PINK1/TAX1BP1-directed mitophagy attenuates vascular endothelial injury induced by copper oxide nanoparticles
- J Nanobiotechnology. 2022 Mar 19;20(1):149. doi: 10.1186/s12951-022-01338-4.
- 1. Molecular Biology Laboratory of Respiratory Disease, Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
- 2. Department of Cardiovascular Medicine, Children's Hospital of Chongqing Medical University, Chongqing, 400014, People's Republic of China.
- 3. Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, 400014, People's Republic of China.
- 4. Dongsheng Lung‒Brain Diseases Joint Laboratory, Chongqing Medical University, Chongqing, 400016, China.
- 5. College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China.
- 6. Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
- 7. Center of Experimental Teaching for Public Health, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
- 8. Department of Occupational and Environmental Health, School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, China.
- 9. Molecular Biology Laboratory of Respiratory Disease, Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People's Republic of China. [email protected].
- 10. Dongsheng Lung‒Brain Diseases Joint Laboratory, Chongqing Medical University, Chongqing, 400016, China. [email protected].
- 11. Molecular Biology Laboratory of Respiratory Disease, Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People's Republic of China. [email protected].
- 12. Dongsheng Lung‒Brain Diseases Joint Laboratory, Chongqing Medical University, Chongqing, 400016, China. [email protected].
- # Contributed equally.
Copper oxide nanoparticles (CuONPs) are widely used metal oxide NPs owing to their excellent physical-chemical properties. Circulation translocation of CuONPs after inhalation leads to vascular endothelial injury. Mitochondria, an important regulatory hub for maintaining cell functions, are signaling organelles in responses to NPs-induced injury. However, how mitochondrial dynamics (fission and fusion) and Mitophagy (an Autophagy process to degrade damaged mitochondria) are elaborately orchestrated to maintain mitochondrial homeostasis in CuONPs-induced vascular endothelial injury is still unclear. In this study, we demonstrated that CuONPs exposure disturbed mitochondrial dynamics through oxidative stress-dependent manner in vascular endothelial cells, as evidenced by the increase of mitochondrial fission and the accumulation of fragmented mitochondria. Inhibition of mitochondrial fission with Mdivi-1 aggravated CuONPs-induced mtROS production and cell death. Furthermore, we found that mitochondrial fission led to the activation of PINK1-mediated Mitophagy, and pharmacological inhibition with wortmannin, chloroquine or genetical inhibition with siRNA-mediated knockdown of PINK1 profoundly repressed Mitophagy, suggesting that the protective role of mitochondrial fission and PINK1-mediated Mitophagy in CuONPs-induced toxicity. Intriguingly, we identified that TAX1BP1 was the primary receptor to link the ubiquitinated mitochondria with autophagosomes, since TAX1BP1 knockdown elevated mtROS production, decreased mitochondrial clearance and aggravated CuONPs-induced cells death. More importantly, we verified that urolithin A, a Mitophagy Activator, promoted mtROS clearance and the removal of damaged mitochondria induced by CuONPs exposure both in vitro and in vivo. Overall, our findings indicated that modulating Mitophagy may be a therapeutic strategy for pathological vascular endothelial injury caused by NPs exposure.
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Cat. No.Product NameDescriptionTargetResearch Area
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target: Drug Metabolite; Reactive Oxygen Species (ROS); DNA/RNA Synthesis; Autophagy; Apoptosis; Endogenous MetaboliteResearch Areas: Cancer