Authors

Jin O-Uchi, Department of Medicine, Jefferson Medical College, Thomas Jefferson UniversityFollow
Bong Sook Jhun, Department of Medicine, Jefferson Medical College, Thomas Jefferson UniversityFollow
Shangcheng Xu, Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington
Stephen Hurst, Department of Medicine, Jefferson Medical College, Thomas Jefferson UniversityFollow
Anna Raffaello, Department of Biomedical Sciences, University of Padua, CNR Neuroscience Institute
Xiaoyun Liu, Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington
Bing Yi, Department of Medicine, Jefferson Medical College, Thomas Jefferson UniversityFollow
Huiliang Zhang, Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington
Polina Gross, Department of Medicine, Jefferson Medical College, Thomas Jefferson UniversityFollow
Jyotsna Mishra, Department of Medicine, Jefferson Medical College, Thomas Jefferson UniversityFollow
Alina Ainbinder, Department of Pharmacology and Physiology, University of Rochester Medical Center
Sarah Kettlewell, Institute of Cardiovascular and Medical Science, University of Glasgow
Godfrey L Smith, Institute of Cardiovascular and Medical Science, University of Glasgow
Robert T Dirksen, Department of Pharmacology and Physiology, University of Rochester Medical Center
Wang Wang, Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington
Rosario Rizzuto, Department of Biomedical Sciences, University of Padua, CNR Neuroscience Institute
Shey-Shing Sheu, Department of Medicine, Jefferson Medical College, Thomas Jefferson University;Follow

Document Type

Article

Publication Date

8-20-2014

Comments

This article has been peer reviewed. It was published in: Antioxidants and Redox Signaling.

Volume 21, Issue 6, 20 August 2014, Pages 863-879.

The published version is available at DOI: 10.1089/ars.2013.5394

Copyright © Mary Ann Liebert, Inc. 2014.

Abstract

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.

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