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Time-Lapse Video Microscopy for Assessment of EYFP-Parkin Aggregation as a Marker for Cellular Mitophagy
Published on: May 4, 2016
Cadmium induces mitophagy through ROS-mediated PINK1/Parkin pathway
Xue Wei1, Yongmei Qi, Xiaoning Zhang
1Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University , Lanzhou , China.
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.
Insights
Cadmium (Cd) exposure induces mitophagy, a cellular cleaning process, in mouse kidneys. This occurs via reactive oxygen species (ROS) and the PINK1/Parkin pathway, offering insights into cadmium
Area of Science:
- Cell Biology
- Toxicology
- Molecular Biology
Background:
- Cadmium (Cd) is a toxic metal with known links to autophagy.
- The specific role of Cd in mitophagy, a selective form of autophagy targeting mitochondria, remains unclear.
Purpose of the Study:
- To investigate the effects of cadmium on mitophagy.
- To elucidate the underlying molecular mechanisms of Cd-induced mitophagy.
Main Methods:
- Mice were treated with cadmium (Cd).
- Evaluated mitochondrial membrane potential (MMP), mitophagosomes, LC3-II/LC3-I ratio, PINK1, and mitochondrial mass.
- Utilized ROS scavengers (NAC, ALC) and a mitophagy inhibitor (CsA) to explore mechanisms.
Main Results:
- Cd exposure induced mitophagy, evidenced by MMP collapse, mitophagosome formation, increased LC3-II/LC3-I ratio, and elevated PINK1.
- ROS scavengers (NAC, ALC) reduced Cd-induced ROS, restored MMP and mitochondrial mass, and decreased PINK1/Parkin levels.
- The mitophagy inhibitor CsA impaired Cd-induced mitophagy and PINK1/Parkin pathway activation without affecting ROS levels.
Conclusions:
- Cadmium induces mitophagy in mouse kidneys through a ROS-dependent mechanism.
- The PINK1/Parkin pathway is crucial for Cd-induced mitophagy, with ROS acting upstream.
- This study provides a new perspective on cadmium nephrotoxicity mechanisms.
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