Autophagy paradox and ceramide

• Sphingolipids, including ceramide and sphigosine 1-phosphate are key bioactive molecules that regulate autophagy.
• This review article focuses on the roles of ceramide on the regulation of autophagy.
• Ceramide and dihydro-ceramide induce macroautophagy in various cell types under different stress conditions.
• Ceramide-mediated autophagy can be protective or lethal in cancer cells, which is context dependent.
• Ceramide-induced autophagy includes lethal mitophagy that results in tumor suppression.

Sphingolipid molecules act as bioactive lipid messengers and exert their actions on the regulation of various cellular signaling pathways. Sphingolipids play essential roles in numerous cellular functions, including controlling cell inflammation, proliferation, death, migration, senescence, tumor metastasis and/or autophagy. Dysregulated sphingolipid metabolism has been also implicated in many human cancers. Macroautophagy (referred to here as autophagy) “self-eating” is characterized by nonselective sequestering of cytosolic materials by an isolation membrane, which can be either protective or lethal for cells. Ceramide (Cer), a central molecule of sphingolipid metabolism, has been extensively implicated in the control of autophagy. The increasing evidence suggests that Cer is highly involved in mediating two opposing autophagic pathways, which regulate either cell survival or death, which is referred here as autophagy paradox. However, the underlying mechanism that regulates the autophagy paradox remains unclear. Therefore, this review focuses on recent studies with regard to the regulation of autophagy by Cer and elucidates the roles and mechanisms of action of Cer in controlling autophagy paradox. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.