Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy

Nat Chem Biol. 2012 Oct;8(10):831-8. doi: 10.1038/nchembio.1059.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Autophagy*
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Ceramides / pharmacology*
  • Humans
  • Lipids / chemistry
  • Microscopy, Confocal
  • Mitophagy / drug effects*
  • Phagosomes / drug effects*


  • Ceramides
  • Lipids