p53 Opens the Mitochondrial Permeability Transition Pore to Trigger Necrosis
Open accessAbstract
Ischemia-associated oxidative damage leading to necrosis is a major cause of catastrophic tissue loss, and elucidating its signaling mechanism is therefore of paramount importance. p53 is a central stress sensor responding to multiple insults, including oxidative stress to orchestrate apoptotic and autophagic cell death. Whether p53 can also activate oxidative stress-induced necrosis is, however, unknown. Here, we uncover a role for p53 in activating necrosis. In response to oxidative stress, p53 accumulates in the mitochondrial matrix and triggers mitochondrial permeability transition pore (PTP) opening and necrosis by physical interaction with the PTP regulator cyclophilin D (CypD). Intriguingly, a robust p53-CypD complex forms during brain ischemia/reperfusion injury. In contrast, reduction of p53 levels or cyclosporine A pretreatment of mice prevents this complex and is associated with effective stroke protection. Our study identifies the mitochondrial p53-CypD axis as an important contributor to oxidative stress-induced necrosis and implicates this axis in stroke pathology.
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p53-CYPD interaction participates in pathogenesis of ischemic stroke in mice.
“The latter interaction has been shown to participate in the pathogenesis of ischemic stroke in mice [416].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [416]
p53 participates in MPT-driven necrosis upon physical interaction with CYPD.
“(3) p53, which participates in MPT-driven necrosis upon physical interaction with CYPD [416].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [416]
Extensive and prolonged activation of mPTP may lead to cell death by necrosis, and rupture of the mitochondrial outer membrane releases proapoptotic proteins, inducing apoptosis or similar processes.
“The inhibition of oxidative phosphorylation depletes cellular ATP and therefore extensive and prolonged activation of mPTP may lead to cell death by necrosis; in addition, the rupture of the mitochondrial outer membrane releases proapoptotic proteins, including cytochrome c, AIF and endonuclease, thereby inducing cell death by apoptosis or similar processes”
From The mitochondrial permeability transition: Nexus of aging, disease and longevity (2021) · cites this paper as [5]
Oxidative stress-dependent cell death largely depends on the activation of mPTP.
“Oxidative stress-dependent cell death largely depends on the activation of mPTP.”
From The mitochondrial permeability transition: Nexus of aging, disease and longevity (2021) · cites this paper as [5]
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- Authors
- Vaseva, A. V., Marchenko, N. D., Ji, K., Tsirka, S. E., Holzmann, S., & Moll, U. M.
- Affiliations
- Stony Brook University (US)
- University of Göttingen (DE)
- Corresponding author
- Moll, Ute M.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 149
- Issue
- 7
- Pages
- 1536-1548
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3383624
- OpenAlex
- W2110048031
- Cited by
- 740
- References
- 43
- Citations by year
- 2026: 19 · 2025: 40 · 2024: 33 · 2023: 44 · 2022: 60 · 2021: 42 · 2020: 45 · 2019: 47 · 2018: 62 · 2017: 61 · 2016: 65 · 2015: 65 · 2014: 81 · 2013: 57 · 2012: 18
- FWCI
- 28.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- GRO (submittedVersion)
- Funders
- National Cancer Institute (R01CA060664, CA060664)
- National Institute of Neurological Disorders and Stroke (R01NS042168)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- p53, mitochondrial permeability transition pore, cyclophilin D, necrosis, oxidative stress, cerebral ischemia-reperfusion injury, stroke, cyclosporine, mitochondrial matrix
- MeSH terms
- Peptidyl-Prolyl Isomerase F, Mitochondrial Permeability Transition Pore, Animals, Brain Ischemia, Embryo, Mammalian, Fibroblasts, Humans, Male, Necrosis, Reperfusion Injury, Tumor Suppressor Protein p53, Oxidative Stress, Cyclophilins, Mitochondrial Membrane Transport Proteins, Cell Line, Tumor, Mice, Mice, 129 Strain
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