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

Shangcheng Xu (), Pei Wang, Huiliang Zhang, Guohua Gong, Nicolas Gutierrez Cortes, Weizhong Zhu, Yisang Yoon, Rong Tian and Wang Wang ()
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Shangcheng Xu: Mitochondria and Metabolism Center, University of Washington
Pei Wang: Mitochondria and Metabolism Center, University of Washington
Huiliang Zhang: Mitochondria and Metabolism Center, University of Washington
Guohua Gong: Mitochondria and Metabolism Center, University of Washington
Nicolas Gutierrez Cortes: Mitochondria and Metabolism Center, University of Washington
Weizhong Zhu: Nantong University School of Pharmacy
Yisang Yoon: Georgia Regents University
Rong Tian: Mitochondria and Metabolism Center, University of Washington
Wang Wang: Mitochondria and Metabolism Center, University of Washington

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract Mitochondrial permeability transition pore (mPTP) is involved in cardiac dysfunction during chronic β-adrenergic receptor (β-AR) stimulation. The mechanism by which chronic β-AR stimulation leads to mPTP openings is elusive. Here, we show that chronic administration of isoproterenol (ISO) persistently increases the frequency of mPTP openings followed by mitochondrial damage and cardiac dysfunction. Mechanistically, this effect is mediated by phosphorylation of mitochondrial fission protein, dynamin-related protein 1 (Drp1), by Ca2+/calmodulin-dependent kinase II (CaMKII) at a serine 616 (S616) site. Mutating this phosphorylation site or inhibiting Drp1 activity blocks CaMKII- or ISO-induced mPTP opening and myocyte death in vitro and rescues heart hypertrophy in vivo. In human failing hearts, Drp1 phosphorylation at S616 is increased. These results uncover a pathway downstream of chronic β-AR stimulation that links CaMKII, Drp1 and mPTP to bridge cytosolic stress signal with mitochondrial dysfunction in the heart.

Date: 2016
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DOI: 10.1038/ncomms13189

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