ArticleCardiovascular research2019
Cyclophilin D-mediated regulation of the permeability transition pore is altered in mice lacking the mitochondrial calcium uniporter.
Article in Cardiovascular research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 84 citations in OpenAlex.
- Mitochondrial Dysfunction at the Crossroads of Necroptosis: Mechanisms, Molecular Mediators, and Therapeutic Opportunities.Journal of cellular and molecular medicine · 2026Review
- Sex differences in mitochondrial CaJournal of molecular and cellular cardiology · 2026Article
- 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
- SARS-CoV-2-infected cardiomyocytes exhibit upregulated necroptosis, but no evidence of mitochondrial permeability transition.Journal of molecular and cellular cardiology plus · 2026Article
- Fetal programming of the cardiac mitochondrial permeability transition pore in male offspring from hypoxic pregnancies.Redox biology · 2026Article
- Mitochondrial targets in ischaemic heart disease and heart failure, and their potential for a more efficient clinical translation. A scientific statement of the ESC Working Group on Cellular Biology of the Heart and the ESC Working Group on Myocardial Function.European journal of heart failure · 2025Review
- Regulated Cell Death in Myocardial Infarction.Circulation research · 2025Article
- Cryo-EM structure of the brine shrimp mitochondrial ATP synthase suggests an inactivation mechanism for the ATP synthase leak channel.Cell death and differentiation · 2025Article
- cGAMP-targeting injectable hydrogel system promotes periodontal restoration by alleviating cGAS-STING pathway activation.Bioactive materials · 2025Article
- Mechanisms of postischemic cardiac death and protection following myocardial injury.The Journal of clinical investigation · 2025Review
- Extracellular Role for the Intracellular Cell Death Mediator RIPK3 in Myocardial Infarction.Circulation · 2024Article
- N-terminal cleavage of cyclophilin D boosts its ability to bind F-ATP synthase.Communications biology · 2024Article
- Monitoring mitochondrial calcium in cardiomyocytes during coverslip hypoxia using a fluorescent lifetime indicator.Journal of molecular and cellular cardiology plus · 2024Article
- MCU-independent CaScientific reports · 2024Article
- Loss of mitochondrial CaThe Journal of physiology · 2024Article
- BAK contributes critically to necrosis and infarct generation during reperfused myocardial infarction.Journal of molecular and cellular cardiology · 2023Article
- Mesenchymal Stem Cell-Derived Exosomal Noncoding RNAs as Alternative Treatments for Myocardial Ischemia-Reperfusion Injury: Current Status and Future Perspectives.Journal of cardiovascular translational research · 2023Review
- Role of RIPK3‑CaMKII‑mPTP signaling pathway‑mediated necroptosis in cardiovascular diseases (Review).International journal of molecular medicine · 2023Review
- Mitochondrial Reactive Oxygen Species and Lytic Programmed Cell Death in Acute Inflammation.Antioxidants & redox signaling · 2023Review
- Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart.Biomolecules · 2023Review
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
Aims: Knockout (KO) of the mitochondrial Ca2+ uniporter (MCU) in mice abrogates mitochondrial Ca2+ uptake and permeability transition pore (PTP) opening. However, hearts from global MCU-KO mice are not protected from ischaemic injury. We aimed to investigate whether adaptive alterations occur in cell death signalling pathways in the hearts of global MCU-KO mice. Methods and results: First, we examined whether cell death may occur via an upregulation in necroptosis in MCU-KO mice. However, our results show that neither RIP1 inhibition nor RIP3 knockout afford protection against ischaemia-reperfusion injury in MCU-KO as in wildtype (WT) hearts, indicating that the lack of protection cannot be explained by upregulation of necroptosis. Instead, we have identified alterations in cyclophilin D (CypD) signalling in MCU-KO hearts. In the presence of a calcium ionophore, MCU-KO mitochondria take up calcium and do undergo PTP opening. Furthermore, PTP opening in MCU-KO mitochondria has a lower calcium retention capacity (CRC), suggesting that the calcium sensitivity of PTP is higher. Phosphoproteomics identified an increase in phosphorylation of CypD-S42 in MCU-KO. We investigated the interaction of CypD with the putative PTP component ATP synthase and identified an approximately 50% increase in this interaction in MCU-KO cardiac mitochondria. Mutation of the novel CypD phosphorylation site S42 to a phosphomimic reduced CRC, increased CypD-ATP synthase interaction by approximately 50%, and increased cell death in comparison to a phospho-resistant mutant. Conclusion: Taken together these data suggest that MCU-KO mitochondria exhibit an increase in phosphorylation of CypD-S42 which decreases PTP calcium sensitivity thus allowing activation of PTP in the absence of an MCU-mediated increase in matrix calcium.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.