Mitochondria-dependent apoptosis in yeast

Pereira, Clara; Silva, Rui D.; Saraiva, Lucı́lia; Johansson, Börje; Sousa, Maria João; Côrte‐Real, Manuela

doi:10.1016/j.bbamcr.2008.03.010

Cited by 120 publications

(111 citation statements)

References 200 publications

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“…In fact, the fragmentation of the mitochondrial network is considered to be an early step in mammalian apoptosis, although its actual function, if any, remains unclear (68,69). We indeed found the presence of apoptotic cells under the conditions of exogenous AdoHcy and homocysteine.…”

Section: Discussionsupporting

confidence: 53%

Converging Evidence of Mitochondrial Dysfunction in a Yeast Model of Homocysteine Metabolism Imbalance

Kumar¹,

John

Maity

et al. 2011

Journal of Biological Chemistry

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An elevated level of homocysteine, a thiol amino acid, is associated with various complex disorders. The cellular effects of homocysteine and its precursors S-adenosylhomocysteine (AdoHcy) and S-adenosylmethionine (AdoMet) are, however, poorly understood. We used Saccharomyces cerevisiae as a model to understand the basis of pathogenicity induced by homocysteine and its precursors. Both homocysteine and AdoHcy but not AdoMet inhibited the growth of the str4⌬ strain (which lacks the enzyme that converts homocysteine to cystathioninemimicking vascular cells). Addition of AdoMet abrogated the inhibitory effect of AdoHcy but not that of homocysteine indicating that an increase in the AdoMet/AdoHcy ratio is sufficient to overcome the AdoHcy-mediated growth defect but not that of homocysteine. Also, the transcriptomic profile of AdoHcy and homocysteine showed gross dissimilarity based on gene enrichment analysis. Furthermore, compared with homocysteine, AdoHcy treatment caused a higher level of oxidative stress in the cells. However, unlike a previously reported response in wild type (Kumar, A., John, L., Alam, M. M., Gupta, A., Sharma, G., Pillai, B., and Sengupta, S. (2006) Biochem. J. 396, 61-69), the str4⌬ strain did not exhibit an endoplasmic reticulum stress response. This suggests that homocysteine induces varied response depending on the flux of homocysteine metabolism. We also observed altered expression of mitochondrial genes, defective membrane potential, and fragmentation of the mitochondrial network together with the increased expression of fission genes indicating that the imbalance in homocysteine metabolism has a major effect on mitochondrial functions. Furthermore, treatment of cells with homocysteine or AdoHcy resulted in apoptosis as revealed by annexin V staining and TUNEL assay. Cumulatively, our results suggest that elevated levels of homocysteine lead to mitochondrial dysfunction, which could potentially initiate pro-apoptotic pathways, and this could be one of the mechanisms underlying homocysteineinduced pathogenicity.

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Section: Discussionsupporting

confidence: 53%

Converging Evidence of Mitochondrial Dysfunction in a Yeast Model of Homocysteine Metabolism Imbalance

Kumar¹,

John

Maity

et al. 2011

Journal of Biological Chemistry

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“…[44][45][46][47][48][49][50] A key protein component of the caspase-dependent apoptotic pathway operating in yeast is the metacaspase Yca1p. 51 It is involved in degrading various cytosolic proteins in about 40% of the numerous apoptotic PCD scenarios initiated in response to a variety of stimuli.…”

Section: The Commitment Of Yeast To Liponecrotic Pcd Elevates the Extmentioning

confidence: 99%

Mechanism of liponecrosis, a distinct mode of programmed cell death

Richard¹,

Beach²,

Piano³

et al. 2014

Cell Cycle

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Section: Introductionmentioning

confidence: 99%

“…The involvement of mitochondria and specific mitochondrial proteins, particularly components of the respiratory chain, in most cases of PCD has been well established. This includes, for example, the generation of reactive oxygen species (ROS) and the release of mitochondrial proteins (Eisenberg et al, 2007;Pereira et al, 2008;Skulachev, 2006).Many of the proteins and mechanisms related to PCD have been intensively studied and characterized. Much less explored has been the analysis of gene expression during the death process (Fedorova et al, 2005;Laun et al, 2005).…”

mentioning

confidence: 99%

Transcriptional analysis of the response of Neurospora crassa to phytosphingosine reveals links to mitochondrial function

et al. 2009

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Treatment of Neurospora crassa cells with phytosphingosine (PHS) induces programmed cell death (PCD) by an unknown mechanism. To determine the relationship between PHS treatment and PCD, we determined changes in global gene expression levels in N. crassa during a time-course of PHS treatment. Most genes having differential expression levels compared to untreated samples showed an increase in relative expression level upon PHS exposure. However, genes encoding mitochondrial proteins were highly enriched among~100 genes that showed a relative decrease in expression levels after PHS treatment, suggesting that repression of these genes might be related to the death-inducing effects of PHS. Since mutants in respiratory chain complex I are more resistant to both PHS and hydrogen peroxide (H 2 O 2 ) than the wild-type strain, possibly related to the production of reactive oxygen species, we also compared gene expression profiles of a complex I mutant (nuo14) and wild-type in response to H 2 O 2 . Genes with higher expression levels in the mutant, in the presence of H 2 O 2 , are also significantly enriched in genes encoding mitochondrial proteins. These data suggest that complex I mutants cope better with drug-induced decrease in expression of genes encoding mitochondrial proteins and may explain their increased resistance to both PHS and H 2 O 2 . As a way of identifying new components required for PHS-induced death, we analysed the PHS sensitivity of 24 strains carrying deletions in genes that showed a significant alteration in expression pattern when the wild-type was exposed to the sphingolipid. Two additional mutants showing increased resistance to PHS were identified and both encode predicted mitochondrial proteins, further supporting the role of the mitochondria in PHS-induced PCD. INTRODUCTIONIn response to endogenous or external stimuli, living cells can undergo a genetic programme eventually leading to death, commonly known as programmed cell death (PCD). This suicide process can take several forms (apoptosis, necrosis, autophagy), each of which displays typical characteristics at both the cellular and molecular level. These processes can be interchangeable and are sometimes difficult to distinguish. In metazoan organisms, the death programme is essential for development and its dysfunction may result in human disease, such as cancer. In addition to multicellular eukaryotic species, both prokaryotic and eukaryotic unicellular organisms also undergo PCD (Cheng et al., 2008;Green & Kroemer, 2004;Hamann et al., 2008;Madeo et al., 2004).Mitochondria are cellular organelles, still possessing their own genome, that are responsible for the production of most cellular energy in eukaryotes. This production occurs mainly in the mitochondrial inner membrane through the process of oxidative phosphorylation, which involves the components of the respiratory chain and ATP synthase (Hatefi, 1985). The involvement of mitochondria and specific mitochondrial proteins, particularly components of the respiratory chain, in most ca...

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Mitochondria-dependent apoptosis in yeast

Cited by 120 publications

References 200 publications

Converging Evidence of Mitochondrial Dysfunction in a Yeast Model of Homocysteine Metabolism Imbalance

Converging Evidence of Mitochondrial Dysfunction in a Yeast Model of Homocysteine Metabolism Imbalance

Mechanism of liponecrosis, a distinct mode of programmed cell death

Transcriptional analysis of the response of Neurospora crassa to phytosphingosine reveals links to mitochondrial function

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