Mitochondrially targeted ceramides preferentially promote autophagy, retard cell growth, and induce apoptosis

Hou, Qi; Jin, Junfei; Zhou, Huaiyu; Novgorodov, Sergei A.; Bielawska, Alicja; Szulc, Zdzisław M.; Hannun, Yusuf A.; Obeid, Lina M.; Hsu, Yi‐Te

doi:10.1194/jlr.m012161

Cited by 46 publications

(31 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…10, B and D) (26,27), which could be confirmed by elevated Lc3 II expression (Fig. 10, E and F, quantification).…”

Section: Glycosphingolipids and Intestinal Functionmentioning

confidence: 52%

“…However, to a similar extent as phospholipids, the major sphingosine-containing SM fraction decreased, probably as a consequence of loss of the brush border accompanied with loss of membrane. Increased ceramide accumulations particularly occurring in adult Ugcg-deficient mutants may have triggered the pronounced autophagy (26,27) and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Glycosphingolipids are essential for intestinal endocytic function

Jennemann¹,

Kaden²,

Sandhoff³

et al. 2012

Exp Clin Endocrinol Diabetes

View full text Add to dashboard Cite

Background:The intestine contains high concentrations of glycosphingolipids, but their function remained unclear. Results: In newborn mice lacking glycosphingolipids, intestinal epithelia were indistinguishable from control littermates. However, a few days after birth, severe defects in epithelial differentiation occurred. Conclusion: Glycosphingolipid expression in the intestinal epithelium is quintessential for maintenance of resorptive function. Significance: Glycosphingolipids are essential for enterocyte function but not for brush border formation.

show abstract

“…10, B and D) (26,27), which could be confirmed by elevated Lc3 II expression (Fig. 10, E and F, quantification).…”

Section: Glycosphingolipids and Intestinal Functionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Glycosphingolipids are essential for intestinal endocytic function

Jennemann¹,

Kaden²,

Sandhoff³

et al. 2012

Exp Clin Endocrinol Diabetes

View full text Add to dashboard Cite

show abstract

“…Indeed, a recent report has demonstrated that mitochondrial ceramide selectively targets mitochondria to LC3-II-containing autophagolysosomes through direct interaction between ceramide and LC3-II ( 93 ). In further support of this model, mitochondrially targeted C6-ceramide preferentially induces mitochondrial damage and protective autophagy in comparison to untargeted C6-ceramide ( 105 ).…”

Section: Ceramidementioning

confidence: 70%

Sphingolipids: regulators of crosstalk between apoptosis and autophagy

Young

Kester

Wang

2013

Journal of Lipid Research

304

274

View full text Add to dashboard Cite

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...

show abstract

“…This finding was recapitulated by various other studies involving different model systems. Interestingly, a recent report has shown that mitochondrially-targeted ceramide analog LCL29 is more potent for retarding cell growth in MCF7 breast cancer cell line through autophagy and apoptosis compared to uncharged ceramides suggesting that targeting ceramides to mitochondria might enhance the efficacy of the compound for therapeutic purposes [46]. In another report, upregulation of ceramide correlated with the activation of proapoptotic genes; and apoptosis is inhibited by blocking the ceramide pathway in breast cancer cells indicating the importance of ceramides in the actual apoptotic induction [47].…”

Section: Cellular Roles Of Bioactive Sphingolipidsmentioning

confidence: 99%

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Ekiz

Baran²

2011

ACAMC

View full text Add to dashboard Cite

Sphingolipids are major constituents of the cells with emerging roles in the regulation of cellular processes. Deregulation of sphingolipid metabolism is reflected as various pathophysiological conditions including metabolic disorders and several forms of cancer. Ceramides, ceramide-1-phosphate (C1P), glucosyl ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P) are among the bioactive sphingolipid species that have important roles in the regulation of cell death, survival and chemotherapeutic resistance. Some of those species are known to accumulate in the cells upon chemotherapy while some others are known to exhibit an opposite pattern. Even though the length of fatty acid chain has a deterministic effect, in general, upregulation of ceramides and sphingosine is known to induce apoptosis. However, S1P, C1P and GluCer are proliferative for cells and they are involved in the development of chemoresistance. Therefore, sphingolipid metabolism appears as a good target for the development of novel therapeutics or supportive interventions to increase the effectiveness of the chemotherapeutic drugs currently in hand. Some approaches involve manipulation of the synthesis pathways yielding the increased production of apoptotic sphingolipids while the proliferative ones are suppressed. Some others are trying to take advantage of cytotoxic sphingolipids like short chain ceramide analogs by directly delivering them to the malignant cells as a distinct chemotherapeutic intervention. Numerous studies in the literature show the feasibility of those approaches especially in acute and chronic leukemias. This review compiles the current knowledge about sphingolipids and their roles in chemotherapeutic response with the particular attention to leukemias.

show abstract

Mitochondrially targeted ceramides preferentially promote autophagy, retard cell growth, and induce apoptosis

Cited by 46 publications

References 50 publications

Glycosphingolipids are essential for intestinal endocytic function

Glycosphingolipids are essential for intestinal endocytic function

Sphingolipids: regulators of crosstalk between apoptosis and autophagy

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Contact Info

Product

Resources

About