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Mol. Cells

Published online April 21, 2022

© The Korean Society for Molecular and Cellular Biology

Pyruvate Dehydrogenase Kinase Protects Dopaminergic Neurons from Oxidative Stress in Drosophila DJ-1 Null Mutants

Yoonjeong Lee1,2,6 , Jaehyeon Kim1,3,6 , Hyunjin Kim1,2 , Ji Eun Han1,3 , Sohee Kim1,3 , Kyong-hwa Kang1,4 , Donghoon Kim1,2,3,4 , Jong-Min Kim5 , and Hyongjong Koh1,2,3,4,*

1Department of Pharmacology, Dong-A University College of Medicine, Busan 49201, Korea, 2Peripheral Neuropathy Research Center, Dong-A University College of Medicine, Busan 49201, Korea, 3Department of Translational Biomedical Sciences, Dong-A University College of Medicine, Busan 49201, Korea, 4Neuroscience Translational Research Solution Center, Dong-A University College of Medicine, Busan 49201, Korea, 5Department of Anatomy and Cell Biology, Dong-A University College of Medicine, Busan 49201, Korea, 6These authors contributed equally to this work.

Correspondence to : hjkoh@dau.ac.kr

Received: September 24, 2021; Revised: December 19, 2021; Accepted: February 2, 2022

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

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 DJ-1, Drosophila, oxidative stress, Parkinson’s disease, pyruvate dehydrogenase kinase

Article

On-line First

Mol. Cells

Published online April 21, 2022

Copyright © The Korean Society for Molecular and Cellular Biology.

Pyruvate Dehydrogenase Kinase Protects Dopaminergic Neurons from Oxidative Stress in Drosophila DJ-1 Null Mutants

Yoonjeong Lee1,2,6 , Jaehyeon Kim1,3,6 , Hyunjin Kim1,2 , Ji Eun Han1,3 , Sohee Kim1,3 , Kyong-hwa Kang1,4 , Donghoon Kim1,2,3,4 , Jong-Min Kim5 , and Hyongjong Koh1,2,3,4,*

1Department of Pharmacology, Dong-A University College of Medicine, Busan 49201, Korea, 2Peripheral Neuropathy Research Center, Dong-A University College of Medicine, Busan 49201, Korea, 3Department of Translational Biomedical Sciences, Dong-A University College of Medicine, Busan 49201, Korea, 4Neuroscience Translational Research Solution Center, Dong-A University College of Medicine, Busan 49201, Korea, 5Department of Anatomy and Cell Biology, Dong-A University College of Medicine, Busan 49201, Korea, 6These authors contributed equally to this work.

Correspondence to:hjkoh@dau.ac.kr

Received: September 24, 2021; Revised: December 19, 2021; Accepted: February 2, 2022

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

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: DJ-1, Drosophila, oxidative stress, Parkinson’s disease, pyruvate dehydrogenase kinase

Mol. Cells
Jun 30, 2022 Vol.45 No.6, pp. 353~434
COVER PICTURE
ERα is modified by UFM1 and this modification (ufmylation) plays a crucial role in promoting the stability of ERα and breast cancer development. However, when ERα is deufmylated and then ubiquitinated, it disappears by proteasome-mediated degradation (Yoo et al., pp. 425-434).

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