ArticleProceedings of the National Academy of Sciences of the United States of America2014
An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 365 papers, 1 of them a synthesis that pooled it.
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Who cites it
365 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Comprehensive analysis of regulated cell death pathways: intrinsic disorder, protein-protein interactions, and cross-pathway communication.Apoptosis : an international journal on programmed cell death · 2025Pooled it
- Mitochondrial calcium and ROS: present understanding and future directions.Mitochondrion · 2026Article
- Glycation proteomics identifies creatine kinase as a mediator of the effects of methylglyoxal on mitochondrial permeability transition.bioRxiv : the preprint server for biology · 2026Article
- NLRX1 emerges as the only observed essential regulator of the mPTP, challenging mPTP inhibition as a valid target of cardioprotection.Basic research in cardiology · 2026Review
- An Evolutionarily Conserved TUSC2-OSCP Interface Suggests a Mitochondrial CaJournal of molecular biology · 2026Article
- ATP synthase subunits e and g are essential for CaCell death and differentiation · 2026Article
- Brown fat protects against hepatic oxidative stress by remodeling the circulating metabolome.Cell metabolism · 2026Article
- Mitochondrial Complex V Dysfunction in Neurodegeneration: Secondary Bystander or Primary Driver?Brain sciences · 2026Review
- Mitochondrial Permeability Transition Regulators As Emerging Therapeutic Targets in Aging and Neurodegeneration: Recent Insights.Journal of molecular neuroscience : MN · 2026Review
- Mitochondrial vulnerability to aldehydic load and the role mitochondrial aldehyde dehydrogenases.Pharmacological research · 2026Review
- Mitochondrial oxidative stress, calcium and dynamics in cardiac ischaemia-reperfusion injury.The Journal of physiology · 2026Review
- Mitochondrial Toxicology of Heavy Metals and Pesticides: Transport Systems, Mitochondrial Dysfunction and Permeability Transition.International journal of molecular sciences · 2026Review
- Mitochondrial Dysfunction at the Crossroads of Necroptosis: Mechanisms, Molecular Mediators, and Therapeutic Opportunities.Journal of cellular and molecular medicine · 2026Review
- Bedaquiline inhibits the ATP synthase leak channel and prevents glutamate-induced neuronal death.Biophysical reports · 2026Article
- Metal-dependent regulated cell death: Molecular architecture and translational frontiers.iMeta · 2026Review
- Inhibition of Cyclophilin D Rescues Cardiac Function and Bioenergetic Defects Caused by Neonatal Hypoxia.JACC. Basic to translational science · 2026Article
- Mitochondrial permeability transition pore desensitization by a novel dispiranic derivative prevents cardiac reperfusion injury.Redox biology · 2026Article
- Review
- Phenotypic CRISPR screens identify NLRX1 as an essential activator of the human mitochondrial permeability transition.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Reversing Mitochondrial Dysfunction in Optineurin E50K Glaucoma: A Metabolic Approach to Neuroprotection.Research square · 2026Article
305 more citing papers are in PubMed but not listed here.
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12 authors.
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Abstract
Mitochondria maintain tight regulation of inner mitochondrial membrane (IMM) permeability to sustain ATP production. Stressful events cause cellular calcium (Ca(2+)) dysregulation followed by rapid loss of IMM potential known as permeability transition (PT), which produces osmotic shifts, metabolic dysfunction, and cell death. The molecular identity of the mitochondrial PT pore (mPTP) was previously unknown. We show that the purified reconstituted c-subunit ring of the FO of the F1FO ATP synthase forms a voltage-sensitive channel, the persistent opening of which leads to rapid and uncontrolled depolarization of the IMM in cells. Prolonged high matrix Ca(2+) enlarges the c-subunit ring and unhooks it from cyclophilin D/cyclosporine A binding sites in the ATP synthase F1, providing a mechanism for mPTP opening. In contrast, recombinant F1 beta-subunit applied exogenously to the purified c-subunit enhances the probability of pore closure. Depletion of the c-subunit attenuates Ca(2+)-induced IMM depolarization and inhibits Ca(2+) and reactive oxygen species-induced cell death whereas increasing the expression or single-channel conductance of the c-subunit sensitizes to death. We conclude that a highly regulated c-subunit leak channel is a candidate for the mPTP. Beyond cell death, these findings also imply that increasing the probability of c-subunit channel closure in a healthy cell will enhance IMM coupling and increase cellular metabolic efficiency.
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