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Mitochondrial fission and mitophagy depend on cofilin-mediated actin depolymerization activity at the mitochondrial fission site

Oncogene volumeĀ 37,Ā pages 1485ā€“1502 (2018)Cite this article

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Abstract

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 (MPPĪ²), 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.

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Fig. 9: A proposed model of cofilin-mediated mitochondrial fission and mitophagy.

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Acknowledgements

We thank James Bamburg (University of Wisconsin) for providing Cofilin-WT; Tamotsu Yoshimori (Osaka University) for RFP-LC3, and Nico Dantuma (Karolinska Institutet) for GFP-UB. This study was supported by the grants from National Natural Science Foundation of China (31571425; 81402970; 81402013) and Clinical Research Projects of Xinqiao Hospital, Third Military Medical University (2016YLC12).

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  1. Guo-Bing Li and Hong-Wei Zhang contributed equally to this work.

Authors and Affiliations

  1. College of Pharmacy, Third Military Medical University, Chongqing, China

    Guo-Bing Li,Ā Hong-Wei Zhang,Ā Ruo-Qiu Fu,Ā Xiao-Ye Hu,Ā Lei Liu,Ā Yu-Nong Li,Ā Yan-Xia Liu,Ā Xin Liu,Ā Jin-Jiao Hu,Ā Qin Deng,Ā Qing-Song LuoĀ &Ā Ning Gao

  2. Department of Pharmacy, The Second Affiliated Hospital of Third Military Medical University, Chongqing, China

    Guo-Bing LiĀ &Ā Rong Zhang

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Li, GB., Zhang, HW., Fu, RQ. et al. Mitochondrial fission and mitophagy depend on cofilin-mediated actin depolymerization activity at the mitochondrial fission site. Oncogene 37, 1485ā€“1502 (2018). https://doi.org/10.1038/s41388-017-0064-4

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