Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy.
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| Abstract |
Mechanisms by which autophagy promotes cell survival or death are unclear. We provide evidence that C(18)-pyridinium ceramide treatment or endogenous C(18)-ceramide generation by ceramide synthase 1 (CerS1) expression mediates autophagic cell death, independent of apoptosis in human cancer cells. C(18)-ceramide-induced lethal autophagy was regulated via microtubule-associated protein 1 light chain 3 β-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 C(18)-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.
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| Authors | R David Sentelle, Can E Senkal, Wenhui Jiang, Suriyan Ponnusamy, Salih Gencer, Shanmugam Panneer Selvam, Venkat K Ramshesh, Yuri K Peterson, John J Lemasters, Zdzislaw M Szulc, Jacek Bielawski, Besim Ogretmen |
| Journal | Nature chemical biology (Nat Chem Biol) Vol. 8 Issue 10 Pg. 831-8 (Oct 2012) ISSN: 1552-4469 [Electronic] United States |
| PMID | 22922758 (Publication Type: Journal Article, Research Support, N.I.H., Extramural) |
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