2. Academic Validation
  3. PINK1/TAX1BP1-directed mitophagy attenuates vascular endothelial injury induced by copper oxide nanoparticles

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.
Yinzhen Fan  # 1,  Zhenli Cheng  # 2 3,  Lejiao Mao 1 4,  Ge Xu 1,  Na Li 1,  Mengling Zhang 5,  Ping Weng 5,  Lijun Zheng 1,  Xiaomei Dong 1,  Siyao Hu 5,  Bin Wang 1,  Xia Qin 6 4,  Xuejun Jiang 7 4,  Chengzhi Chen 8 4,  Jun Zhang 9 10,  Zhen Zou 11 12
Affiliations

Affiliations

  • 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. zhangjun@cqmu.edu.cn.
  • 10 Dongsheng Lung‒Brain Diseases Joint Laboratory, Chongqing Medical University, Chongqing, 400016, China. zhangjun@cqmu.edu.cn.
  • 11 Molecular Biology Laboratory of Respiratory Disease, Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People's Republic of China. zouzhen@cqmu.edu.cn.
  • 12 Dongsheng Lung‒Brain Diseases Joint Laboratory, Chongqing Medical University, Chongqing, 400016, China. zouzhen@cqmu.edu.cn.
  • # Contributed equally.
PMID: 35305662 DOI: 10.1186/s12951-022-01338-4
Abstract

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.

Keywords

CuONPs; Mitophagy; PINK1/TAX1BP1; Urolithin A; Vascular endothelial injury.

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