Systems biology of yeast cell death

Munoz, Ana Joyce; Wanichthanarak, Kwanjeera; Meza, Eugenio; Petranović, Dina

doi:10.1111/j.1567-1364.2011.00781.x

Cited by 52 publications

(44 citation statements)

References 159 publications

(281 reference statements)

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“…ROS production has been implicated in the induction and regulation of the apoptotic pathway in yeast (8,18). DHR-123 is oxidized by intracellular ROS to the fluorescent chromophore rhodamine 123.…”

Section: Caspofungin Effects On Other Markers Of Apoptosis (I) Ros Pmentioning

confidence: 99%

“…Indeed, apoptosis can be induced in C. albicans by oxidative stress (6), intracellular acidification, and the antifungal agent amphotericin B (7). Notably, C. albicans cells exhibit apoptotic markers that are similar to those of mammalian cells, including phosphatidylserine externalization, reactive oxygen species (ROS) accumulation, mitochondrial membrane potential dissipation, and DNA condensation and fragmentation (8). In this study, we evaluated the mechanisms of C. albicans cell death caused by caspofungin.…”

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confidence: 99%

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Caspofungin Kills Candida albicans by Causing both Cellular Apoptosis and Necrosis

Hao

Cheng

Clancy

et al. 2013

Antimicrob Agents Chemother

152

132

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Caspofungin exerts candidacidal activity by inhibiting cell wall (1,3)-␤-D-glucan synthesis. We investigated the physiologic mechanisms of caspofungin-induced Candida albicans cell death. Apoptosis (programmed cell death) and necrosis were studied after C. albicans SC5314 cells were exposed to caspofungin at 0.06, 0.125, and 0.5 g/ml (0.5؋, 1؋, and 4؋ the MIC, respectively) for 3 h. Caspofungin at 0.125 and 0.5 g/ml reduced cellular viability by >50%, as measured by colony counts and methylene blue exclusion. Apoptosis and necrosis were demonstrated by annexin V and propidium iodide staining for phosphatidylserine externalization and loss of membrane integrity, respectively. At all concentrations of caspofungin, 20 to 25% and 5 to 7% of C. albicans cells exhibited early apoptosis and late apoptosis/necrosis, respectively (P value was not significant [NS]). Necrosis, on the other hand, was significantly greater at 0.125 (43%) and 0.5 (48%) g/ml than at 0.06 g/ml (26%) (P values of 0.003 and 0.003, respectively). The induction of apoptosis at concentrations less than or equal to the MIC was corroborated by dihydrorhodamine 123 (DHR-123) and dihydroethidium (DHE) staining (reactive oxygen species production), JC-1 staining (mitochondrial membrane potential dissipation), and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and 4=,6-diamidino-2-phenylindole dihydrochloride (DAPI) staining (DNA damage and nuclear fragmentation). Moreover, electron microscopy of cells exposed to 0.125 g/ml of caspofungin showed hallmark apoptotic features like chromatin margination and condensation and nuclear blebs. Apoptosis was associated with metacaspase 1 activation, as demonstrated by D2R staining. Caspofungin exerts activity against C. albicans by directly killing cells (resulting in necrosis) and causing others to undergo programmed cell death (apoptosis). Apoptosis is initiated at subinhibitory concentrations, suggesting that strategies to target this process may augment the benefits of antifungal agents.C aspofungin and other agents in the echinocandin class of antifungals have assumed an increasingly important role in the therapy of invasive candidiasis (1). These agents are nontoxic and exert potent fungicidal activity against Candida albicans and other Candida spp. Their antifungal activity is achieved through inhibition of (1,3)-␤-D-glucan synthase (2), an enzyme that synthesizes a major constituent of the fungal cell wall. Although the mechanism of activity for the echinocandins is known, the physiological mechanisms by which they cause cell death are not defined. At least two types of mammalian cell death, necrosis and apoptosis, have been described (3). Necrosis is death resulting from direct cellular injury, which is best defined by cell and organelle swelling and lysis (4). Apoptosis, on the other hand, is programmed cell death, the principal morphological feature of which is shrinkage of the cell and its nucleus (3, 4).Over the last decade, there have been a number of reports on apoptosis in yeas...

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Section: Caspofungin Effects On Other Markers Of Apoptosis (I) Ros Pmentioning

confidence: 99%

mentioning

confidence: 99%

Caspofungin Kills Candida albicans by Causing both Cellular Apoptosis and Necrosis

Hao

Cheng

Clancy

et al. 2013

Antimicrob Agents Chemother

152

132

View full text Add to dashboard Cite

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“…This demands mechanisms of quality control and coordinated regulation, in order to avoid (or reduce) cellular stress that can result in reduced cell growth and protein secretion (1,2) or even apoptosis and cell death (3,4). Misfolded proteins are detected and removed via the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway (5), the ubiquitin-proteasome system (UPS) (5), the autophagy pathway (6), or the unfolded protein response (UPR) pathway (7).…”

mentioning

confidence: 99%

Anaerobic α-Amylase Production and Secretion with Fumarate as the Final Electron Acceptor in Saccharomyces cerevisiae

Liu

Österlund

Hou

et al. 2013

Appl Environ Microbiol

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bIn this study, we focus on production of heterologous ␣-amylase in the yeast Saccharomyces cerevisiae under anaerobic conditions. We compare the metabolic fluxes and transcriptional regulation under aerobic and anaerobic conditions, with the objective of identifying the final electron acceptor for protein folding under anaerobic conditions. We find that yeast produces more amylase under anaerobic conditions than under aerobic conditions, and we propose a model for electron transfer under anaerobic conditions. According to our model, during protein folding the electrons from the endoplasmic reticulum are transferred to fumarate as the final electron acceptor. This model is supported by findings that the addition of fumarate under anaerobic (but not aerobic) conditions improves cell growth, specifically in the ␣-amylase-producing strain, in which it is not used as a carbon source. Our results provide a model for the molecular mechanism of anaerobic protein secretion using fumarate as the final electron acceptor, which may allow for further engineering of yeast for improved protein secretion under anaerobic growth conditions.

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“…Despite nearly a billion years of evolutionary divergence, recent estimates showed that a fifth of yeast genes have human disease orthologs lending support to functional discovery investigations using this model [92]. Moreover, thanks to amenability of S. cerevisiae to both classical and advanced molecular genetic techniques, to relatively simple, cheap and quick genetic and environmental manipulations, to the large knowledge base and data collections, high-throughput screening technologies and functional genomics that are not possible in humans [93][94][95], this organism has become a valuable and prevalent eukaryotic model organism to unravel complex and fundamental intracellular mechanisms underlying neurodegeneration [96][97][98][99][100][101][102][103][104].…”

Section: Yeast Models For Admentioning

confidence: 99%