Mitochondrial fission and mitophagy depend on cofilin-mediated actin depolymerization activity at the mitochondrial fission site
Mitochondrial fission and mitophagy depend on cofilin-mediated actin depolymerization activity at the mitochondrial fission site
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线粒体裂变和线粒体自噬取决于线粒体裂变位点丝切蛋白介导的肌动蛋白解聚活性
DOI：
10.1038/s41388-017-0064-4
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发表时间：
2018-03-01
期刊：
影响因子：
8
通讯作者：
Gao, Ning
中科院分区：
文献类型：
--
作者：
Li, Guo-Bing;Zhang, Hong-Wei;Gao, Ning
线粒体分裂和线粒体自噬对细胞生理学至关重要，并在癌症进展中发挥重要作用。全面了解线粒体分裂和线粒体自噬的分子机制将为癌症的预防和治疗提供新的策略。肌动蛋白已被证明参与线粒体分裂和线粒体自噬调节。Cofilin是最有名的肌动蛋白解聚因子。然而，cofilin调节线粒体分裂和线粒体自噬的分子机制在很大程度上仍然未知。在这里，我们报告敲除cofilin减弱和cofilin的过度表达增强线粒体分裂以及PINK 1/PARK 2依赖性线粒体自噬诱导的星形孢菌素（STS），依托泊苷（ETO），和羰基氰3-氯苯腙（CCCP）。Cofilin介导的PINK 1（PTEN诱导的推定激酶1）积累主要依赖于其通过线粒体膜电位活性调节线粒体蛋白酶，包括肽酶线粒体加工β（MPPβ）、早老蛋白相关菱形样蛋白酶（PARL）和ATP酶家族基因3样2（AFG 3L 2）。我们还发现CCCP处理后，G-actin/F-actin与cofilin在线粒体分裂位点的相互作用和共定位发生收缩。用肌动蛋白聚合抑制剂latrunculin B（LatB）预处理可增加STS、ETO和CCCP诱导的线粒体肌动蛋白转位，而肌动蛋白解聚抑制剂jasplakinase（Jas）则可减少STS、ETO和CCCP诱导的线粒体肌动蛋白转位。LatB和Jas都能抑制CCCP介导的线粒体分裂和线粒体自噬。我们的数据表明，G-肌动蛋白是肌动蛋白的形式，是易位到线粒体，肌动蛋白解聚活性调节的cofilin在线粒体分裂位点是至关重要的诱导线粒体分裂和线粒体自噬。
Mitochondria fission and mitophagy are fundamentally crucial to cellular physiology and play important roles in cancer progression. Developing a comprehensive understanding of the molecular mechanism underlying mitochondrial fission and mitophagy will provide novel strategies for cancer prevention and treatment. Actin has been shown to participate in mitochondrial fission and mitophagy regulation. Cofilin is best known as an actin-depolymerizing factor. However, the molecular mechanism by which cofilin regulates mitochondrial fission and mitophagy remains largely unknown. Here we report that knockdown of cofilin attenuates and overexpression of cofilin potentiates mitochondrial fission as well as PINK1/PARK2-dependent mitophagy induced by staurosporine (STS), etoposide (ETO), and carbonyl cyanide 3-chlorophenylhydrazone (CCCP). Cofilin-mediated-PINK1 (PTEN-induced putative kinase 1) accumulation mainly depends on its regulation of mitochondrial proteases, including peptidase mitochondrial processing beta (MPPβ), presenilin-associated rhomboid-like protease (PARL), and ATPase family gene 3-like 2 (AFG3L2), via mitochondrial membrane potential activity. We also found that the interaction and colocalization of G-actin/F-actin with cofilin at mitochondrial fission sites undergo constriction after CCCP treatment. Pretreatment with the actin polymerization inhibitor latrunculin B (LatB) increased and actin-depolymerization inhibitor jasplakinolide (Jas) decreased mitochondrial translocation of actin induced by STS, ETO, and CCCP. Both LatB and Jas abrogated CCCP-mediated mitochondrial fission and mitophagy. Our data suggest that G-actin is the actin form that is translocated to mitochondria, and the actin-depolymerization activity regulated by cofilin at the mitochondrial fission site is crucial for inducing mitochondrial fission and mitophagy.