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Pyrroloquinoline quinone promotes mitochondrial biogenesis in rotenone-induced Parkinson’s disease model via AMPK activation

Abstract

Mitochondrial dysfunction is considered to be one of the important pathogenesis in Parkinson’s disease (PD). We previously showed that pyrroloquinoline quinone (PQQ) could protect SH-SY5Y cells and dopaminergic neurons from cytotoxicity and prevent mitochondrial dysfunction in rotenone-induced PD models. In the present study we investigated the mechanisms underlying the protective effects of PQQ in a mouse PD model, which was established by intraperitoneal injection of rotenone (3 mg·kg−1·d−1, ip) for 3 weeks. Meanwhile the mice were treated with PQQ (0.8, 4, 20 mg·kg−1·d−1, ip) right after rotenone injection for 3 weeks. We showed that PQQ treatment dose-dependently alleviated the locomotor deficits and nigral dopaminergic neuron loss in PD mice. Furthermore, PQQ treatment significantly diminished the reduction of mitochondria number and their pathological change in the midbrain. PQQ dose-dependently blocked rotenone-caused reduction in the expression of PGC-1α and TFAM, two key activators of mitochondrial gene transcription, in the midbrain. In rotenone-injured human neuroblastoma SH-SY5Y cells, PTMScan Direct analysis revealed that treatment with PQQ (100 μM) differentially regulated protein phosphorylation; the differentially expressed phosphorylated proteins included the signaling pathways related with adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) pathway. We conducted Western blot analysis and confirmed that AMPK was activated by PQQ both in PD mice and in rotenone-injured SH-SY5Y cells. Pretreatment with AMPK inhibitor dorsomorphin (4 μM) significantly attenuated the protective effect and mitochondrial biogenesis by PQQ treatment in rotenone-injured SH-SY5Y cells. Taken together, PQQ promotes mitochondrial biogenesis in rotenone-injured mice and SH-SY5Y cells via activation of AMPK signaling pathway.

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Fig. 1: PQQ alleviated rotenone-induced locomotor deficits in mice.
Fig. 2: PQQ prevented rotenone-induced neuronal loss in the SNpc of mice.
Fig. 3: PQQ affected the content and morphology of mitochondria in midbrains of PD mice.
Fig. 4: PQQ regulated the expression of mitochondrial biogenesis-related genes and proteins in PD mice.
Fig. 5: PQQ promoted mitochondrial biogenesis in rotenone-injured SH-SY5Y cells.
Fig. 6: PQQ changed the proteomic phosphorylation profile of rotenone-injured SH-SY5Y cells.
Fig. 7: Western blotting validation of PQQ-induced activation of AMPK signaling in rotenone-injured SH-SY5Y cells and rotenone-injured PD mice.
Fig. 8: Inhibition of AMPK by dorsomorphin (compound C) 2HCl eliminated the protective effect of PQQ in rotenone-injured SH-SY5Y cells.
Fig. 9: Inhibition of AMPK by dorsomorphin (compound C) 2HCl attenuated mitochondrial biogenesis induced by PQQ in rotenone-injured SH-SY5Y cells.

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Acknowledgements

This study was supported by the National Key Research and Development Program of China (Grant No. 2017YFA0104700), National Natural Science Foundation of China (81771404), the Natural Science Foundation of Jiangsu Province (Grant No. BK20161285), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), Jiangsu Provincial Key Medical Center, and Jiangsu Students’ innovation and entrepreneurship training program (Grant No. 201810304096X).

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QC and JC carried out the cell culture, qPCR, and Western blotting experiments. HG, JLL, and JZ carried out the animal model and behavior tests. XYG, YS, and YZ carried out the TH staining. SY and QZ carried out the PTMscan analysis and TEM observation. QZ and QC analyzed the data and wrote the paper. FD edited the paper. QZ and FD designed the study and supervised the research.

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Correspondence to Qi Zhang or Fei Ding.

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The authors declare no competing interests.

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Cheng, Q., Chen, J., Guo, H. et al. Pyrroloquinoline quinone promotes mitochondrial biogenesis in rotenone-induced Parkinson’s disease model via AMPK activation. Acta Pharmacol Sin 42, 665–678 (2021). https://doi.org/10.1038/s41401-020-0487-2

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Keywords

  • Parkinson’s disease
  • rotenone
  • pyrroloquinoline quinone
  • mitochondrial biogenesis
  • AMPK
  • PTMScan Direct analysis

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