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, Wang Wang

Research output: Contribution to journalArticle

63 Scopus citations

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.

Original languageEnglish (US)
Article number13189
JournalNature communications
Volume7
DOIs
StatePublished - Oct 14 2016

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Xu, S., Wang, P., Zhang, H., Gong, G., Gutierrez Cortes, N., Zhu, W., Yoon, Y., Tian, R., & Wang, W. (2016). CaMKII induces permeability transition through Drp1 phosphorylation during chronic β-AR stimulation. Nature communications, 7, [13189]. https://doi.org/10.1038/ncomms13189