Preconditioning involves selective mitophagy mediated by Parkin and p62/SQSTM1.
Preconditioning involves selective mitophagy mediated by Parkin and p62/SQSTM1.
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DOI：
10.1371/journal.pone.0020975
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Gottlieb RA
中科院分区：
文献类型：
--
作者：
Huang C;Andres AM;Ratliff EP;Hernandez G;Lee P;Gottlieb RA
依赖自噬的线粒体翻转是维持细胞内环境稳定所必需的。然而，控制受损线粒体选择性靶向的机制却知之甚少。Parkin是一种E3泛素连接酶，已被证明对选择性清除受损的线粒体是必不可少的。Parkin在心脏中表达，但其功能尚未在心脏保护的背景下进行研究。我们以前曾报道，缺血预适应(IPC)对心脏的保护需要自噬。在本研究中，我们使用体外模拟缺血(Si)和心脏IPC来研究Parkin在体内外介导心脏保护中的作用。在HL-1细胞中，si诱导Parkin易位和线粒体消除。IPC可诱导朗宁多夫灌流的大鼠心脏和局部IPC小鼠体内的Parkin易位到线粒体。使用解偶联剂的线粒体去极化类似地诱导细胞和朗宁多夫灌流的大鼠心脏中的Parkin易位到线粒体。线粒体丢失在ATG5缺陷细胞中被钝化，揭示了在线粒体消除过程中需要自噬。与先前报道的p62/SQSTM1在吞噬有丝分裂中的作用一致，我们发现p62的缺失减弱了吞噬有丝分裂并加剧了SI后HL-1心肌细胞的死亡。野生型小鼠表现出p62易位到线粒体，泛素化增加，而Parkin基因敲除小鼠表现出IPC诱导的p62易位到线粒体的减弱。重要的是，切除小鼠的Parkin消除了IPC的心脏保护作用。这些结果首次揭示了Parkin和有丝分裂在心脏保护中的关键作用。
Autophagy-dependent mitochondrial turnover in response to cellular stress is necessary for maintaining cellular homeostasis. However, the mechanisms that govern the selective targeting of damaged mitochondria are poorly understood. Parkin, an E3 ubiquitin ligase, has been shown to be essential for the selective clearance of damaged mitochondria. Parkin is expressed in the heart, yet its function has not been investigated in the context of cardioprotection. We previously reported that autophagy is required for cardioprotection by ischemic preconditioning (IPC). In the present study, we used simulated ischemia (sI) in vitro and IPC of hearts to investigate the role of Parkin in mediating cardioprotection ex vivo and in vivo. In HL-1 cells, sI induced Parkin translocation to mitochondria and mitochondrial elimination. IPC induced Parkin translocation to mitochondria in Langendorff-perfused rat hearts and in vivo in mice subjected to regional IPC. Mitochondrial depolarization with an uncoupling agent similarly induced Parkin translocation to mitochondria in cells and Langendorff-perfused rat hearts. Mitochondrial loss was blunted in Atg5-deficient cells, revealing the requirement for autophagy in mitochondrial elimination. Consistent with previous reports indicating a role for p62/SQSTM1 in mitophagy, we found that depletion of p62 attenuated mitophagy and exacerbated cell death in HL-1 cardiomyocytes subjected to sI. While wild type mice showed p62 translocation to mitochondria and an increase in ubiquitination, Parkin knockout mice exhibited attenuated IPC-induced p62 translocation to the mitochondria. Importantly, ablation of Parkin in mice abolished the cardioprotective effects of IPC. These results reveal for the first time the crucial role of Parkin and mitophagy in cardioprotection.
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影响因子：
37.8
作者：
Huang C;Zhang X;Ramil JM;Rikka S;Kim L;Lee Y;Gude NA;Thistlethwaite PA;Sussman MA;Gottlieb RA;Gustafsson AB
通讯作者：
Gustafsson AB
p62/SQSTM1形成自噬降解的蛋白质聚集体，并对亨廷顿蛋白诱导的细胞死亡具有保护作用。
影响因子：
7.8
作者：
Bjorkoy, Geir;Lamark, Trond;Brech, Andreas;Outzen, Heidi;Perander, Maria;Overvatn, Aud;Stenmark, Harald;Johansen, Terje
通讯作者：
Johansen, Terje
DOI：
10.1083/jcb.200910140
发表时间：
2010-04-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Matsuda N;Sato S;Shiba K;Okatsu K;Saisho K;Gautier CA;Sou YS;Saiki S;Kawajiri S;Sato F;Kimura M;Komatsu M;Hattori N;Tanaka K
通讯作者：
Tanaka K
Parkin对泛素 - 蛋白酶体系统的广泛激活对于线粒体至关重要。
影响因子：
3.5
作者：
Chan NC;Salazar AM;Pham AH;Sweredoski MJ;Kolawa NJ;Graham RL;Hess S;Chan DC
通讯作者：
Chan DC
DOI：
10.1073/pnas.052713199
发表时间：
2002-03-05
影响因子：
11.1
作者：
Korge, P;Honda, HM;Weiss, JN
通讯作者：
Weiss, JN