Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death
Abstract
Mitochondria play an important role in energy production, Ca2+ homeostasis and cell death. In recent years, the role of the mitochondria in apoptotic and necrotic cell death has attracted much attention. In apoptosis and necrosis, the mitochondrial permeability transition (mPT), which leads to disruption of the mitochondrial membranes and mitochondrial dysfunction, is considered to be one of the key events, although its exact role in cell death remains elusive. We therefore created mice lacking cyclophilin D (CypD), a protein considered to be involved in the mPT, to analyse its role in cell death. CypD-deficient mice were developmentally normal and showed no apparent anomalies, but CypD-deficient mitochondria did not undergo the cyclosporin A-sensitive mPT. CypD-deficient cells died normally in response to various apoptotic stimuli, but showed resistance to necrotic cell death induced by reactive oxygen species and Ca2+ overload. In addition, CypD-deficient mice showed a high level of resistance to ischaemia/reperfusion-induced cardiac injury. Our results indicate that the CypD-dependent mPT regulates some forms of necrotic death, but not apoptotic death.
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To date, PPIF (CYPD) is the only protein whose in vivo requirement for MPT induction has been formally validated with robust genetic tools.
“To date, peptidylprolyl isomerase F (PPIF; best known as cyclophilin D, CYPD) is the only protein whose in vivo requirement for MPT induction has been formally validated with robust genetic tools (although there is consensus around the notion that CYPD does not constitute the pore-forming unit of the PTPC) [376–379].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [377]
There is consensus that CYPD does not constitute the pore-forming unit of PTPC.
“although there is consensus around the notion that CYPD does not constitute the pore-forming unit of the PTPC) [376–379].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [377]
MPT pore formation can occur in response to many stimuli, including Ca2+ overload and oxidant stress.
“Formation of the pore can occur in response to many stimuli, including Ca2+ overload and oxidant stress, but MPT does not play a role in all forms of apoptosis (46, 125, 309, 438).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [309]
MPT does not play a role in all forms of apoptosis.
“Formation of the pore can occur in response to many stimuli, including Ca2+ overload and oxidant stress, but MPT does not play a role in all forms of apoptosis (46, 125, 309, 438).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [309]
In the absence of cyclophilin D, mice are more protected from cardiac damage after ischemia/reperfusion.
“In addition, in the absence of cyclophilin D, mice are more protected from cardiac damage after ischemia/reperfusion (25, 309);”
From Redox regulation of mitochondrial function (2012) · cites this paper as [309]
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- Authors
- Nakagawa, T., Shimizu, S., Watanabe, T., Yamaguchi, O., Otsu, K., Yamagata, H., Inohara, H., Kubo, T., & Tsujimoto, Y.
- Affiliations
- Laboratory of Molecular Genetics (PL)
- Japan Science and Technology Agency (JP)
- The University of Osaka (JP)
- Corresponding author
- Tsujimoto, Yoshihide
- ORCID
- Venue
- Nature
- Published
- 2005-03
- Volume
- 434
- Issue
- 7033
- Pages
- 652-658
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2063099262
- Cited by
- 1,635
- References
- 32
- Citations by year
- 2026: 27 · 2025: 40 · 2024: 32 · 2023: 42 · 2022: 47 · 2021: 54 · 2020: 55 · 2019: 58 · 2018: 73 · 2017: 70 · 2016: 77 · 2015: 74 · 2014: 119 · 2013: 81 · 2012: 115
- FWCI
- 41.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- cyclophilin D, mitochondrial permeability transition, necrosis, apoptosis, cyclosporine, reactive oxygen species, calcium overload, ischemia-reperfusion injury, cardiac injury, mitochondrial dysfunction
- MeSH terms
- Peptidyl-Prolyl Isomerase F, Animals, Calcium, Cells, Cultured, Enzyme Activation, Fibroblasts, Hydrogen Peroxide, Mitochondria, Liver, Mitochondrial Swelling, Necrosis, Thymus Gland, Myocardial Reperfusion Injury, Myocardial Ischemia, Apoptosis, Reactive Oxygen Species, Mice, Knockout, Caspases, Cyclophilins, Hepatocytes, Mice
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