Mitochondrial Targeted Cyclophilin D Protects Cells from Cell Death by Peptidyl Prolyl Isomerization
Open accessAbstract
Cyclophilin D (CyPD) is thought to sensitize opening of the mitochondrial permeability transition pore (mPTP) based on the findings that cyclosporin A (CsA), a pseudo-CyPD substrate, hyperpolarizes the mitochondrial membrane potential (DeltaPsi) and inhibits apoptosis. We provide evidence that contrasts with this model. Using live cell imaging and two photon microscopy, we report that overexpression of CyPD desensitizes HEK293 and rat glioma C6 cells to apoptotic stimuli. By site-directed mutagenesis of CyPD that compromises peptidyl-prolyl cis-trans isomerase (PPIase) activity, we demonstrate that the mechanism involved in this protective effect requires PPIase activity. Furthermore, we show that, under resting conditions, DeltaPsi is hyperpolarized in CyPD wild type-overexpressing cells but not in cells overexpressing mutant forms of CyPD that lack PPIase activity. Finally, in glutathione S-transferase (GST) pull-down assays, we demonstrate that CyPD binding to the adenine nucleotide translocator (ANT), which is considered to be the core component of the mPTP, is not affected by the loss of PPIase activity. Collectively, our data suggest that CyPD should be viewed as a cell survival-signaling molecule and indicate a protective role of CyPD against apoptosis that is mediated by one or more targets other than the ANT.
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Cyclosporine A acts as an MPT inhibitor by preventing CyPD from interacting with MPTP.
“Cyclosporine A (CsA), a pseudosubstrate of CyPD (Lin and Lechleiter, 2002), keeps CyPD from interacting with MPTP then acts as an MPT inhibitor (Broekemeier et al., 1989).”
From Mitochondrial Dysfunction Induced by Sertraline, an Antidepressant Agent (2012) · cites this paper as Lin and Lechleiter, 2002
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References 57 · Cited by 181
Research works printed but not linked: 3
- Ke, H., Mayrose, D., and Cao, W. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 3324 -3328
- Halestrap, A. P., Doran, E., Gillespie, J. P., and O'Toole, A. (2000) Biochem. Soc. Trans. 28, 170 -177
- Davis, E. S., Becker, A., Heitman, J., Hall, M. N., and Brennan, M. B. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 11169 -11173
- Authors
- Lin, D.-T., & Lechleiter, J. D.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Lechleiter, James D.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-08
- Volume
- 277
- Issue
- 34
- Pages
- 31134-31141
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2023555853
- Cited by
- 181
- References
- 57
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 2 · 2023: 5 · 2022: 15 · 2021: 8 · 2020: 5 · 2019: 1 · 2018: 3 · 2017: 10 · 2016: 11 · 2015: 9 · 2014: 9 · 2013: 7 · 2012: 8
- FWCI
- 4.07
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- University of Texas Health Science Center at San Antonio
- National Institute of General Medical Sciences (GM 48451, R01GM048451)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- 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
- Keywords
- cyclophilin D, peptidyl-prolyl isomerase, apoptosis, mitochondrial permeability transition pore, mitochondrial membrane potential, adenine nucleotide translocase, cell survival signaling, cyclosporine, mitochondrial hyperpolarization, glioma cells, HEK293 cells
- MeSH terms
- Peptidyl-Prolyl Isomerase F, Mitochondrial Permeability Transition Pore, Mitochondrial ADP, ATP Translocases, Animals, Binding Sites, Humans, Ion Channels, Membrane Potentials, Cyclosporine, Apoptosis, Oxidative Stress, Staurosporine, Peptidylprolyl Isomerase, tert-Butylhydroperoxide, Cyclophilins, Mitochondrial Membrane Transport Proteins, Rats
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