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

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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 (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.

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

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References

  1. Wang C, Youle RJ. The role of mitochondria in apoptosis*. Annu Rev Genet. 2009;43:95–118.

    Article  CAS  Google Scholar 

  2. van Raam BJ, Verhoeven AJ, Kuijpers TW. Mitochondria in neutrophil apoptosis. Int J Hematol. 2006;84:199–204.

    Article  Google Scholar 

  3. Jeong SY, Seol DW. The role of mitochondria in apoptosis. BMB Rep. 2008;41:11–22.

    Article  CAS  Google Scholar 

  4. Pereira C, Silva RD, Saraiva L, Johansson B, Sousa MJ, Corte-Real M. Mitochondria-dependent apoptosis in yeast. Biochim Biophys Acta. 2008;1783:1286–302.

    Article  CAS  Google Scholar 

  5. Karbowski M. Mitochondria on guard: role of mitochondrial fusion and fission in the regulation of apoptosis. Adv Exp Med Biol. 2010;687:131–42.

    Article  CAS  Google Scholar 

  6. Vyas S, Zaganjor E, Haigis MC. Mitochondria and cancer. Cell. 2016;166:555–66.

    Article  CAS  Google Scholar 

  7. Seo AY, Joseph AM, Dutta D, Hwang JC, Aris JP, Leeuwenburgh C. New insights into the role of mitochondria in aging: mitochondrial dynamics and more. J Cell Sci. 2010;123:2533–42.

    Article  CAS  Google Scholar 

  8. Kasahara A, Scorrano L. Mitochondria: from cell death executioners to regulators of cell differentiation. Trends Cell Biol. 2014;24:761–70.

    Article  CAS  Google Scholar 

  9. Ban-Ishihara R, Ishihara T, Sasaki N, Mihara K, Ishihara N. Dynamics of nucleoid structure regulated by mitochondrial fission contributes to cristae reformation and release of cytochrome c. Proc Natl Acad Sci USA. 2013;110:11863–8.

    Article  CAS  Google Scholar 

  10. Estaquier J, Arnoult D. Inhibiting Drp1-mediated mitochondrial fission selectively prevents the release of cytochrome c during apoptosis. Cell Death Differ. 2007;14:1086–94.

    Article  CAS  Google Scholar 

  11. Li S, Xu S, Roelofs BA, Boyman L, Lederer WJ, Sesaki H, et al. Transient assembly of F-actin on the outer mitochondrial membrane contributes to mitochondrial fission. J Cell Biol. 2015;208:109–23.

    Article  CAS  Google Scholar 

  12. Hatch AL, Gurel PS, Higgs HN. Novel roles for actin in mitochondrial fission. J Cell Sci. 2014;127:4549–60.

    Article  Google Scholar 

  13. De Vos KJ, Allan VJ, Grierson AJ, Sheetz MP. Mitochondrial function and actin regulate dynamin-related protein 1-dependent mitochondrial fission. Curr Biol. 2005;15:678–83.

    Article  Google Scholar 

  14. Ji WK, Hatch AL, Merrill RA, Strack S, Higgs HN, Actin filaments target the oligomeric maturation of the dynamin GTPase Drp1 to mitochondrial fission sites. Elife. 2015;4:e11553

    Article  Google Scholar 

  15. Korobova F, Ramabhadran V, Higgs HN. An actin-dependent step in mitochondrial fission mediated by the ER-associated formin INF2. Science. 2013;339:464–7.

    Article  CAS  Google Scholar 

  16. Beck H, Flynn K, Lindenberg KS, Schwarz H, Bradke F, Di Giovanni S, et al. Serum response factor (SRF)-cofilin-actin signaling axis modulates mitochondrial dynamics. Proc Natl Acad Sci USA. 2012;109:E2523–32.

    Article  CAS  Google Scholar 

  17. Ding WX, Yin XM. Mitophagy: mechanisms, pathophysiological roles, and analysis. Biol Chem. 2012;393:547–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Ashrafi G, Schwarz TL. The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. 2013;20:31–42.

    Article  CAS  Google Scholar 

  19. de Vries RL, Przedborski S. Mitophagy and Parkinson’s disease: be eaten to stay healthy. Mol Cell Neurosci. 2013;55:37–43.

    Article  Google Scholar 

  20. Greene AW, Grenier K, Aguileta MA, Muise S, Farazifard R, Haque ME, et al. Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment. EMBO Rep. 2012;13:378–85.

    Article  CAS  Google Scholar 

  21. Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2011;12:9–14.

    Article  CAS  Google Scholar 

  22. Chen H, Chan DC. Mitochondrial dynamics--fusion, fission, movement, and mitophagy--in neurodegenerative diseases. Hum Mol Genet. 2009;18:R169–76.

    Article  CAS  Google Scholar 

  23. Kast DJ, Dominguez R. WHAMM links actin assembly via the Arp2/3 complex to autophagy. Autophagy. 2015;11:1702–4.

    Article  CAS  Google Scholar 

  24. Aguilera MO, Beron W, Colombo MI. The actin cytoskeleton participates in the early events of autophagosome formation upon starvation induced autophagy. Autophagy. 2012;8:1590–603.

    Article  CAS  Google Scholar 

  25. Bernstein BW, Bamburg JR. ADF/cofilin: a functional node in cell biology. Trends Cell Biol. 2010;20:187–95.

    Article  CAS  Google Scholar 

  26. Chua BT, Volbracht C, Tan KO, Li R, Yu VC, Li P. Mitochondrial translocation of cofilin is an early step in apoptosis induction. Nat Cell Biol. 2003;5:1083–9.

    Article  CAS  Google Scholar 

  27. Kim JE, Ryu HJ, Kim MJ, Kang TC. LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission. Cell Death Differ. 2014;21:1036–49.

    Article  CAS  Google Scholar 

  28. Li G, Zhou J, Budhraja A, Hu X, Chen Y, Cheng Q, et al. Mitochondrial translocation and interaction of cofilin and Drp1 are required for erucin-induced mitochondrial fission and apoptosis. Oncotarget. 2015;6:1834–49.

    PubMed  Google Scholar 

  29. Preau S, Delguste F, Yu Y, Remy-Jouet I, Richard V, Saulnier F, et al. Endotoxemia engages the rhoa kinase pathway to impair cardiac function by altering cytoskeleton, mitochondrial fission, and autophagy. Antioxid Redox Signal. 2016;24:529–42.

    Article  CAS  Google Scholar 

  30. Pi H, Xu S, Zhang L, Guo P, Li Y, Xie J, et al. Dynamin 1-like-dependent mitochondrial fission initiates overactive mitophagy in the hepatotoxicity of cadmium. Autophagy. 2013;9:1780–800.

    Article  CAS  Google Scholar 

  31. Frank M, Duvezin-Caubet S, Koob S, Occhipinti A, Jagasia R, Petcherski A, et al. Mitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner. Biochim Biophys Acta. 2012;1823:2297–310.

    Article  CAS  Google Scholar 

  32. Jin SM, Lazarou M, Wang C, Kane LA, Narendra DP, Youle RJ. Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J Cell Biol. 2010;191: 933–42.

    Article  CAS  Google Scholar 

  33. Springer W, Kahle PJ. Regulation of PINK1-Parkin-mediated mitophagy. Autophagy. 2011;7:266–78.

    Article  CAS  Google Scholar 

  34. Sekino Y, Kojima N, Shirao T. Role of actin cytoskeleton in dendritic spine morphogenesis. Neurochem Int. 2007;51:92–104.

    Article  CAS  Google Scholar 

  35. Campello S, Strappazzon F, Cecconi F. Mitochondrial dismissal in mammals, from protein degradation to mitophagy. Biochim Biophys Acta. 2014;1837:451–60.

    Article  CAS  Google Scholar 

  36. Bordi M, Nazio F, Campello S. The close interconnection between mitochondrial dynamics and mitophagy in cancer. Front Oncol. 2017;7:81.

    Article  Google Scholar 

  37. Senft D, Ronai ZA. Regulators of mitochondrial dynamics in cancer. Curr Opin Cell Biol. 2016;39:43–52.

    Article  CAS  Google Scholar 

  38. Chourasia AH, Boland ML, Macleod KF. Mitophagy and cancer. Cancer & Metab. 2015;3:4.

    Article  Google Scholar 

  39. Kulikov AV, Luchkina EA, Gogvadze V, Zhivotovsky B. Mitophagy: Link to cancer development and therapy. Biochem Biophys Res Commun. 2017;482:432–9.

    Article  CAS  Google Scholar 

  40. Zhu JS, Ouyang DY, Shi ZJ, Xu LH, Zhang YT, He XH. Cucurbitacin B induces cell cycle arrest, apoptosis and autophagy associated with G actin reduction and persistent activation of cofilin in Jurkat cells. Pharmacology. 2012;89:348–56.

    Article  CAS  Google Scholar 

  41. Yamaguchi H, Condeelis J. Regulation of the actin cytoskeleton in cancer cell migration and invasion. Biochim Biophys Acta. 2007;1773:642–52.

    Article  CAS  Google Scholar 

  42. Nagai S, Moreno O, Smith CA, Ivanchuk S, Romagnuolo R, Golbourn B, et al. Role of the cofilin activity cycle in astrocytoma migration and invasion. Genes Cancer. 2011;2:859–69.

    Article  CAS  Google Scholar 

  43. Huttemann M, Lee I, Pecinova A, Pecina P, Przyklenk K, Doan JW. Regulation of oxidative phosphorylation, the mitochondrial membrane potential, and their role in human disease. J Bioenerg Biomembr. 2008;40:445–56.

    Article  CAS  Google Scholar 

  44. Ly JD, Grubb DR, Lawen A. The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis. 2003;8: 115–28.

    Article  CAS  Google Scholar 

  45. Matsuda S, Nakanishi A, Minami A, Wada Y, Kitagishi Y. Functions and characteristics of PINK1 and Parkin in cancer. Front Biosci (Landmark Ed). 2015;20:491–501.

    Article  CAS  Google Scholar 

  46. O’Flanagan CH, O’Neill C. PINK1 signalling in cancer biology. Biochim Biophys Acta. 2014;1846:590–8.

    PubMed  Google Scholar 

  47. Fedorowicz MA, de Vries-Schneider RL, Rub C, Becker D, Huang Y, Zhou C, et al. Cytosolic cleaved PINK1 represses Parkin translocation to mitochondria and mitophagy. EMBO Rep. 2014;15:86–93.

    Article  CAS  Google Scholar 

  48. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 2010;8:e1000298

    Article  Google Scholar 

  49. Pon LA. Mitochondrial fission: rings around the organelle. Curr Biol. 2013;23:R279–81.

    Article  CAS  Google Scholar 

  50. Korobova F, Gauvin TJ, Higgs HN. A role for myosin II in mammalian mitochondrial fission. Curr Biol. 2014;24:409–14.

    Article  CAS  Google Scholar 

  51. Li GB, Cheng Q, Liu L, Zhou T, Shan CY, Hu XY, et al. Mitochondrial translocation of cofilin is required for allyl isothiocyanate-mediated cell death via ROCK1/PTEN/PI3K signaling pathway. Cell Commun Signal. 2013;11:50.

    Article  Google Scholar 

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

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

    Guo-Bing Li & 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, 1485–1502 (2018). https://doi.org/10.1038/s41388-017-0064-4

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