RNAi-mediated knockdown of DJ-1 leads to mitochondrial dysfunction via Akt/GSK-3ß and JNK signaling pathways in dopaminergic neuron-like cells

Wang, Zhenzhen; Shao, Qianhang; Zhang, Zhao; Li, Lin; Guo, Zhenyu; Sun, Haixiang; Zhang, Yi; Chen, Nai‐Hong

doi:10.1016/j.brainresbull.2019.01.007

Cited by 27 publications

(26 citation statements)

References 44 publications

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“…Previous studies revealed that DJ-1 knockdown in human neuroblastoma SH-SY5Y cells and rat adrenal pheochromocytoma PC12 cells decreased Akt phosphorylation, thus suppressing the Akt signaling pathway. Besides, it also increased JNK phosphorylation, thus overactivating JNK signaling pathway and promoting cell death [51,52]. Analysis of Akt and JNK phosphorylation levels in our DJ-1-deficient cells confirmed the presence of similar molecular alterations (Fig.…”

Section: Zaprinast Activates Akt Signaling and Downregulates The Jnk Pathway In Dj-1-deficient Human Cellssupporting

confidence: 71%

A High-Throughput Chemical Screen in DJ-1β Mutant Flies Identifies Zaprinast as a Potential Parkinson's Disease Treatment

et al. 2021

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Dopamine replacement represents the standard therapy for Parkinson’s disease (PD), a common, chronic, and incurable neurological disorder; however, this approach only treats the symptoms of this devastating disease. In the search for novel disease-modifying therapies that target other relevant molecular and cellular mechanisms, Drosophila has emerged as a valuable tool to study neurodegenerative diseases due to the presence of a complex central nervous system, the blood–brain barrier, and a similar neurotransmitter profile to humans. Human PD-related genes also display conservation in flies; DJ-1β is the fly ortholog of DJ-1, a gene for which mutations prompt early-onset recessive PD. Interestingly, flies mutant for DJ-1β exhibit PD-related phenotypes, including motor defects, high oxidative stress (OS) levels and metabolic alterations. To identify novel therapies for PD, we performed an in vivo high-throughput screening assay using DJ-1β mutant flies and compounds from the Prestwick® chemical library. Drugs that improved motor performance in DJ-1ß mutant flies were validated in DJ-1-deficient human neural-like cells, revealing that zaprinast displayed the most significant ability to suppress OS-induced cell death. Zaprinast inhibits phosphodiesterases and activates GPR35, an orphan G-protein-coupled receptor not previously associated with PD. We found that zaprinast exerts its beneficial effect in both fly and human PD models through several disease-modifying mechanisms, including reduced OS levels, attenuated apoptosis, increased mitochondrial viability, and enhanced glycolysis. Therefore, our results support zaprinast as a potential therapeutic for PD in future clinical trials.

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Section: Zaprinast Activates Akt Signaling and Downregulates The Jnk Pathway In Dj-1-deficient Human Cellssupporting

confidence: 71%

A High-Throughput Chemical Screen in DJ-1β Mutant Flies Identifies Zaprinast as a Potential Parkinson's Disease Treatment

et al. 2021

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“…Further study revealed that the mechanism responsible for such phenotypes might rely on the regulation of SQSTM1/p62 on brown adipose tissue (BAT) mitochondrial thermogenesis ( Muller et al., 2013 ). In addition, a study performed in neuroblastoma cells demonstrated SQSTM1/p62 could affect mitochondrial complex I respiration ( Zhang et al, 2019 ). Besides, via yet-unknown mechanisms, SQSTM1/p62 could regulate the availability of NADH for electron transfer chain (ETC) ( Blacker and Duchen, 2016 ; Bartolome et al., 2017 ).…”

Section: Introductionmentioning

confidence: 99%

SQSTM1/p62 Controls mtDNA Expression and Participates in Mitochondrial Energetic Adaption via MRPL12

Zhu

et al. 2020

iScience

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Summary Mitochondrial DNA (mtDNA) encodes thirteen core components of OXPHOS complexes, and its steady expression is crucial for cellular energy homeostasis. However, the regulation of mtDNA expression machinery, along with its sensing mechanism to energetic stresses, is not fully understood. Here, we identified SQSTM1/p62 as an important regulator of mtDNA expression machinery, which could effectively induce mtDNA expression and the effects were mediated by p38-dependent upregulation of mitochondrial ribosomal protein L12 (MRPL12) in renal tubular epithelial cells (TECs), a highly energy-demanding cell type related to OXPHOS. We further identified a direct binding site within the MRPL12 promoter to ATF2, the downstream effector of p38. Besides, SQSTM1/p62-induced mtDNA expression is involved in both serum deprivation and hypoxia-induced mitochondrial response, which was further highlighted by kidney injury phenotype of TECs-specific SQSTM1/p62 knockout mice. Collectively, these data suggest that SQSTM1/p62 is a key regulator and energetic sensor of mtDNA expression machinery.

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“…Experimental studies have demonstrated that the activation of DJ-1 in response to myocardial I/R injury protects the heart by regulating the SUMOylation status of Drp1 and attenuating excessive mitochondrial ssion [12]. A recent study has also shown that mouse embryonic lacking DJ-1 had impaired mitochondrial respiration due to complex I inhibition, increased mitochondrial oxidative stress, reduced mitochondrial membrane potential, more fragmented mitochondria, and impaired mitophagy, ndings which con rmed that DJ-1 is required for normal mitochondrial function [25,26]. Furthermore, we observed that IPO was able to increased DJ-1 expression and modulation DJ-1 translocate from the cytosol to the mitochondria in non-diabetic rats, but not in diabetic rats.…”

Section: Discussionmentioning

confidence: 90%

Ischemic post-conditioning promotes mitochondrial translocation of DJ-1 and stabilizes binding to Bcl- xL to attenuate myocardial ischemic-reperfusion injury in STZ-induced diabetic rats

Xiong

Leng

et al. 2021

Preprint

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Background Ischemic post-conditioning (IPO) is a strategy in reducing myocardial ischemic-reperfusion (I/R) injury, but its specific molecular mechanism is incompletely understood. Deletions or mutations in the DJ-1 gene are directly linked to the cardiovascular system. DJ-1 plays a critical role in regulating mitochondrial homeostasis in response to stress through translocation of DJ-1 from the cytoplasm into the nucleus. Meanwhile, how the DJ-1 is removed in myocardial I/R injury and regulating apoptosis is needed to further verified. Given the discovery mentioned above, we hypothesize that DJ-1 translocate to mitochondria recover IPO induced cardioprotection in STZ-induced diabetic rats. To evaluate our hypothesis, we overexpressed the DJ-1 protein under high glucose condition, subjected IPO or not. And then measure the expression of DJ-1 in mitochondria and cytoplasm after myocardial I/R. Results We found that DJ-1 translocated to mitochondria combined with Bcl-xL was reduced cardiomyocyte injury and apoptosis in diabetic myocardial I/R heart. Additionally, the binding of DJ-1 and Bcl-xL is dependent on the oxidative state of DJ-1(oxidation of DJ-1 at Cys-106 is important for its protective effect). Conclusions If our hypothesis is correct, promote DJ-1 mitochondrial transfer may be critical with respect to restoring myocardial responsiveness to IPO in diabetes.

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RNAi-mediated knockdown of DJ-1 leads to mitochondrial dysfunction via Akt/GSK-3ß and JNK signaling pathways in dopaminergic neuron-like cells

Cited by 27 publications

References 44 publications

A High-Throughput Chemical Screen in DJ-1β Mutant Flies Identifies Zaprinast as a Potential Parkinson's Disease Treatment

A High-Throughput Chemical Screen in DJ-1β Mutant Flies Identifies Zaprinast as a Potential Parkinson's Disease Treatment

SQSTM1/p62 Controls mtDNA Expression and Participates in Mitochondrial Energetic Adaption via MRPL12

Ischemic post-conditioning promotes mitochondrial translocation of DJ-1 and stabilizes binding to Bcl- xL to attenuate myocardial ischemic-reperfusion injury in STZ-induced diabetic rats

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