Adrenergic Signaling Regulates Mitochondrial Ca2+ Uptake Through Pyk2-Dependent Tyrosine Phosphorylation of the Mitochondrial Ca2+ Uniporter
| العنوان: | Adrenergic Signaling Regulates Mitochondrial Ca2+ Uptake Through Pyk2-Dependent Tyrosine Phosphorylation of the Mitochondrial Ca2+ Uniporter |
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| المؤلفون: | Anna Raffaello, Jyotsna Mishra, Wang Wang, Godfrey L. Smith, Xiaoyun Liu, Stephen Hurst, Shangcheng Xu, Polina Gross, Shey-Shing Sheu, Rosario Rizzuto, Jin O-Uchi, Huiliang Zhang, Alina Ainbinder, Bing Yi, Bong Sook Jhun, Robert T. Dirksen, Sarah Kettlewell |
| المصدر: | Antioxidants & Redox Signaling. 21:863-879 |
| بيانات النشر: | Mary Ann Liebert Inc, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Physiology, Clinical Biochemistry, Biology, Mitochondrion, Models, Biological, Biochemistry, Mitochondrial apoptosis-induced channel, Cell Line, chemistry.chemical_compound, Cytosol, Forum Original Research Communication, Receptors, Adrenergic, alpha-1, Animals, Humans, Myocytes, Cardiac, Phosphorylation, Uniporter, Molecular Biology, General Environmental Science, Tyrosine phosphorylation, Cell Biology, Mitochondria, Rats, Cell biology, Protein Transport, Focal Adhesion Kinase 2, Mitochondrial permeability transition pore, chemistry, General Earth and Planetary Sciences, Calcium, Calcium Channels, ATP–ADP translocase, Protein Multimerization, Signal transduction, Apoptosis Regulatory Proteins, Reactive Oxygen Species, Protein Binding, Signal Transduction |
| الوصف: | Aims: Mitochondrial Ca2+ homeostasis is crucial for balancing cell survival and death. The recent discovery of the molecular identity of the mitochondrial Ca2+ uniporter pore (MCU) opens new possibilities for applying genetic approaches to study mitochondrial Ca2+ regulation in various cell types, including cardiac myocytes. Basal tyrosine phosphorylation of MCU was reported from mass spectroscopy of human and mouse tissues, but the signaling pathways that regulate mitochondrial Ca2+ entry through posttranslational modifications of MCU are completely unknown. Therefore, we investigated α1-adrenergic-mediated signal transduction of MCU posttranslational modification and function in cardiac cells. Results: α1-adrenoceptor (α1-AR) signaling translocated activated proline-rich tyrosine kinase 2 (Pyk2) from the cytosol to mitochondrial matrix and accelerates mitochondrial Ca2+ uptake via Pyk2-dependent MCU phosphorylation and tetrametric MCU channel pore formation. Moreover, we found that α1-AR stimulation increases reactive oxygen species production at mitochondria, mitochondrial permeability transition pore activity, and initiates apoptotic signaling via Pyk2-dependent MCU activation and mitochondrial Ca2+ overload. Innovation: Our data indicate that inhibition of α1-AR-Pyk2-MCU signaling represents a potential novel therapeutic target to limit or prevent mitochondrial Ca2+ overload, oxidative stress, mitochondrial injury, and myocardial death during pathophysiological conditions, where chronic adrenergic stimulation is present. Conclusion: The α1-AR-Pyk2-dependent tyrosine phosphorylation of the MCU regulates mitochondrial Ca2+ entry and apoptosis in cardiac cells. Antioxid. Redox Signal. 21, 863–879. |
| تدمد: | 1557-7716 1523-0864 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::da71751c0979cec19bd222f8e1b5fb28Test https://doi.org/10.1089/ars.2013.5394Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....da71751c0979cec19bd222f8e1b5fb28 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15577716 15230864 |
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