Properties of the Permeability Transition Pore in Mitochondria Devoid of Cyclophilin D
Open accessAbstract
We have studied the properties of the permeability transition pore (PTP) in mitochondria from the liver of mice where the Ppif gene encoding for mitochondrial Cyclophilin D (CyP-D) had been inactivated. Mitochondria from Ppif-/- mice had no CyP-D and displayed a striking desensitization of the PTP to Ca2+, in that pore opening required about twice the Ca2+ load necessary to open the pore in strain-matched, wild-type mitochondria. Mitochondria lacking CyP-D were insensitive to Cyclosporin A (CsA), which increased the Ca2+ retention capacity only in mitochondria from wild-type mice. The PTP response to ubiquinone 0, depolarization, pH, adenine nucleotides, and thiol oxidants was similar in mitochondria from wild-type and Ppif-/- mice. These experiments demonstrate that (i) the PTP can form and open in the absence of CyP-D, (ii) that CyP-D represents the target for PTP inhibition by CsA, and (iii) that CyP-D modulates the sensitivity of the PTP to Ca2+ but not its regulation by the proton electrochemical gradient, adenine nucleotides, and oxidative stress. These results have major implications for our current understanding of the PTP and its modulation in vitro and in vivo.
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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 [378]
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 [378]
At very high levels of Ca2+, cyclophilin D-deficient cells or cells treated with cyclosporin A still have an MPT response.
“Interestingly, at very high levels of Ca2+, cyclophilin D-deficient cells or cells treated with cyclosporin A still have an MPT response (25, 31, 167, 309).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [31]
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- Authors
- Basso, E., Fante, L., Fowlkes, J., Petronilli, V., Forte, M. A., & Bernardi, P.
- Affiliations
- University of Padua (IT)
- Oregon Health & Science University (US)
- Corresponding author
- Forte, Michael A.
- Bernardi, Paolo
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-05
- Volume
- 280
- Issue
- 19
- Pages
- 18558-18561
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1971608015
- Cited by
- 808
- References
- 44
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 11 · 2023: 21 · 2022: 20 · 2021: 32 · 2020: 27 · 2019: 31 · 2018: 35 · 2017: 36 · 2016: 34 · 2015: 45 · 2014: 71 · 2013: 36 · 2012: 48
- FWCI
- 19.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by)
- INFM-OAR (INFN Catania) (submittedVersion, cc-by)
- Funders
- National Institute of General Medical Sciences (R01GM069883, GM 69883)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Keywords
- mitochondrial permeability transition pore, cyclophilin D, cyclosporine, calcium sensitivity, calcium retention capacity, mitochondrial permeability transition, proton gradient, adenine nucleotides, liver mitochondria
- MeSH terms
- Peptidyl-Prolyl Isomerase F, Alleles, Animals, Calcium, Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone, Diamide, Electrochemistry, Hydrogen-Ion Concentration, Liver, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Mitochondria, Liver, Models, Genetic, Oxygen, Oxygen Consumption, Permeability, Protons, Benzoquinones, Cyclosporine, Oxidative Stress, Cyclophilins, Mitochondrial Proteins, Mice
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