The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
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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