SIRT3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin

Huifeng Pi, Shangcheng Xu, Russel J. Reiter, Pan Guo, Lei Zhang, Yuming Li, Min Li, Zhenwang Cao, Li Tian, Jia Xie, Ruiqi Zhang, Mindi He, Yonghui Lu, Chuan Liu, Weixia Duan, Zhengping Yu, Zhou Zhou

Research output: Contribution to journalArticlepeer-review

151 Scopus citations

Abstract

Cadmium is one of the most toxic metal compounds found in the environment. It is well established that Cd induces hepatotoxicity in humans and multiple animal models. Melatonin, a major secretory product of the pineal gland, has been reported to protect against Cd-induced hepatotoxicity. However, the mechanism behind this protection remains to be elucidated. We exposed HepG2 cells to different concentrations of cadmium chloride (2.5, 5, and 10 mM) for 12 h. We found that Cd induced mitochondrial-derived superoxide anion-dependent autophagic cell death. Specifically, Cd decreased SIRT3 protein expression and activity and promoted the acetylation of SOD2, superoxide dismutase 2, mitochondrial, thus decreasing its activity, a key enzyme involved in mitochondrial ROS production, although Cd did not disrupt the interaction between SIRT3 and SOD2. These effects were ameliorated by overexpression of SIRT3. However, a catalytic mutant of SIRT3 (SIRT3H248Y) lacking deacetylase activity lost the capacity to suppress Cd-induced autophagy. Notably, melatonin treatment enhanced the activity but not the expression of SIRT3, decreased the acetylation of SOD2, inhibited mitochondrial-derived O2 •¯ production and suppressed the autophagy induced by 10 mM Cd. Moreover, 3-(1H-1,2,3-triazol-4-yl)pyridine, a confirmed selective SIRT3 inhibitor, blocked the melatoninmediated suppression of autophagy by inhibiting SIRT3-SOD2 signaling. Importantly, melatonin suppressed Cd-induced autophagic cell death by enhancing SIRT3 activity in vivo. These results suggest that melatonin exerts a hepatoprotective effect on mitochondrial-derived O2 •¯-stimulated autophagic cell death that is dependent on the SIRT3/SOD2 pathway.

Original languageEnglish (US)
Pages (from-to)1037-1051
Number of pages15
JournalAutophagy
Volume11
Issue number7
DOIs
StatePublished - Jan 1 2015

Keywords

  • Autophagy
  • Cadmium
  • Hepatotoxicity
  • Melatonin
  • Mitochondrial ROS
  • SIRT3
  • SOD2

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'SIRT3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin'. Together they form a unique fingerprint.

Cite this