CaMKII induces permeability transition through Drp1 phosphorylation during chronic β-AR stimulation.
CaMKII induces permeability transition through Drp1 phosphorylation during chronic β-AR stimulation.
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CaMKII 在慢性 β-AR 刺激过程中通过 Drp1 磷酸化诱导通透性转变
DOI：
10.1038/ncomms13189
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发表时间：
2016-10-14
影响因子：
16.6
通讯作者：
Wang W
中科院分区：
文献类型：
--
作者：
Xu S;Wang P;Zhang H;Gong G;Gutierrez Cortes N;Zhu W;Yoon Y;Tian R;Wang W
线粒体通透性过渡孔（mPTP）参与慢性β-肾上腺素能受体（β-AR）刺激心功能障碍。慢性β-AR刺激导致mPTP打开的机制尚不清楚。本研究表明，长期服用异丙肾上腺素（ISO）持续增加mPTP打开的频率，随后出现线粒体损伤和心功能障碍。从机制上讲，这种作用是通过Ca2+/钙调素依赖性激酶II （CaMKII）在丝氨酸616 （S616）位点磷酸化线粒体裂变蛋白，动力蛋白相关蛋白1 （Drp1）介导的。突变该磷酸化位点或抑制Drp1活性可阻断CaMKII-或iso诱导的mPTP开放和心肌细胞死亡，并在体内挽救心脏肥大。在人类衰竭的心脏中，Drp1在S616位点的磷酸化增加。这些结果揭示了慢性β-AR刺激的下游途径，该途径将CaMKII， Drp1和mPTP连接起来，以桥接细胞质应激信号与心脏线粒体功能障碍。β-肾上腺素能受体信号传导诱导线粒体通透性过渡孔（mPTP）开放。在这里，Xu等人发现这种作用是由CamKII磷酸化线粒体裂变蛋白Drp1介导的，这增加了瞬时mPTP打开的频率。
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. β-adrenergic receptor signaling induces mitochondrial permeability transition pore (mPTP) opening. Here, Xu et al. show that this effect is mediated by phosphorylation of mitochondrial fission protein Drp1 by CamKII, which increases the frequency of transient mPTP opening.
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