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

Xu, Shangcheng ; Wang, Pei ; Zhang, Huiliang ; Gong, Guohua ; Gutierrez Cortes, Nicolas ; Zhu, Weizhong ; Yoon, Yisang ; Tian, Rong ; Wang, Wang

Nature communications, 2016-10, Vol.7 (1), p.13189-13189, Article 13189 [Revista revisada por pares]

England: Nature Publishing Group

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CaMKII induces permeability transition through Drp1 phosphorylation during chronic β-AR stimulation
Autor: Xu, Shangcheng ; Wang, Pei ; Zhang, Huiliang ; Gong, Guohua ; Gutierrez Cortes, Nicolas ; Zhu, Weizhong ; Yoon, Yisang ; Tian, Rong ; Wang, Wang
Materias: Adrenergic beta-Agonists - pharmacology ; Animals ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism ; Cell Line ; Cells, Cultured ; Dynamins - metabolism ; Female ; Isoproterenol - pharmacology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Mitochondria - drug effects ; Mitochondria - metabolism ; Mitochondrial Membrane Transport Proteins - metabolism ; Myocytes, Cardiac - cytology ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - metabolism ; Phosphorylation - drug effects ; Rats, Sprague-Dawley ; Receptors, Adrenergic, beta - metabolism
Es parte de: Nature communications, 2016-10, Vol.7 (1), p.13189-13189, Article 13189
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
These authors contributed equally to this work
Descripción: 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 Ca /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.
Editor: England: Nature Publishing Group
Idioma: Inglés

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

Xu, Shangcheng ; Wang, Pei ; Zhang, Huiliang ; Gong, Guohua ; Gutierrez Cortes, Nicolas ; Zhu, Weizhong ; Yoon, Yisang ; Tian, Rong ; Wang, Wang

England: Nature Publishing Group

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