Somatic and germline mutations in the tumor suppressor gene PARK2 impair PINK1/Parkin-mediated mitophagy in lung cancer cells


PARK2, which encodes Parkin, is a disease-causing gene for both neurodegenerative disorders and cancer. Parkin can function as a neuroprotector that plays a crucial role in the regulation of mitophagy, and germline mutations in PARK2 are associated with Parkinson’s disease (PD). Intriguingly, recent studies suggest that Parkin can also function as a tumor suppressor and that somatic and germline mutations in PARK2 are associated with various human cancers, including lung cancer. However, it is presently unknown how the tumor suppressor activity of Parkin is affected by these mutations and whether it is associated with mitophagy. Herein, we show that wild-type (WT) Parkin can rapidly translocate onto mitochondria following mitochondrial damage and that Parkin promotes mitophagic clearance of mitochondria in lung cancer cells. However, lung cancer-linked mutations inhibit the mitochondrial translocation and ubiquitin-associated activity of Parkin. Among all lung cancer-linked mutants that we tested, A46T Parkin failed to translocate onto mitochondria and could not recruit downstream mitophagic regulators, including optineurin (OPTN) and TFEB, whereas N254S and R275W Parkin displayed slower mitochondrial translocation than WT Parkin. Moreover, we found that deferiprone (DFP), an iron chelator that can induce mitophagy, greatly increased the death of A46T Parkin-expressing lung cancer cells. Taken together, our results reveal a novel mitophagic mechanism in lung cancer, suggesting that lung cancer-linked mutations in PARK2 are associated with impaired mitophagy and identifying DFP as a novel therapeutic agent for PARK2-linked lung cancer and possibly other types of cancers driven by mitophagic dysregulation.

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  1. 1.

    McWilliams TG, Muqit MM. PINK1 and Parkin: emerging themes in mitochondrial homeostasis. Curr Opin Cell Biol. 2017;45:83–91.

  2. 2.

    Harper JW, Ordureau A, Heo JM. Building and decoding ubiquitin chains for mitophagy. Nat Rev Mol Cell Biol. 2018;19:93–108.

  3. 3.

    Walden H, Muqit MM. Ubiquitin and Parkinson’s disease through the looking glass of genetics. Biochem J. 2017;474:1439–51.

  4. 4.

    Zhang C, Lin M, Wu R, Wang X, Yang B, Levine AJ, et al. Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proc Natl Acad Sci USA. 2011;108:16259–64.

  5. 5.

    Fujiwara M, Marusawa H, Wang HQ, Iwai A, Ikeuchi K, Imai Y, et al. Parkin as a tumor suppressor gene for hepatocellular carcinoma. Oncogene. 2008;27:6002–11.

  6. 6.

    Picchio MC, Martin ES, Cesari R, Calin GA, Yendamuri S, Kuroki T, et al. Alterations of the tumor suppressor gene Parkin in non-small cell lung cancer. Clin Cancer Res. 2004;10:2720–4.

  7. 7.

    Bernardini JP, Lazarou M, Dewson G. Parkin and mitophagy in cancer. Oncogene. 2017;36:1315–27.

  8. 8.

    Veeriah S, Taylor BS, Meng S, Fang F, Yilmaz E, Vivanco I, et al. Somatic mutations of the Parkinson’s disease-associated gene PARK2 in glioblastoma and other human malignancies. Nat Genet. 2010;42:77–82.

  9. 9.

    Xiong D, Wang Y, Kupert E, Simpson C, Pinney SM, Gaba CR, et al. A recurrent mutation in PARK2 is associated with familial lung cancer. Am J Hum Genet. 2015;96:301–8.

  10. 10.

    Yeo CW, Ng FS, Chai C, Tan JM, Koh GR, Chong YK, et al. Parkin pathway activation mitigates glioma cell proliferation and predicts patient survival. Cancer Res. 2012;72:2543–53.

  11. 11.

    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.

  12. 12.

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

  13. 13.

    Dikic I, Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol. 2018;19:349–64.

  14. 14.

    Levine B, Kroemer G. Biological functions of autophagy genes: a disease perspective. Cell. 2019;176:11–42.

  15. 15.

    Wauer T, Simicek M, Schubert A, Komander D. Mechanism of phospho-ubiquitin-induced PARKIN activation. Nature. 2015;524:370–4.

  16. 16.

    Kane LA, Lazarou M, Fogel AI, Li Y, Yamano K, Sarraf SA, et al. PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J Cell Biol. 2014;205:143–53.

  17. 17.

    Lazarou M, Sliter DA, Kane LA, Sarraf SA, Wang C, Burman JL, et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature. 2015;524:309–14.

  18. 18.

    Wong YC, Holzbaur EL. Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation. Proc Natl Acad Sci USA. 2014;111:E4439–48.

  19. 19.

    Moore AS, Holzbaur EL. Dynamic recruitment and activation of ALS-associated TBK1 with its target optineurin are required for efficient mitophagy. Proc Natl Acad Sci USA. 2016;113:E3349–58.

  20. 20.

    Nezich CL, Wang C, Fogel AI, Youle RJ. MiT/TFE transcription factors are activated during mitophagy downstream of Parkin and Atg5. J Cell Biol. 2015;210:435–50.

  21. 21.

    Allen GF, Toth R, James J, Ganley IG. Loss of iron triggers PINK1/Parkin-independent mitophagy. EMBO Rep. 2013;14:1127–35.

  22. 22.

    Ying Z, Wang H, Fan H, Zhu X, Zhou J, Fei E, et al. Gp78, an ER associated E3, promotes SOD1 and ataxin-3 degradation. Hum Mol Genet. 2009;18:4268–81.

  23. 23.

    Ying Z, Wang H, Fan H, Wang G. The endoplasmic reticulum (ER)-associated degradation system regulates aggregation and degradation of mutant neuroserpin. J Biol Chem. 2011;286:20835–44.

  24. 24.

    Wang H, Ying Z, Wang G. Ataxin-3 regulates aggresome formation of copper–zinc superoxide dismutase (SOD1) by editing K63-linked polyubiquitin chains. J Biol Chem. 2012;287:28576–85.

  25. 25.

    Tao Z, Wang H, Xia Q, Li K, Jiang X, Xu G, et al. Nucleolar stress and impaired stress granule formation contribute to C9orf72 RAN translation-induced cytotoxicity. Hum Mol Genet. 2015;24:2426–41.

  26. 26.

    Xia Q, Wang G, Wang H, Hu Q, Ying Z. Folliculin, a tumor suppressor associated with Birt–Hogg–Dube (BHD) syndrome, is a novel modifier of TDP-43 cytoplasmic translocation and aggregation. Hum Mol Genet. 2016;25:83–96.

  27. 27.

    Xia Q, Wang H, Hao Z, Fu C, Hu Q, Gao F, et al. TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion. EMBO J. 2016;35:121–42.

  28. 28.

    Zhou L, Wang HF, Ren HG, Chen D, Gao F, Hu QS, et al. Bcl-2-dependent upregulation of autophagy by sequestosome 1/p62 in vitro. Acta Pharmacol Sin. 2013;34:651–6.

  29. 29.

    Lv G, Sun D, Zhang J, Xie X, Wu X, Fang W, et al. Lx2-32c, a novel semi-synthetic taxane, exerts antitumor activity against prostate cancer cells in vitro and in vivo. Acta Pharm Sin B. 2017;7:52–8.

  30. 30.

    Liu D, Tang H, Li XY, Deng MF, Wei N, Wang X, et al. Targeting the HDAC2/HNF-4A/miR-101b/AMPK pathway rescues tauopathy and dendritic abnormalities in Alzheimer’s disease. Mol Ther. 2017;25:752–64.

  31. 31.

    Yang Y, Guan D, Lei L, Lu J, Liu JQ, Yang G, et al. H6, a novel hederagenin derivative, reverses multidrug resistance in vitro and in vivo. Toxicol Appl Pharm. 2018;341:98–105.

  32. 32.

    Wang X, Liu D, Huang HZ, Wang ZH, Hou TY, Yang X, et al. A novel microRNA-124/PTPN1 signal pathway mediates synaptic and memory deficits in Alzheimer’s disease. Biol Psychiatry. 2018;83:395–405.

  33. 33.

    Su Y, Deng MF, Xiong W, Xie AJ, Guo J, Liang ZH, et al. MicroRNA-26a/death-associated protein kinase 1 signaling induces synucleinopathy and dopaminergic neuron degeneration in Parkinson’s disease. Biol Psychiatry. 2019;85:769–81.

  34. 34.

    Wu JC, Qi L, Wang Y, Kegel KB, Yoder J, Difiglia M, et al. The regulation of N-terminal Huntingtin (Htt552) accumulation by Beclin1. Acta Pharmacol Sin. 2012;33:743–51.

  35. 35.

    Ren ZX, Zhao YF, Cao T, Zhen XC. Dihydromyricetin protects neurons in an MPTP-induced model of Parkinson’s disease by suppressing glycogen synthase kinase-3 beta activity. Acta Pharmacol Sin. 2016;37:1315–24.

  36. 36.

    Fang LM, Li B, Guan JJ, Xu HD, Shen GH, Gao QG, et al. Transcription factor EB is involved in autophagy-mediated chemoresistance to doxorubicin in human cancer cells. Acta Pharmacol Sin. 2017;38:1305–16.

  37. 37.

    Sun N, Malide D, Liu J, Rovira II, Combs CA, Finkel T. A fluorescence-based imaging method to measure in vitro and in vivo mitophagy using mt-Keima. Nat Protoc. 2017;12:1576–87.

  38. 38.

    Chen Y, Xu S, Wang N, Ma Q, Peng P, Yu Y, et al. Dynasore suppresses mTORC1 activity and induces autophagy to regulate the clearance of protein aggregates in neurodegenerative diseases. Neurotox Res. 2019; in press.

  39. 39.

    Sentelle RD, Senkal CE, Jiang W, Ponnusamy S, Gencer S, Selvam SP, et al. Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy. Nat Chem Biol. 2012;8:831–8.

  40. 40.

    Georgakopoulos ND, Wells G, Campanella M. The pharmacological regulation of cellular mitophagy. Nat Chem Biol. 2017;13:136–46.

  41. 41.

    Narendra D, Kane LA, Hauser DN, Fearnley IM, Youle RJ. p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy. 2010;6:1090–106.

  42. 42.

    Pickrell AM, Huang CH, Kennedy SR, Ordureau A, Sideris DP, Hoekstra JG, et al. Endogenous Parkin preserves dopaminergic substantia nigral neurons following mitochondrial DNA mutagenic stress. Neuron. 2015;87:371–81.

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This work was supported by the National Natural Science Foundation of China (Nos. 31771117, 31701222 and 31571053), the National Key Plan for Scientific Research and Development of China (No. 2017YFC0909100), a Project Funded by Jiangsu Key Laboratory of Neuropsychiatric Diseases (BM2013003) and a Project Funded by the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD).

Author information

ZY, HFW, MHS and QSL designed the experiments and drafted the manuscript; ZLZ, NNW, QLM, YC, LY and LZ performed the experiments.

Correspondence to Hong-feng Wang or Zheng Ying.

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The authors declare no competing interests.

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Zhang, Z., Wang, N., Ma, Q. et al. Somatic and germline mutations in the tumor suppressor gene PARK2 impair PINK1/Parkin-mediated mitophagy in lung cancer cells. Acta Pharmacol Sin 41, 93–100 (2020) doi:10.1038/s41401-019-0260-6

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  • autophagy
  • mitophagy
  • Parkin
  • ubiquitin
  • cancer

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