Cadmium induces mitophagy through ROS-mediated PINK1/Parkin pathway

Abstract

Context and objective: Recent reports have highlighted the relationship between cadmium (Cd) and autophagy, however, whether Cd can activate mitophagy remains enigmatic. This study aims to investigate the effects of Cd on mitophagy and its potential mechanism.

Methods: Mice were intraperitoneally injected with Cd for 3 d. Mitochondrial membrane potential (MMP), mitophagosomes, LC3-II/LC3-I ratio, PINK1 level and mitochondrial mass were evaluated to indicate the effects of Cd on mitophagy. To elucidate the mechanism, reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC) or acetyl-l-carnitine (ALC) as well as the mitophagy inhibitor cyclosporine A (CsA) were introduced to verify the role of ROS in mitophagy.

Results and conclusions: The results showed that Cd significantly induced MMP collapse and typical mitophagosomes formation, increased LC3-II/LC3-I ratio and PINK1 level, and decreased mitochondrial mass, revealing that Cd could induce mitophagy. However, NAC or ALC pretreatment markedly decreased Cd-induced ROS and simultaneously rescued MMP and mitochondrial mass, suggesting ROS played a crucial role in regulating mitophagy. NAC or ALC also dramatically lessened PINK1 level and mitochondrial accumulation of Parkin, indicating that ROS were related to PINK1/Parkin pathway. Notably, CsA compromised Cd-induced mitophagy, PINK1 accumulation and Parkin translocation while failed to block ROS increase, suggesting ROS functioned as an upstream signal for PINK1/Parkin pathway. Taken together, the results indicated that Cd induced ROS-mediated mitophagy through PINK1/Parkin pathway in kidneys of mice. The present study proposes a new perspective to evaluate the nephrotoxicity and its molecular mechanism under Cd exposure in vivo.

• Cadmium
• mitophagy
• mouse
• PINK1/Parkin pathway
• ROS

Acknowledgements

We would like to thank Dr. Prof. Shengxiang Zhang (School of Life Sciences, Lanzhou University) for his valuable comments.