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- Title
Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy.
- Authors
Sentelle, R David; Senkal, Can E; Jiang, Wenhui; Ponnusamy, Suriyan; Gencer, Salih; Panneer Selvam, Shanmugam; Ramshesh, Venkat K; Peterson, Yuri K; Lemasters, John J; Szulc, Zdzislaw M; Bielawski, Jacek; Ogretmen, Besim
- Abstract
Mechanisms by which autophagy promotes cell survival or death are unclear. We provide evidence that C18-pyridinium ceramide treatment or endogenous C18-ceramide generation by ceramide synthase 1 (CerS1) expression mediates autophagic cell death, independent of apoptosis in human cancer cells. C18-ceramide-induced lethal autophagy was regulated via microtubule-associated protein 1 light chain 3 ?-lipidation, forming LC3B-II, and selective targeting of mitochondria by LC3B-II-containing autophagolysosomes (mitophagy) through direct interaction between ceramide and LC3B-II upon Drp1-dependent mitochondrial fission, leading to inhibition of mitochondrial function and oxygen consumption. Accordingly, expression of mutant LC3B with impaired ceramide binding, as predicted by molecular modeling, prevented CerS1-mediated mitochondrial targeting, recovering oxygen consumption. Moreover, knockdown of CerS1 abrogated sodium selenite-induced mitophagy, and stable LC3B knockdown protected against CerS1- and C18-ceramide-dependent mitophagy and blocked tumor suppression in vivo. Thus, these data suggest a new receptor function of ceramide for anchoring LC3B-II autophagolysosomes to mitochondrial membranes, defining a key mechanism for the induction of lethal mitophagy.
- Subjects
MITOCHONDRIA; AUTOPHAGY; CERAMIDES; CELL death; GENE expression; CANCER cells; OXYGEN consumption
- Publication
Nature Chemical Biology, 2012, Vol 8, Issue 10, p831
- ISSN
1552-4450
- Publication type
Article
- DOI
10.1038/nchembio.1059