PINK1 and PARK2 Suppress Pancreatic Tumorigenesis through Control of Mitochondrial Iron-Mediated Immunometabolism

Changfeng Li, Ying Zhang, Xing Cheng, Hua Yuan, Shan Zhu, Jiao Liu, Qirong Wen, Yangchun Xie, Jinbao Liu, Guido Kroemer, Daniel J. Klionsky, Michael T. Lotze, Herbert J. Zeh, Rui Kang, Daolin Tang

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Pancreatic cancer is an aggressive malignancy with changes in the tumor microenvironment. Here, we demonstrate that PINK1 and PARK2 suppressed pancreatic tumorigenesis through control of mitochondrial iron-dependent immunometabolism. Using mouse models of spontaneous pancreatic cancer, we show that depletion of Pink1 and Park2 accelerates mutant Kras-driven pancreatic tumorigenesis. PINK1-PARK2 pathway-mediated degradation of SLC25A37 and SLC25A28 increases mitochondrial iron accumulation, which leads to the HIF1A-dependent Warburg effect and AIM2-dependent inflammasome activation in tumor cells. AIM2-mediated HMGB1 release further induces expression of CD274/PD-L1. Consequently, pharmacological administration of mitochondrial iron chelator, anti-HMGB1 antibody, or genetic depletion of Hif1a or Aim2 in pink1−/− and park2−/− mice confers protection against pancreatic tumorigenesis. Low PARK2 expression and high SLC25A37 and AIM2 expression are associated with poor prognosis in patients with pancreatic cancer. These findings suggest that disrupted mitochondrial iron homeostasis may contribute to cancer development and hence constitute a target for therapeutic intervention. Li et al. demonstrate in mouse models that Pink1 and Park2 deficiency accelerates pancreatic tumorigenesis through mitochondrial iron-dependent immunometabolic dysfunction. These findings shed light on how the autophagy pathway controls iron homeostasis and could have implications for the development of strategies to target mitochondrial iron metabolism in pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)441-455.e8
JournalDevelopmental cell
Volume46
Issue number4
DOIs
StatePublished - Aug 20 2018
Externally publishedYes

Keywords

  • aim2
  • hmgb1
  • immunosuppression
  • inflammasomes
  • iron
  • mitochondrial quality control
  • mitophagy
  • pancreatic tumorigenesis
  • park2
  • pink1

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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    Li, C., Zhang, Y., Cheng, X., Yuan, H., Zhu, S., Liu, J., Wen, Q., Xie, Y., Liu, J., Kroemer, G., Klionsky, D. J., Lotze, M. T., Zeh, H. J., Kang, R., & Tang, D. (2018). PINK1 and PARK2 Suppress Pancreatic Tumorigenesis through Control of Mitochondrial Iron-Mediated Immunometabolism. Developmental cell, 46(4), 441-455.e8. https://doi.org/10.1016/j.devcel.2018.07.012