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The Role of Pink1-Mediated Mitochondrial Pathway in Propofol-Induced Developmental Neurotoxicity

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Abstract

The mechanisms underlying propofol-induced toxicity in developing neurons are still unclear. The aim of present study was to explore the role of Pink1 mediated mitochondria pathway in propofol-induced developmental neurotoxicity. The primary Neural Stem Cells (NSCs) were isolated from the hippocampus of E15.5 mice embryos and then treated with propofol. The effects of propofol on proliferation, differentiation, apoptosis, mitochondria ultrastructure and MMP of NSCs were investigated. In addition, the abundance of Pink1 and a group of mitochondria related proteins in the cytoplasm and/or mitochondria were investigated, which mainly included CDK1, Drp1, Parkin1, DJ-1, Mfn1, Mfn2 and OPA1. Moreover, the relationship between Pink1 and these molecules was explored using gene silencing, or pretreatment with protein inhibitors. Finally, the NSCs were pretreated with mitochondrial specific antioxidant (MitoQ) or Drp1 inhibitor (Mdivi-1), and then the toxic effects of propofol on NSCs were investigated. Our results indicated that propofol treatment inhibited NSCs proliferation and division, and promoted NSCs apoptosis. Propofol induced significant NSCs mitochondria deformation, vacuolization and swelling, and decreased MMP. Additional studies showed that propofol affected a group of mitochondria related proteins via Pink1 inhibition, and CDK1, Drp1, Parkin1 and DJ-1 are the important downstream proteins of Pink1. Finally, the effects of propofol on proliferation, differentiation, apoptosis, mitochondrial ultrastructure and MMP of NSCs were significantly attenuated by MitoQ or Mdivi-1 pretreatment. The present study demonstrated that propofol regulates the proliferation, differentiation and apoptosis of NSCs via Pink1mediated mitochondria pathway.

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Data Availability

The data sets used and analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This research was supported by Natural Science Foundation of Shanghai (20ZR1411000, 20ZR1439800).

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  1. Chao Liang and Minli Sun have contributed equally to this study

Authors and Affiliations

  1. Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China

    Chao Liang, Minli Sun, Jing Zhong, Changhong Miao & Xiaodan Han

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  1. Chao Liang
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  2. Minli Sun
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  3. Jing Zhong
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  4. Changhong Miao
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Contributions

CL; performed the experiments: MS, JZ; Statistical analysis: CM, XH, Wrote the paper CL. All authors read and approved the final manuscript.

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Correspondence to Changhong Miao or Xiaodan Han.

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Our study was approved by the Ethics Review Board of Zhongshan Hospital.

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Liang, C., Sun, M., Zhong, J. et al. The Role of Pink1-Mediated Mitochondrial Pathway in Propofol-Induced Developmental Neurotoxicity. Neurochem Res 46, 2226–2237 (2021). https://doi.org/10.1007/s11064-021-03359-1

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  • DOI: https://doi.org/10.1007/s11064-021-03359-1

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