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The Interaction of Mitochondrial Biogenesis and Fission/Fusion Mediated by PGC-1α Regulates Rotenone-Induced Dopaminergic Neurotoxicity

Molecular Neurobiology volume 54, pages 3783–3797 (2017)Cite this article

Abstract

Parkinson’s disease is a common neurodegenerative disease in the elderly, and mitochondrial defects underlie the pathogenesis of PD. Impairment of mitochondrial homeostasis results in reactive oxygen species formation, which in turn can potentiate the accumulation of dysfunctional mitochondria, forming a vicious cycle in the neuron. Mitochondrial fission/fusion and biogenesis play important roles in maintaining mitochondrial homeostasis. It has been reported that PGC-1α is a powerful transcription factor that is widely involved in the regulation of mitochondrial biogenesis, oxidative stress, and other processes. Therefore, we explored mitochondrial biogenesis, mitochondrial fission/fusion, and especially PGC-1α as the key point in the signaling mechanism of their interaction in rotenone-induced dopamine neurotoxicity. The results showed that mitochondrial number and mass were reduced significantly, accompanied by alterations in proteins known to regulate mitochondrial fission/fusion (MFN2, OPA1, Drp1, and Fis1) and mitochondrial biogenesis (PGC-1α and mtTFA). Further experiments proved that inhibition of mitochondrial fission or promotion of mitochondrial fusion has protective effects in rotenone-induced neurotoxicity and also promotes mitochondrial biogenesis. By establishing cell models of PGC-1α overexpression and reduced expression, we found that PGC-1α can regulate MFN2 and Drp1 protein expression and phosphorylation to influence mitochondrial fission/fusion. In summary, it can be concluded that PGC-1α-mediated cross talk between mitochondrial biogenesis and fission/fusion contributes to rotenone-induced dopaminergic neurodegeneration.

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Acknowledgments

This work was supported by grants from the NSFC (Natural Science Foundation of China) (81473006, 81273106) to Yan Sai and the Natural Science Foundation of Chongqing (cstc2012jjA10028) to Yan Sai.

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Affiliations

  1. Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, People’s Republic of China

    Kaige Peng, Likui Yang, Jian Wang, Feng Ye, Guorong Dan, Yuanpeng Zhao, Ying Cai, Zhihong Cui, Lin Ao, Jinyi Liu, Zhongmin Zou, Yan Sai & Jia Cao

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  1. Kaige Peng
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  2. Likui Yang
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  3. Jian Wang
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Correspondence to Yan Sai or Jia Cao.

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Peng, K., Yang, L., Wang, J. et al. The Interaction of Mitochondrial Biogenesis and Fission/Fusion Mediated by PGC-1α Regulates Rotenone-Induced Dopaminergic Neurotoxicity. Mol Neurobiol 54, 3783–3797 (2017). https://doi.org/10.1007/s12035-016-9944-9

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Keywords

  • Rotenone
  • Dopamine neurotoxicity
  • PGC-1α
  • Mitochondrial biogenesis
  • Mitochondrial fission/fusion
  • Parkinson’s disease