Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Pyruvate Dehydrogenase Kinase Protects Dopaminergic Neurons from Oxidative Stress in Drosophila DJ-1 Null Mutants

  • Lee, Yoonjeong (Department of Pharmacology, Dong-A University College of Medicine) ;
  • Kim, Jaehyeon (Department of Pharmacology, Dong-A University College of Medicine) ;
  • Kim, Hyunjin (Department of Pharmacology, Dong-A University College of Medicine) ;
  • Han, Ji Eun (Department of Pharmacology, Dong-A University College of Medicine) ;
  • Kim, Sohee (Department of Pharmacology, Dong-A University College of Medicine) ;
  • Kang, Kyong-hwa (Department of Pharmacology, Dong-A University College of Medicine) ;
  • Kim, Donghoon (Department of Pharmacology, Dong-A University College of Medicine) ;
  • Kim, Jong-Min (Department of Anatomy and Cell Biology, Dong-A University College of Medicine) ;
  • Koh, Hyongjong (Department of Pharmacology, Dong-A University College of Medicine)
  • Received : 2021.09.24
  • Accepted : 2022.02.02
  • Published : 2022.07.31
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Abstract

DJ-1 is one of the causative genes of early-onset familial Parkinson's disease (PD). As a result, DJ-1 influences the pathogenesis of sporadic PD. DJ-1 has various physiological functions that converge to control the levels of intracellular reactive oxygen species (ROS). Based on genetic analyses that sought to investigate novel antioxidant DJ-1 downstream genes, pyruvate dehydrogenase (PDH) kinase (PDK) was demonstrated to increase survival rates and decrease dopaminergic (DA) neuron loss in DJ-1 mutant flies under oxidative stress. PDK phosphorylates and inhibits the PDH complex (PDC), subsequently downregulating glucose metabolism in the mitochondria, which is a major source of intracellular ROS. A loss-of-function mutation in PDK was not found to have a significant effect on fly development and reproduction, but severely ameliorated oxidative stress resistance. Thus, PDK plays a critical role in the protection against oxidative stress. Loss of PDH phosphatase (PDP), which dephosphorylates and activates PDH, was also shown to protect DJ-1 mutants from oxidative stress, ultimately supporting our findings. Further genetic analyses suggested that DJ-1 controls PDK expression through hypoxia-inducible factor 1 (HIF-1), a transcriptional regulator of the adaptive response to hypoxia and oxidative stress. Furthermore, CPI-613, an inhibitor of PDH, protected DJ-1 null flies from oxidative stress, suggesting that the genetic and pharmacological inhibition of PDH may be a novel treatment strategy for PD associated with DJ-1 dysfunction.

Keywords

Acknowledgement

This work was supported by grants from the National Research Foundation of Korea, funded by the Ministry of Science and ICT (grant Nos. 2020R1F1A105165912 and 2016R1A5A2007009) and a Korea Basic Science Institute (National Research Facilities and Equipment Center) grant funded by the Ministry of Education (grant No. 2021R1A6C101A425).

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