Ceramide induced mitophagy and tumor suppression

Abstract

Sphingolipids are bioactive lipid effectors, which are involved in the regulation of various cellular signaling pathways. Sphingolipids play essential roles in controlling cell inflammation, proliferation, death, migration, senescence, metastasis and autophagy. Alterations in sphingolipid metabolism has been also implicated in many human cancers. Macroautophagy (referred to here as autophagy) is a form of nonselective sequestering of cytosolic materials by double membrane structures, autophagosomes, which can be either protective or lethal for cells. Ceramide, a central molecule of sphingolipid metabolism is involved in the regulation of autophagy at various levels, including the induction of lethal mitophagy, a selective autophagy process to target and eliminate damaged mitochondria. In this review, we focused on recent studies with regard to the regulation of autophagy, in particular lethal mitophagy, by ceramide, and aimed at providing discussion points for various context-dependent roles and mechanisms of action of ceramide in controlling mitophagy.

Novel function of ceramide for regulation of mitochondrial ATP release in astrocytes

“…It should be by guest, on May 11, 2018 www.jlr.org There is some discrepancy in which VDAC isoform is more critical for regulation of intracellular ATP, which is likely to be cell-type specific (51,52). Most recently, excess elevation of ceramide has been shown to induce mitophagy, suggesting that the physiological function of ceramide as discussed in our study requires limitation of its concentration at mitochondria (88,89). While ATP levels observed in our study are consistent with CATregulated ATP release under normal physiological conditions, several studies have shown that under pathophysiological conditions, reduction of ATP levels are concurrent with decreased mitochondrial motility and increased fragmentation (44,(90)(91)(92).…”

Ceramide Signaling and p53 Pathways

“…While the mechanisms of ceramide function in biological membranes and the biological consequences of ceramide alterations for cellular processes are still poorly understood, overwhelming data point to the role of these sphingolipids as important cellular regulators. Over the last 3 decades ceramides were established as second messengers regulating key cellular processes including cytoskeleton dynamics, endocytosis, protein transport and subcellular localization, cell cycle, autophagy, and apoptosis (Castro et al, 2014; Coant, Sakamoto, Mao, & Hannun, 2017; Dany & Ogretmen, 2015; Mullen, Hannun, & Obeid, 2012). Therefore, ceramides are indispensable for cellular homeostasis and control of fundamental functions, such as proliferation, migration, differentiation, adaptation to stress, survival, and senescence (Hannun & Obeid, 2008, 2017).…”

Crosstalk between autophagy and intracellular radiation response (Review)

“…Further evidence indicated that ceramide increases BECN1 expression by activating JNK kinase, which in turn activates c-Jun, a known transcription factor for BECN1 expression (110). Ceramide accumulation also can induce ER stress, mTOR inhibition via TRB3 (tribbles homologue 3), which triggered lethal autophagy (111)(112)(113). Moreover, ceramide can be generated by neutral sphingomyelinase in mitochondria, which is a late event upon the cell irradiation following the early phase of ceramide accumulation at the cell plasma membrane (106).…”