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Adrenergic signaling regulates mitochondrial Ca2+ uptake through Pyk2-dependent tyrosine phosphorylation of the

Jin O-Uchi1, Bong Sook Jhun, Shangcheng Xu

  • 11 Department of Medicine, Center for Translational Medicine, Jefferson Medical College, Thomas Jefferson University , Philadelphia, Pennsylvania.

Antioxidants & Redox Signaling
|May 8, 2014
PubMed
Abstract

Insights

Alpha-1 adrenergic receptor signaling activates proline-rich tyrosine kinase 2, leading to mitochondrial calcium uniporter phosphorylation and increased mitochondrial calcium uptake, promoting apoptosis in cardiac cells.

Area of Science:

  • Cardiovascular Biology
  • Mitochondrial Physiology
  • Cell Signaling

Background:

  • Mitochondrial calcium (Ca2+) homeostasis is vital for cell survival and death.
  • The mitochondrial calcium uniporter (MCU) regulates Ca2+ entry, but its posttranslational modifications are poorly understood.
  • Alpha-1 adrenergic receptor (α1-AR) signaling pathways influencing MCU function in cardiac cells remain largely unknown.

Purpose of the Study:

  • To investigate the role of α1-adrenergic-mediated signal transduction in MCU posttranslational modification and function.
  • To elucidate the signaling pathways regulating mitochondrial Ca2+ entry via MCU in cardiac myocytes.

Main Methods:

  • Utilized cardiac cells to study α1-adrenergic-mediated signal transduction.
  • Investigated the translocation of proline-rich tyrosine kinase 2 (Pyk2) in response to α1-AR stimulation.
  • Assessed mitochondrial Ca2+ uptake, reactive oxygen species production, and apoptotic signaling.

Main Results:

  • α1-AR signaling translocated activated Pyk2 to the mitochondrial matrix, enhancing Ca2+ uptake through Pyk2-dependent MCU phosphorylation and tetrameric pore formation.
  • α1-AR stimulation increased mitochondrial reactive oxygen species, mitochondrial permeability transition pore activity, and initiated apoptotic signaling.
  • Pyk2-dependent MCU activation led to mitochondrial Ca2+ overload and subsequent apoptotic signaling.

Conclusions:

  • α1-AR-Pyk2-dependent tyrosine phosphorylation of MCU regulates mitochondrial Ca2+ entry and apoptosis in cardiac cells.
  • Inhibition of this signaling pathway offers a potential therapeutic target against mitochondrial Ca2+ overload and cardiac injury in conditions with chronic adrenergic stimulation.

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