Zhang Xianghong, Yuan Du, Sun Qian, Xu Li, Lee Emma, Lewis Anthony J, Zuckerbraun Brian S, Rosengart Matthew R
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Department of Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.
FASEB J. 2017 Oct;31(10):4382-4395. doi: 10.1096/fj.201601096RRR. Epub 2017 Jun 14.
During sepsis and shock states, mitochondrial dysfunction occurs. Consequently, adaptive mechanisms, such as fission, fusion, and mitophagy, are induced to eliminate damaged portions or entire dysfunctional mitochondria. The regulatory PINK1/Parkin and DJ-1 pathways are strongly induced by mitochondrial depolarization, although a direct link between loss of mitochondrial membrane potential (Δ) and mitophagy has not been identified. Mitochondria also buffer Ca, and their buffering capacity is dependent on Δ Here, we characterize a role for calcium/calmodulin-dependent protein kinase (CaMK) I in the regulation of these mechanisms. Loss of Δ with either pharmacologic depolarization or LPS leads to Ca-dependent mitochondrial recruitment and activation of CaMKI that precedes the colocalization of PINK1/Parkin and DJ-1. CaMKI is required and serves as both a PINK1 and Parkin kinase. The mechanisms operate in both immune and nonimmune cells and are induced in models of endotoxemia, sepsis, and hemorrhagic shock. These data support the idea that CaMKI links mitochondrial stress with the PINK1/Parkin and DJ-1 mechanisms of mitophagy.-Zhang, X., Yuan, D., Sun, Q., Xu, L., Lee, E., Lewis, A. J., Zuckerbraun, B. S., Rosengart, M. R. Calcium/calmodulin-dependent protein kinase regulates the PINK1/Parkin and DJ-1 pathways of mitophagy during sepsis.
在脓毒症和休克状态下，会发生线粒体功能障碍。因此，会诱导诸如分裂、融合和线粒体自噬等适应性机制，以消除受损部分或整个功能失调的线粒体。尽管尚未确定线粒体膜电位（Δ）丧失与线粒体自噬之间的直接联系，但线粒体去极化会强烈诱导PINK1/Parkin和DJ-1调节通路。线粒体还能缓冲钙离子，其缓冲能力取决于Δ。在此，我们阐述了钙/钙调蛋白依赖性蛋白激酶（CaMK）I在这些机制调节中的作用。药理学去极化或脂多糖（LPS）导致的Δ丧失会引发钙离子依赖性的线粒体募集和CaMKI的激活，这先于PINK1/Parkin和DJ-1的共定位。CaMKI是必需的，并且同时作为PINK1和Parkin激酶发挥作用。这些机制在免疫细胞和非免疫细胞中均起作用，并且在内毒素血症、脓毒症和失血性休克模型中被诱导。这些数据支持了CaMKI将线粒体应激与线粒体自噬的PINK1/Parkin和DJ-1机制联系起来的观点。——张X、袁D、孙Q、徐L、李E、刘易斯A.J.、祖克布劳恩B.S.、罗森加特M.R. 钙/钙调蛋白依赖性蛋白激酶在脓毒症期间调节线粒体自噬的PINK1/Parkin和DJ-1通路
