucker CM, Dunham MJ, Hardwick JM . Fis1 deficiency selects for compensatory mutations responsible for cell death and growth control defects. Cell Death Differ 2008; 15: 1838–1846.
Rinnerthaler M, Jarolim S, Heeren G, Palle E, Perju S, Klinger H et al. MMI1 (YKL056c, TMA19), the yeast orthologue of the translationally controlled tumor protein (TCTP) has apoptotic functions and interacts with both microtubules and mitochondria. Biochim Biophys Acta 2006; 1757: 631–638.
Boya P, Kroemer G . Lysosomal membrane permeabilization in cell death. Oncogene 2008; 27: 6434–6451.
Thompson DM, Parker R . The RNase Rny1p cleaves tRNAs and promotes cell death during oxidative stress in Saccharomyces cerevisiae. J Cell Biol 2009; 185: 43–50.
Mason DA, Shulga N, Undavai S, Ferrando-May E, Rexach MF, Goldfarb DS . Increased nuclear envelope permeability and Pep4p-dependent degradation of nucleoporins during hydrogen peroxide-induced cell death. FEMS Yeast Res 2005; 5: 1237–1251.
Jungwirth H, Ring J, Mayer T, Schauer A, Buttner S, Eisenberg T et al. Loss of peroxisome function triggers necrosis. FEBS Lett 2008; 582: 2882–2886.
Reggiori F, Monastyrska I, Shintani T, Klionsky DJ . The actin cytoskeleton is required for selective types of autophagy, but not nonspecific autophagy, in the yeast Saccharomyces cerevisiae. Mol Biol Cell 2005; 16: 5843–5856.
Gourlay CW, Carpp LN, Timpson P, Winder SJ, Ayscough KR . A role for the actin cytoskeleton in cell death and aging in yeast. J Cell Biol 2004; 164: 803–809.
Ruckenstuhl C, Buttner S, Carmona-Gutierrez D, Eisenberg T, Kroemer G, Sigrist SJ et al. The Warburg effect suppresses oxidative stress induced apoptosis in a yeast model for cancer. PLoS One 2009; 4: e4592.
Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ 2009; 16: 3–11.
Acknowledgements
We are grateful to the Austrian Science Fund FWF (Austria) for grant S-9304-B05 to FM, SB, and DC-G; grant ‘SFB Lipotox’ to FM and DC-G; grant T-414-B09 to SB (Hertha-Firnberg fellowship); and to the European Commission for project APOSYS to FM and TE. CM is supported by the Excellence Initiative of the German Federal & State Governments (EXC 294) and the Trinational Research Training Group (GRK 1478); GK is supported by the Ligue Nationale contre le Cancer (Equipe labellisée), Agence Nationale pour la Recherche (ANR), European Commission (Apo-Sys, ChemoRes, ApopTrain), Fondation pour la Recherche Médicale (FRM), Institut National du Cancer (INCa), and Cancéropôle Ile-de-France.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Edited by G Melino
Rights and permissions
About this article
Cite this article
Carmona-Gutierrez, D., Eisenberg, T., Büttner, S. et al. Apoptosis in yeast: triggers, pathways, subroutines. Cell Death Differ 17, 763–773 (2010). https://doi.org/10.1038/cdd.2009.219
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/cdd.2009.219
This article is cited by
-
Trachyspermum ammi seed extract-mediated Ag nanoparticles: an insight into its in vitro biopotency
Biomass Conversion and Biorefinery (2023)
-
Roles of the pro-apoptotic factors CaNma111 and CaYbh3 in apoptosis and virulence of Candida albicans
Scientific Reports (2022)
-
Selection in a growing colony biases results of mutation accumulation experiments
Scientific Reports (2022)
-
Mechanisms of gene regulation by histone degradation in adaptation of yeast: an overview of recent advances
Archives of Microbiology (2022)
-
Adaptation Strategy to Increase the Tolerance of Scheffersomyces stipitis NRRL Y-7124 to Inhibitors of Sugarcane Bagasse Hemicellulosic Hydrolysate Through Comparative Studies of Proteomics and Fermentation
BioEnergy Research (2022)
