Sphingolipid Metabolism Cooperates with BAK and BAX to Promote the Mitochondrial Pathway of Apoptosis
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Mitochondria are functionally and physically associated with heterotypic membranes, yet little is known about how these interactions impact mitochondrial outer-membrane permeabilization (MOMP) and apoptosis. We observed that dissociation of heterotypic membranes from mitochondria inhibited BAK/BAX-dependent cytochrome c (cyto c) release. Biochemical purification of neutral sphingomyelinases that correlated with MOMP sensitization suggested that sphingolipid metabolism coordinates BAK/BAX activation. Using purified lipids and enzymes, sensitivity to MOMP was achieved by in vitro reconstitution of the sphingolipid metabolic pathway. Sphingolipid metabolism inhibitors blocked MOMP from heavy membrane preparations but failed to influence MOMP in the presence of sphingolipid-reconstituted, purified mitochondria. Furthermore, the sphingolipid products, sphingosine-1-PO(4) and hexadecenal, cooperated specifically with BAK and BAX, respectively. Sphingolipid metabolism was also required for cellular responses to apoptosis. Our studies suggest that BAK/BAX activation and apoptosis are coordinated through BH3-only proteins and a specific lipid milieu that is maintained by heterotypic membrane-mitochondrial interactions.
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Mitochondrial size and shape as well as lipid composition can influence the likelihood of mitochondria to undergo irreversible MOMP.
“Finally, it is becoming increasingly evident that mitochondrial size and shape [139–141] as well as lipid composition [142, 143] can influence the likelihood of mitochondria to undergo irreversible MOMP.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [143]
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- Authors
- Chipuk, J. E., McStay, G. P., Bharti, A., Kuwana, T., Clarke, C. J., Siskind, L. J., Obeid, L. M., & Green, D. R.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- St. Jude Children's Research Hospital (US)
- University of Iowa (US)
- Medical University of South Carolina (US)
- Corresponding author
- Chipuk, Jerry E.
- Green, Douglas R.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 148
- Issue
- 5
- Pages
- 988-1000
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3506012
- OpenAlex
- W2068444709
- Cited by
- 436
- References
- 66
- Citations by year
- 2026: 12 · 2025: 20 · 2024: 27 · 2023: 22 · 2022: 28 · 2021: 32 · 2020: 30 · 2019: 26 · 2018: 29 · 2017: 41 · 2016: 35 · 2015: 33 · 2014: 33 · 2013: 41 · 2012: 26
- FWCI
- 17.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Staffordshire Online Repository (Staffordshire University) (submittedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (P20AA017067)
- National Institute on Aging (R21AG024478, AG024478)
- National Cancer Institute (CA 69381, CA157740, R01CA157740, P 30CA 21765, P01CA069381, P30CA021765, P30CA138313)
- National Institute of Allergy and Infectious Diseases (AI-52735)
- National Center for Research Resources (P20RR017677, P20 RR17677)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- sphingolipid metabolism, Bak, Bax, mitochondrial apoptosis, mitochondrial outer membrane permeabilization, cytochrome c release, neutral sphingomyelinase, sphingosine-1-phosphate, BH3-only proteins, lipid reconstitution
- MeSH terms
- Animals, Female, HeLa Cells, Humans, Liver, Mice, Inbred C57BL, Mitochondria, Sphingolipids, Sphingomyelin Phosphodiesterase, Apoptosis, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, Mitochondrial Membranes, Mice, Metabolic Networks and Pathways
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