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CaMKII induces permeability transition through Drp1 phosphorylation during chronic β-AR stimulation

Shangcheng Xu1,2, Pei Wang1, Huiliang Zhang1

  • 1Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington 98109, USA.

Nature Communications
|October 15, 2016
PubMed

Insights

Chronic beta-adrenergic receptor stimulation causes heart dysfunction by opening the mitochondrial permeability transition pore (mPTP). This involves CaMKII-dependent Drp1 phosphorylation, linking stress signals to mitochondrial damage.

Area of Science:

  • Cardiology
  • Mitochondrial Biology
  • Molecular Medicine

Background:

  • Chronic beta-adrenergic receptor (β-AR) stimulation is linked to cardiac dysfunction.
  • The mitochondrial permeability transition pore (mPTP) plays a role in this dysfunction.
  • The precise mechanism linking β-AR stimulation to mPTP opening remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which chronic β-AR stimulation leads to mPTP opening and subsequent cardiac dysfunction.
  • To identify key molecular players in the pathway from β-AR stimulation to mitochondrial damage.

Main Methods:

  • Chronic administration of isoproterenol (ISO) in vivo.
  • Assessment of mPTP opening frequency, mitochondrial damage, and cardiac function.
  • Investigation of Ca2+/calmodulin-dependent kinase II (CaMKII) and dynamin-related protein 1 (Drp1) phosphorylation at serine 616 (S616).
  • Site-directed mutagenesis of Drp1 phosphorylation site and inhibition of Drp1 activity.
  • In vitro myocyte death assays and in vivo heart hypertrophy rescue experiments.
  • Analysis of Drp1 phosphorylation in human failing hearts.

Main Results:

  • Chronic ISO administration increases mPTP opening frequency, leading to mitochondrial damage and cardiac dysfunction.
  • This effect is mediated by CaMKII-dependent phosphorylation of Drp1 at S616.
  • Blocking Drp1 phosphorylation at S616 or inhibiting Drp1 activity prevents ISO- or CaMKII-induced mPTP opening and myocyte death.
  • Inhibition of Drp1 activity rescues cardiac hypertrophy in vivo.
  • Increased Drp1 phosphorylation at S616 is observed in human failing hearts.

Conclusions:

  • A novel pathway downstream of chronic β-AR stimulation is identified, involving CaMKII, Drp1, and mPTP.
  • This pathway links cytosolic stress signals to mitochondrial dysfunction in the heart.
  • Targeting the CaMKII-Drp1-mPTP axis may offer therapeutic strategies for heart failure associated with chronic β-AR stimulation.

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