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

Abstract

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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Acknowledgements

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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Keywords

  • autophagy
  • mitophagy
  • Parkin
  • ubiquitin
  • cancer

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