Ceramide and activated Bax act synergistically to permeabilize the mitochondrial outer membrane

Ganesan, Vidyaramanan; Perera, Meenu N.; Colombini, David; Datskovskiy, Debra; Chadha, Kirti; Colombini, Marco

doi:10.1007/s10495-009-0449-0

Cited by 144 publications

(140 citation statements)

References 42 publications

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“…One possibility compatible with our data is that the poreforming activity of ceramides synergizes with that of Bax to induce MOMP and initiate end-stage apoptosis. Indeed, experiments performed on mitochondria that had been isolated from rat liver or yeast indicated that, at concentrations at which externally added ceramides and Bax have little effect on their own, the combination induces substantial MOMP (Ganesan et al, 2010). Other studies have revealed that ceramides accumulating in the mitochondrial membrane of mammalian cells upon irradiation might form platforms into which Bax inserts, oligomerizes and functions as a pore (Lee et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Other studies have revealed that ceramides can form pores in planar membranes as well as in the outer membrane of isolated mitochondria that are large enough to allow passage of cytochrome c (Siskind et al, 2002(Siskind et al, , 2006. Interestingly, members of the anti-apoptotic Bcl-2 protein family prevent ceramide-induced permeabilization of isolated mitochondria, whereas a combination of pro-apoptotic Bax and ceramides enhances permeabilization (Ganesan et al, 2010;Siskind et al, 2008). This indicates that ceramides can act directly on mitochondria to promote MOMP and trigger apoptotic cell death.…”

Section: Introductionmentioning

confidence: 98%

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Diverting CERT-mediated ceramide transport to mitochondria triggers Bax-dependent apoptosis

Jain

Beutel

Ebell

et al. 2017

Journal of Cell Science

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A deregulation of ceramide biosynthesis in the endoplasmic reticulum (ER) is frequently linked to induction of mitochondrial apoptosis. Although in vitro studies suggest that ceramides might initiate cell death by acting directly on mitochondria, their actual contribution to the apoptotic response in living cells is unclear. Here, we have analyzed the consequences of targeting the biosynthetic flow of ceramides to mitochondria using a ceramide transfer protein (encoded by COL4A3BP) equipped with an OMM anchor, mitoCERT. Cells expressing mitoCERT import ceramides into mitochondria and undergo Bax-dependent apoptosis. Apoptosis induction by mitoCERT was abolished through (i) removal of its ceramide transfer domain, (ii) disruption of its interaction with VAMPassociated proteins (VAPs) in the ER, (iii) addition of antagonistic CERT inhibitor HPA12, (iv) blocking de novo ceramide synthesis and (v) targeting of a bacterial ceramidase to mitochondria. Our data provide the first demonstration that translocation of ER ceramides to mitochondria specifically commits cells to death and establish mitoCERT as a valuable new tool to unravel the molecular principles underlying ceramide-mediated apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Diverting CERT-mediated ceramide transport to mitochondria triggers Bax-dependent apoptosis

Jain

Beutel

Ebell

et al. 2017

Journal of Cell Science

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“…Apoptosis-associated MOMP is known to require pro-apoptotic Bax-like proteins (in regulation of the formation of pores in the mitochondria) and anti-apoptotic Bcl-2-like proteins (functionally distinct from their role in mitochondrial morphogenesis) (30). Therefore, the ratio of Bax/Bcl-2 is a critical for determining the release of many apoptogenic proteins from the mitochondrial intermembrane space to drive the caspase cascade (31). Caspases are the key proteins that modulate the apoptotic response.…”

Section: Discussionmentioning

confidence: 99%

Millimeter wave radiation induces apoptosis via affecting the ratio of Bax/Bcl-2 in SW1353 human chondrosarcoma cells

Ye²,

Cai³

et al. 2011

Oncol Rep

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Abstract. The efficacy and safety of millimeter wave radiation has been proven for various types of malignant tumors. However, the mechanisms underlying effects of millimeter wave radiation on apoptosis are still unclear. The present study was undertaken to examine the effects of millimeter wave radiation on cell apoptosis and mitochondrial membrane potential, and to determine the molecular mechanism of millimeter wave radiation-induced apoptosis by investigating the expression of Bcl-2 family proteins (Bcl-2, Bax), caspase-9 and caspase-3 in SW1353 cells. We found that millimeter wave radiation suppressed the viability of SW1353 cells, demonstrating that millimeter wave radiation induced cell apoptosis and reduced cell viability in a time-dependent manner. Furthermore, we observed that treatment of cells with millimeter wave radiation significantly induced loss of mitochondrial membrane potential, upregulated proapoptotic Bax, caspase-9 and caspase-3, but did not significantly change levels of antiapoptotic Bcl-2. These data suggested that millimeter wave radiation may induce apoptosis via affecting the ratio of Bax/Bcl-2 in SW1353 cells.

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“…Increased mitochondrial ceramide enhances Bax translocation to the mitochondria in both a cell free system as well as MCF7 cells stimulated with TNF-␣ ( 58 ). Furthermore, ceramide and activated Bax directly interact in vitro to synergistically induce outer membrane permeabilization in isolated mitochondria ( 61 ). Moreover, Bax association with ceramideenriched detergent-resistant membrane domains occurs in situ upon ischemia/reperfusion, a well-characterized apoptotic model ( 62 ).…”

Section: Ceramidementioning

confidence: 99%

Sphingolipids: regulators of crosstalk between apoptosis and autophagy

Young

Kester

Wang

2013

Journal of Lipid Research

297

274

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decades ago, pioneering work by Hannun et al. and Kolesnick et al. established the foundation for the bioactive nature of sphingolipids by demonstrating the inhibition of protein kinase C (PKC) by sphingosine and the stimulation of a ceramide-activated protein kinase in response to tumor necrosis factor (TNF)-␣ , respectively ( 1, 2 ). Sphingolipids have since been recognized as critical activators or inhibitors of various protein kinases and phosphatases, receptors, and ion transporters ( 3 ). Moreover, sphingolipids have been identifi ed as key regulators of a vast number of cellular processes, including cell growth, adhesion, migration, senescence, apoptosis, and most recently, autophagy ( 3, 4 ).Much of the investigation into sphingolipid signaling has focused on the disparate nature of ceramide and sphingosine-1-phosphate (S1P). Ceramide is typically associated with growth arrest and apoptosis, while S1P promotes cell proliferation and survival. The opposing nature and dynamic balance of intracellular ceramide and S1P, termed the "sphingolipid rheostat," has been proposed to determine cell fate ( 5 ). However, emerging evidence and extensive characterization of the sphingolipid metabolic network suggests that this two-dimensional model does not adequately refl ect sphingolipid signaling and function within the cell. In addition to ceramide and S1P, other sphingolipid metabolites, such as sphingosine, dihydroceramide, and gangliosides, have been implicated in the regulation of apoptosis and macroautophagy (hereafter referred to as autophagy). Although autophagy is typically considered to be a cytoprotective mechanism for the suppression of apoptosis, recent evidence indicates that autophagy can also promote cell death ( 6 ). Due to the differential regulation of apoptosis and autophagy by sphingolipid metabolites, the sphingolipid network has emerged as a novel molecular switch between the apoptotic and autophagic Abstract Apoptosis and autophagy are two evolutionarily conserved processes that maintain homeostasis during stress. Although the two pathways utilize fundamentally distinct machinery, apoptosis and autophagy are highly interconnected and share many key regulators. The crosstalk between apoptosis and autophagy is complex, as autophagy can function to promote cell survival or cell death under various cellular conditions. The molecular mechanisms of crosstalk are beginning to be elucidated and have critical implications for the treatment of various diseases, such as cancer. Sphingolipids are a class of bioactive lipids that mediate many key cellular processes, including apoptosis and autophagy. By targeting several of the shared regulators, sphingolipid metabolites differentially regulate the induction of apoptosis and autophagy. Importantly, individual sphingolipid species appear to "switch" autophagy toward cell survival (e.g., sphingosine-1-phosphate) or cell death (e.g., ceramide, gangliosides). This review assesses the current understanding of sphingolipid-induced apoptosis and autophagy to addr...

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Ceramide and activated Bax act synergistically to permeabilize the mitochondrial outer membrane

Cited by 144 publications

References 42 publications

Diverting CERT-mediated ceramide transport to mitochondria triggers Bax-dependent apoptosis

Diverting CERT-mediated ceramide transport to mitochondria triggers Bax-dependent apoptosis

Millimeter wave radiation induces apoptosis via affecting the ratio of Bax/Bcl-2 in SW1353 human chondrosarcoma cells

Sphingolipids: regulators of crosstalk between apoptosis and autophagy

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