1. Arsenic induces pancreatic dysfunction and ferroptosis via mitochondrial ROS-autophagy-lysosomal pathway.
- Author
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Wei S, Qiu T, Yao X, Wang N, Jiang L, Jia X, Tao Y, Wang Z, Pei P, Zhang J, Zhu Y, Yang G, Liu X, Liu S, and Sun X
- Subjects
- Animals, Cell Line, Tumor, Cell Survival drug effects, Dose-Response Relationship, Drug, Insulin blood, Iron metabolism, Islets of Langerhans drug effects, Islets of Langerhans metabolism, Islets of Langerhans pathology, Lysosomes metabolism, Lysosomes pathology, Male, Membrane Potential, Mitochondrial drug effects, Mice, Mitochondria metabolism, Mitochondria ultrastructure, Pancreas metabolism, Pancreas pathology, Rats, Sprague-Dawley, Arsenites toxicity, Autophagy drug effects, Ferroptosis drug effects, Lysosomes drug effects, Mitochondria drug effects, Pancreas drug effects, Reactive Oxygen Species metabolism
- 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, NaAsO
2 -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., (Copyright © 2019 Elsevier B.V. All rights reserved.)- Published
- 2020
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