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Cyclophilin D controls mitochondrial pore–dependent Ca2+ exchange, metabolic flexibility, and propensity for heart failure in mice
Open accessAbstract
Cyclophilin D (which is encoded by the Ppif gene) is a mitochondrial matrix peptidyl-prolyl isomerase known to modulate opening of the mitochondrial permeability transition pore (MPTP). Apart from regulating necrotic cell death, the physiologic function of the MPTP is largely unknown. Here we have shown that Ppif(-/-) mice exhibit substantially greater cardiac hypertrophy, fibrosis, and reduction in myocardial function in response to pressure overload stimulation than control mice. In addition, Ppif(-/-) mice showed greater hypertrophy and lung edema as well as reduced survival in response to sustained exercise stimulation. Cardiomyocyte-specific transgene expression of cyclophilin D in Ppif(-/-) mice rescued the enhanced hypertrophy, reduction in cardiac function, and rapid onset of heart failure following pressure overload stimulation. Mechanistically, the maladaptive phenotype in the hearts of Ppif(-/-) mice was associated with an alteration in MPTP-mediated Ca(2+) efflux resulting in elevated levels of mitochondrial matrix Ca(2+) and enhanced activation of Ca(2+)-dependent dehydrogenases. Elevated matrix Ca(2+) led to increased glucose oxidation relative to fatty acids, thereby limiting the metabolic flexibility of the heart that is critically involved in compensation during stress. These findings suggest that the MPTP maintains homeostatic mitochondrial Ca(2+) levels to match metabolism with alterations in myocardial workload, thereby suggesting a physiologic function for the MPTP.
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“however, lack of cyclophilin D in cardiac cells may be detrimental under certain conditions, as this deficiency compromises Ca2+ handling in mitochondria, decreasing the ability of mitochondria to efflux Ca2+ after alterations in myocardial workload due to lack of beneficial (perhaps transient) MPT pore formation (123).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [123]
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Metadata
- Authors
- Elrod, J. W., Wong, R., Mishra, S., Vagnozzi, R. J., Sakthievel, B., Goonasekera, S. A., Karch, J., Gabel, S., Farber, J., Force, T., Heller Brown, J., Murphy, E., & Molkentin, J. D.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- National Institutes of Health (US)
- University of California San Diego (US)
- Thomas Jefferson University (US)
- Corresponding author
- Molkentin, Jeffery D.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2010-10-01
- Volume
- 120
- Issue
- 10
- Pages
- 3680-3687
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2947235
- OpenAlex
- W1966536813
- Cited by
- 384
- References
- 47
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 13 · 2023: 21 · 2022: 20 · 2021: 29 · 2020: 29 · 2019: 23 · 2018: 24 · 2017: 25 · 2016: 34 · 2015: 36 · 2014: 32 · 2013: 21 · 2012: 31
- FWCI
- 10.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Fondation Leducq
- National Institutes of Health (HL80101)
- National Heart, Lung, and Blood Institute (HL-62927, HL80101, R01HL081104, P01HL080101, F32HL092737, R37HL028143, HL81104, R01HL062927)
- National Institute of General Medical Sciences (T32GM007752)
- 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
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- cyclophilin D, mitochondrial permeability transition pore, mitochondrial calcium, cardiac hypertrophy, heart failure, pressure overload, metabolic flexibility, glucose oxidation, fatty acid oxidation, cardiomyocyte-specific overexpression, myocardial fibrosis, pulmonary edema
- MeSH terms
- Peptidyl-Prolyl Isomerase F, Mitochondrial Permeability Transition Pore, Aging, Animals, Calcium, Cardiomegaly, Heart Failure, Mice, Transgenic, Mitochondria, Heart, Myocardial Contraction, Cyclophilins, Mitochondrial Membrane Transport Proteins, Mice
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