title: Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
authors.forename: R David
authors.initials: RD
authors.lastname: Sentelle
authors.forename: Can E
authors.initials: CE
authors.lastname: Senkal
authors.forename: Wenhui
authors.initials: W
authors.lastname: Jiang
authors.forename: Suriyan
authors.initials: S
authors.lastname: Ponnusamy
authors.forename: Salih
authors.initials: S
authors.lastname: Gencer
authors.forename: Shanmugam Panneer
authors.initials: SP
authors.lastname: Selvam
authors.forename: Venkat K
authors.initials: VK
authors.lastname: Ramshesh
authors.forename: Yuri K
authors.initials: YK
authors.lastname: Peterson
authors.forename: John J
authors.initials: JJ
authors.lastname: Lemasters
authors.forename: Zdzislaw M
authors.initials: ZM
authors.lastname: Szulc
authors.forename: Jacek
authors.initials: J
authors.lastname: Bielawski
authors.forename: Besim
authors.initials: B
authors.lastname: Ogretmen
mesh_terms: D001343:Autophagy; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002518:Ceramides / Q000494:pharmacology*; D006801:Humans; D008055:Lipids / Q000737:chemistry; D018613:Microscopy, Confocal; D063306:Mitophagy / Q000187:drug effects*; D010588:Phagosomes / Q000187:drug effects*
chemical_list: D002518:Ceramides; D008055:Lipids