Adrenergic Signaling Regulates Mitochondrial Ca(2+) Uptake Through Pyk2-Dependent Tyrosine Phosphorylation of the Mitochondrial Ca(2+) Uniporter.

Authors

Jin O-Uchi, Thomas Jefferson UniversityFollow
Bong Sook Jhun, Thomas Jefferson UniversityFollow
Shangcheng Xu, University of WashingtonFollow
Stephen Hurst, Thomas Jefferson UniversityFollow
Anna Raffaello, University of Padua and CNR Neuroscience Institute, Padua, ItalyFollow
Xiaoyun Liu, University of WashingtonFollow
Bing Yi, Thomas Jefferson UniversityFollow
Huiliang Zhang, University of WashingtonFollow
Polina Gross, Thomas Jefferson UniversityFollow
Jyotsna Mishra, Thomas Jefferson UniversityFollow
Alina Ainbinder, University of Rochester Medical Center, Rochester, New York.Follow
Sarah Kettlewell, University of Glasgow, Glasgow, United Kingdom.Follow
Godfrey L Smith, University of Glasgow, Glasgow, United Kingdom.Follow
Robert T Dirksen, University of Rochester Medical Center, Rochester, New York.Follow
Wang Wang, University of WashingtonFollow
Rosario Rizzuto, University of Padua and CNR Neuroscience Institute, Padua, ItalyFollow
Shey-Shing Sheu, Department of Medicine, Center for Translational Medicine, Jefferson Medical College, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

Spring 5-7-2014

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Antioxidants & redox signaling.

Volume 21, Issue 6, June 2014, Pages 1-17.

The published version is available at DOI: 10.1089/ars.2013.5394. Copyright © Mary Ann Liebert, Inc.

Abstract

Abstract Aims: Mitochondrial Ca(2+) homeostasis is crucial for balancing cell survival and death. The recent discovery of the molecular identity of the mitochondrial Ca(2+) uniporter pore (MCU) opens new possibilities for applying genetic approaches to study mitochondrial Ca(2+) 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 Ca(2+) 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 Ca(2+) 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 Ca(2+) overload. Innovation: Our data indicate that inhibition of α1-AR-Pyk2-MCU signaling represents a potential novel therapeutic target to limit or prevent mitochondrial Ca(2+) 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 Ca(2+) entry and apoptosis in cardiac cells. Antioxid. Redox Signal. 00, 000-000.

Recommended Citation

O-Uchi, Jin; Jhun, Bong Sook; Xu, Shangcheng; Hurst, Stephen; Raffaello, Anna; Liu, Xiaoyun; Yi, Bing; Zhang, Huiliang; Gross, Polina; Mishra, Jyotsna; Ainbinder, Alina; Kettlewell, Sarah; Smith, Godfrey L; Dirksen, Robert T; Wang, Wang; Rizzuto, Rosario; and Sheu, Shey-Shing, "Adrenergic Signaling Regulates Mitochondrial Ca(2+) Uptake Through Pyk2-Dependent Tyrosine Phosphorylation of the Mitochondrial Ca(2+) Uniporter." (2014). Center for Translational Medicine Faculty Papers. Paper 28.
https://jdc.jefferson.edu/transmedfp/28

PubMed ID

24800979