Arsenic induces pancreatic dysfunction and ferroptosis via mitochondrial ROS-autophagy-lysosomal pathway

J Hazard Mater. 2020 Feb 15;384:121390. doi: 10.1016/j.jhazmat.2019.121390. Epub 2019 Oct 5.

Abstract

Chronic arsenic exposure is a significantly risk factor for pancreatic dysfunction and type 2 diabetes (T2D). Ferroptosis is a newly identified iron-dependent form of oxidative cell death that relies on lipid peroxidation. Previous data have indicated that ferroptosis is involved in various diseases, including cancers, neurodegenerative diseases, and T2D. However, the concrete effect and mechanism of ferroptosis on pancreatic dysfunction triggered by arsenic remains unknown. In this study, we verified that ferroptosis occurred in animal models of arsenic-induced pancreatic dysfunction through assessing proferroptotic markers and morphological changes in mitochondria. In vitro, arsenic caused execution of ferroptosis in a dose-dependent manner, which could be significantly reduced by ferrostatin-1. Additionally, arsenic damaged mitochondria manifested as diminishing of mitochondrial membrane potential, reduced cytochrome c level and production of mitochondrial reactive oxygen species (MtROS) in MIN6 cells. Using the Mito-TEMPO, we found the autophagy level and subsequent ferroptotic cell death induced by arsenic were both alleviated. With autophagy inhibitor chloroquine, we further revealed that ferritin regulated ferroptosis through the MtROS-autophagy pathway. Collectively, NaAsO2-induced ferroptotic cell death is relied on the MtROS-dependent autophagy by regulating the iron homeostasis. Ferroptosis is involved in pancreatic dysfunction triggered by arsenic, and arsenic-induced ferroptosis involves MtROS, autophagy, ferritin.

Keywords: Arsenic; Autophagy; Ferroptosis; Iron homeostasis; MtROS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arsenites / toxicity*
  • Autophagy / drug effects*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Ferroptosis / drug effects*
  • Insulin / blood
  • Iron / metabolism
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Lysosomes / drug effects*
  • Lysosomes / metabolism
  • Lysosomes / pathology
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • Pancreas / drug effects*
  • Pancreas / metabolism
  • Pancreas / pathology
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism*

Substances

  • Arsenites
  • Insulin
  • Reactive Oxygen Species
  • Iron
  • arsenite