Inhibition of mitochondrial permeability transition by deletion of the ANT family and CypD
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Abstract
Abstract The mitochondrial permeability transition pore (MPTP) has resisted molecular identification for decades. The original model of the MPTP had the adenine nucleotide translocator (ANT) as the inner membrane pore-forming component. Indeed, reconstitution experiments showed that recombinant or purified ANT generates MPTP-like pores in lipid bilayers. This model was challenged when mitochondria from Ant1/2 double null mouse liver still showed MPTP activity. Because mice contain and express 3 Ant genes, here we reinvestigated the genetic basis for the ANTs as comprising the MPTP. Liver mitochondria from Ant1, Ant2 , and Ant4 deficient mice were highly refractory to Ca 2+ -induced MPT, and when also given cyclosporine A, MPT was completely inhibited. Moreover, liver mitochondria from mice with quadruple deletion of Ant1, Ant2, Ant4 and Ppif (cyclophilin D, target of CsA) lacked Ca 2+ -induced MPT. Finally, inner membrane patch clamping in mitochondria from Ant1, Ant2 and Ant4 triple null mouse embryonic fibroblasts (MEFs) showed a loss of MPT-like pores. Our findings suggest a new model of MPT consisting of two distinct molecular components, one of which is the ANTs and the other of which is unknown but requires CypD. One Sentence Summary Genetic deletion of Ant1/2/4 and Ppif in mice fully inhibits the mitochondrial permeability transition pore
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Some combination of mitochondrial proteins (CypD, ANT, ATP synthase, VDAC, PiC, SPG-7) is necessary to fully exhibit the properties of mPTP.
“The inescapable conclusion from these studies is that some combination of these proteins is necessary to fully exhibit the properties of mPTP [1,18,20,21].”
From The mitochondrial permeability transition: Nexus of aging, disease and longevity (2021) · cites this paper as [18]
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Mitochondrial Volume Regulation and Swelling Mechanisms in Cardiomyocytes
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- Authors
- Karch, J., Bround, M. J., Khalil, H., Sargent, M. A., Latchman, N., Terada, N., Peixoto, P. M., & Molkentin, J. D.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- Baruch College (US)
- University of Florida Health (US)
- Corresponding author
- Molkentin, Jeffery D.
- ORCID
- Venue
- Science Advances
- Published
- 2019-08-02
- Volume
- 5
- Issue
- 8
- Pages
- eaaw4597-eaaw4597
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC6713508
- OpenAlex
- W2970506751
- Cited by
- 250
- References
- 33
- Citations by year
- 2026: 25 · 2025: 29 · 2024: 28 · 2023: 37 · 2022: 32 · 2021: 41 · 2020: 53 · 2019: 4
- FWCI
- 10.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Science Advances (publishedVersion, cc-by-nc)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- CUNY Academic Works (City University of New York) (submittedVersion, cc-by-nc)
- Funders
- National Heart, Lung, and Blood Institute (R01HL132831)
- 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 › ATP Synthase and ATPases Research
- Keywords
- mitochondrial permeability transition, mitochondrial permeability transition pore, adenine nucleotide translocase, mitochondrial permeability
- MeSH terms
- Mitochondrial Transmembrane Permeability-Driven Necrosis, Peptidyl-Prolyl Isomerase F, Mitochondrial Permeability Transition Pore, Adenine Nucleotides, Animals, Cells, Cultured, Female, Male, Mitochondria, Sequence Deletion, Mice, Knockout, Mitochondrial Membrane Transport Proteins, Mice
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