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Subcellular Fractionation for ERK Activation Upon Mitochondrial-derived Peptide Treatment
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PHO-ERK1/2 interaction with mitochondria regulates the permeability transition pore in cardioprotective signaling

Sauri Hernández-Reséndiz1, Cecilia Zazueta1

  • 1Department of Cardiovascular Biomedicine, National Institute of Cardiology, I.Ch., Juan Badiano No. 1, Colonia Sección XVI, Mexico 14080, DF, Mexico.

Life Sciences
|May 20, 2014
PubMed
Abstract

Insights

Activated ERK1/2 kinases target mitochondria via caveolin-3 vesicles, phosphorylating mitochondrial proteins and inhibiting the permeability transition pore to promote cardioprotection.

Area of Science:

  • Molecular biology
  • Cardiovascular research
  • Mitochondrial signaling

Background:

  • The precise mechanisms linking extracellular signal-regulated kinase 1/2 (ERK1/2) and other kinases to downstream targets in cardioprotective signaling remain unclear.
  • Spatiotemporal redistribution of multiprotein signaling complexes, potentially involving mitochondria and caveolae, may enhance effector protein interaction and promote cardioprotection.

Purpose of the Study:

  • To investigate the interaction between phosphorylated ERK1/2 (PHO-ERK1/2) and mitochondria.
  • To determine if this interaction provides a mechanistic link in regulating mitochondrial function during cardioprotective signaling.

Main Methods:

  • Utilized a model of dilated cardiomyopathy with subsequent ischemia-reperfusion injury.
  • Quantified ERK1/2 signaling specifically at the mitochondrial level.
  • Assessed the impact of ERK1/2 signaling on mitochondrial permeability transition pore (mPTP) opening.

Main Results:

  • Under cardioprotective conditions, activated ERK1/2 was observed to traffic to mitochondrial membranes via vesicular transport.
  • This mitochondrial localization correlated with increased phosphorylation of mitochondrial proteins and inhibition of mPTP opening.
  • Vesicles containing caveolin-3 appeared to facilitate the transport of ERK1/2, GSK3β, and Akt to mitochondria.

Conclusions:

  • Signaling complexes involving phosphorylated ERK (PHO-ERK), phosphorylated Akt (PHO-Akt), phosphorylated eNOS (PHO-eNOS), and caveolin-3 are crucial for cardioprotection.
  • These complexes directly modulate the mitochondrial proteome.
  • Regulation of the mitochondrial permeability transition pore opening by these complexes contributes significantly to the cardioprotective effect.
Keywords:
CardioprotectionDilated cardiomyopathyMitochondrial ERK1/2PostconditioningReperfusionSignalosomes

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