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Abstract
The yeast Saccharomyces cerevisiae undergoes a mitochondrial-dependent programmed cell death in response to different stimuli, such as acetic acid, with features similar to those of mammalian apoptosis. However, the upstream signaling events in this process, including those leading to mitochondrial membrane permeabilization, are still poorly characterized. Changes in sphingolipid metabolism have been linked to modulation of apoptosis in both yeast and mammalian cells, and ceramides have been detected in mitochondria upon apoptotic stimuli. In this study, we aimed to characterize the contribution of enzymes involved in ceramide metabolism to apoptotic cell death induced by acetic acid. We show that isc1Δ and lag1Δ mutants, lacking inositol phosphosphingolipid phospholipase C and ceramide synthase, respectively, exhibited a higher resistance to acetic acid that was associated with lower levels of some phytoceramide species. Consistently, these mutant cells displayed lower levels of ROS production and reduced mitochondrial alterations, such as mitochondrial fragmentation and degradation, and decreased translocation of cytochrome c into the cytosol in response to acetic acid. These results suggest that ceramide production contributes to cell death induced by acetic acid, especially through hydrolysis of complex sphingolipids catalyzed by Isc1p and de novo synthesis catalyzed by Lag1p, and provide the first in vivo indication of its involvement in mitochondrial outer membrane permeabilization in yeast.
Highlights
Apoptosis is an evolutionary conserved type of programmed cell death (PCD) that is crucial for normal tissue homeostasis and development
We found that the ADP/ATP carrier is involved in mitochondrial outer membrane permeabilization (MOMP) and cytochrome c release [7], and that Pep4p, an orthologue of the mammalian cathepsin D (CatD), is released from the vacuole into the cytosol during acetic acidinduced apoptosis to act in mitochondrial degradation [6]
We found that absence of two enzymes involved in ceramide production (Isc1p and Lag1p) led to increased resistance to acetic acid-induced PCD that was associated with lower levels of some phytoceramide species and reduced mitochondrial dysfunction, namely reactive oxygen species (ROS) production, mitochondrial fragmentation and degradation, and cytochrome c release into the cytosol
Summary
Apoptosis is an evolutionary conserved type of programmed cell death (PCD) that is crucial for normal tissue homeostasis and development. We have previously shown that acetic acid triggers a mitochondria-mediated apoptotic pathway in Saccharomyces cerevisiae associated with chromatin condensation, exposure of phosphatidylserine to the outer leaflet of the plasma membrane, formation of DNA strand breaks, accumulation of mitochondrial reactive oxygen species (ROS) and mitochondrial outer membrane permeabilization (MOMP) and subsequent release of cytochrome c [2,3] and yeast apoptosis-inducing factor [4]. Acetic acid-induced apoptosis has been linked with mitochondrial fragmentation and degradation [5,6]. We found that the ADP/ATP carrier is involved in MOMP and cytochrome c release [7], and that Pep4p, an orthologue of the mammalian cathepsin D (CatD), is released from the vacuole into the cytosol during acetic acidinduced apoptosis to act in mitochondrial degradation [6]
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