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Molybdenum and cadmium co-induce mitophagy and mitochondrial dysfunction via ROS-mediated PINK1/Parkin pathway in
He Bai1, Fan Yang2, Wenjuan Jiang3
1Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Economic and Technological Development District, Nanchang 330045, Jiangxi, PR China; Medical Research Center, Mudanjiang Medical University, No. 3 Tongxiang street, Aimin District, Mudanjiang 157011, Heilongjiang, PR China.
Abstract:
Excessive molybdenum (Mo) and Cadmium (Cd) can adversely affect health status. However, the correlation between mitophagy and mitochondrial dysfunction caused by Mo and Cd and the underlying mechanisms are still unknown. The aim of this study was to investigate the relationship between mitophagy and mitochondrial dysfunction via the ROS-mediated PINK1/Parkin pathway caused by Mo and Cd. Here, Hepa1-6 cells were incubated with (NH4)6Mo7O24.4 H2O (600.0 μM Mo), CdCl2 (10.0 μM Cd), and the combination of reactive oxygen species (ROS) scavenger (N-acetyl-L-cysteine, NAC, 100.0 μM), or mitophagy inhibitor (Cyclosporin A, CsA, 1.0 μM) for 24 h. Results revealed that Mo or/and Cd elevated the level of intracellular ROS and malondialdehyde (MDA) content, reduced superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities. Additionally, Mo or/and Cd could observably increase the percentage of cells with low membrane potential and decrease the content of ATP, elevate the number of autophagosomes and LC3 puncta, upregulate the mRNA and protein levels of LC3II/LC3I, Parkin, Pink1, VDAC1, downregulate mRNA and protein levels of P62. Moreover, treatments with NAC could significantly alleviate the changes of the above factors co-induced by Mo and Cd, and CsA intensify the changes of the above factors. In summary, our results reveal that Mo and Cd co-exposure can cause oxidative stress and mitophagy via the ROS-mediated PINK1/Parkin pathway in Hepa1-6 cells, and inhibition of mitophagy aggravates Mo and Cd co-induced mitochondrial dysfunction.
Insights
Excessive molybdenum and cadmium exposure cause oxidative stress and mitophagy via the ROS-mediated PINK1/Parkin pathway. Inhibiting mitophagy worsens mitochondrial dysfunction from these heavy metals.
Area of Science:
- Toxicology
- Cell Biology
- Biochemistry
Background:
- Heavy metals like molybdenum (Mo) and cadmium (Cd) pose health risks.
- Mechanisms linking Mo/Cd-induced mitochondrial dysfunction and mitophagy remain unclear.
- Oxidative stress is implicated in heavy metal toxicity.
Purpose of the Study:
- Investigate the role of mitophagy in Mo/Cd-induced mitochondrial dysfunction.
- Elucidate the involvement of the ROS-mediated PINK1/Parkin pathway.
- Determine the impact of inhibiting mitophagy on cellular responses to Mo and Cd.
Main Methods:
- Hepa1-6 cells were exposed to Mo, Cd, or both, with or without ROS scavenger (NAC) or mitophagy inhibitor (CsA).
- Assessed intracellular reactive oxygen species (ROS), malondialdehyde (MDA), and antioxidant enzyme activities (SOD, CAT, GSH-Px).
- Evaluated mitochondrial membrane potential, ATP content, autophagosome formation (LC3 puncta), and protein/mRNA levels (LC3II/LC3I, Parkin, Pink1, P62).
Main Results:
- Mo and/or Cd increased ROS and MDA, decreased antioxidant enzyme activities.
- Mitochondrial dysfunction markers (low membrane potential, reduced ATP) were elevated.
- Mitophagy markers (LC3II/LC3I, Parkin, Pink1) were upregulated, while P62 decreased.
- NAC treatment alleviated Mo/Cd-induced changes; CsA exacerbated them.
Conclusions:
- Mo and Cd co-exposure induce oxidative stress and mitophagy through the ROS-mediated PINK1/Parkin pathway in Hepa1-6 cells.
- Mitophagy plays a protective role against Mo/Cd-induced mitochondrial dysfunction.
- Inhibition of mitophagy aggravates cellular damage caused by combined Mo and Cd exposure.
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