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Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy
Open accessAbstract
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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“The localization of CerS1 to the mitochondria and the synthesis of ceramide in the outer mitochondrial membrane recruit the autophagic machinery and induce mitophagy (15) by binding autophagosome-associated LC3.”
From Alzheimer's Disease–Associated Amyloid-β Precursor Protein Prevents Aging Stress–Induced Mitophagy and Fumarate Depletion to Improve Antitumor Immunity (2025) · cites this paper as [15]
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Metadata
- Authors
- Sentelle, R. D., Senkal, C. E., Jiang, W., Ponnusamy, S., Gencer, S., Panneer Selvam, S., Ramshesh, V. K., Peterson, Y. K., Lemasters, J. J., Szulc, Z. M., Bielawski, J., & Ogretmen, B.
- Affiliations
- Medical University of South Carolina (US)
- Venue
- Nature Chemical Biology
- Published
- 2012-08-26
- Volume
- 8
- Issue
- 10
- Pages
- 831-838
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC3689583
- OpenAlex
- W1981224101
- Cited by
- 539
- References
- 44
- Citations by year
- 2026: 36 · 2025: 44 · 2024: 50 · 2023: 56 · 2022: 35 · 2021: 47 · 2020: 38 · 2019: 37 · 2018: 48 · 2017: 41 · 2016: 32 · 2015: 31 · 2014: 27 · 2013: 15 · 2012: 2
- FWCI
- 17.96
- Type
- journal article
- Language
- en
- Update notices
- erratum (2012-11-26)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1c06rr015455-01a1)
- National Institute on Alcohol Abuse and Alcoholism (P50AA011605, 1-P50-AA11605)
- National Cancer Institute (CA088932, R01CA088932, CA097165, P30CA138313)
- National Institute of Diabetes and Digestive and Kidney Diseases (5P30 DK 34987, P30DK034987)
- National Institute of Dental and Craniofacial Research (DE-016572, R01DE016572)
- National Center for Research Resources (C06 RR-015455)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- ceramide, mitophagy, autophagy, LC3B-II, LC3B lipidation, CERS1, autophagic cell death, Drp1, mitochondrial fission, autophagolysosomes, mitochondrial targeting, oxygen consumption, sodium selenite, tumor suppression, cancer cells
- MeSH terms
- Autophagy, Ceramides, Humans, Lipids, Phagosomes, Cell Death, Microscopy, Confocal, Cell Line, Tumor, Mitophagy
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