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

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.

• Authors: 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
• Journal: Developmental cell (Dev Cell) Vol. 46 Issue 4 Pg. 441-455.e8 (08 20 2018) ISSN: 1878-1551 [Electronic] United States
• PMID: 30100261 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Mitochondrial Proteins
• Iron
• Ubiquitin-Protein Ligases
• parkin protein
• Protein Kinases
• PTEN-induced putative kinase

Topics

• Animals
• Autophagy (physiology)
• Carcinogenesis (metabolism)
• Cell Transformation, Neoplastic (pathology)
• Iron (metabolism)
• Mice, Transgenic
• Mitochondria (genetics, metabolism)
• Mitochondrial Proteins (metabolism)
• Mitophagy (genetics)
• Protein Kinases (genetics, metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)