title: Adrenergic signaling regulates mitochondrial Ca2+ uptake through Pyk2-dependent tyrosine phosphorylation of the mitochondrial Ca2+ uniporter.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  The α1-AR-Pyk2-dependent tyrosine phosphorylation of the MCU regulates mitochondrial Ca2+ entry and apoptosis in cardiac cells.
authors.affiliation: 1 Department of Medicine, Center for Translational Medicine, Jefferson Medical College, Thomas Jefferson University , Philadelphia, Pennsylvania.
authors.forename: Jin
authors.initials: J
authors.lastname: O-Uchi
authors.forename: Bong Sook
authors.initials: BS
authors.lastname: Jhun
authors.forename: Shangcheng
authors.initials: S
authors.lastname: Xu
authors.forename: Stephen
authors.initials: S
authors.lastname: Hurst
authors.forename: Anna
authors.initials: A
authors.lastname: Raffaello
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Liu
authors.forename: Bing
authors.initials: B
authors.lastname: Yi
authors.forename: Huiliang
authors.initials: H
authors.lastname: Zhang
authors.forename: Polina
authors.initials: P
authors.lastname: Gross
authors.forename: Jyotsna
authors.initials: J
authors.lastname: Mishra
authors.forename: Alina
authors.initials: A
authors.lastname: Ainbinder
authors.forename: Sarah
authors.initials: S
authors.lastname: Kettlewell
authors.forename: Godfrey L
authors.initials: GL
authors.lastname: Smith
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dirksen
authors.forename: Wang
authors.initials: W
authors.lastname: Wang
authors.forename: Rosario
authors.initials: R
authors.lastname: Rizzuto
authors.forename: Shey-Shing
authors.initials: SS
authors.lastname: Sheu
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D055503:Protein Multimerization; D021381:Protein Transport; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051017:Apoptosis Regulatory Proteins; D015220:Calcium Channels; D017382:Reactive Oxygen Species; D018340:Receptors, Adrenergic, alpha-1; D051418:Focal Adhesion Kinase 2; D002118:Calcium