Nur77 exacerbates PC12 cellular injury in vitro by aggravating mitochondrial impairment and endoplasmic reticulum stress

Huimin Gao, Zhaoyu Chen, Yongmei Fu, Xiaoyan Yang, Ruihui Weng, Rui Wang, Jianjun Lu, Mengqiu Pan, Kunlin Jin, Chris McElroy, Beisha Tang, Ying Xia, Qing Wang

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Abstract

The nuclear orphan receptor, Nur77 plays important roles in neuroimflammation, apoptosis, and dopaminergic neurodegeneration. We conducted a further mechanistic investigation into the association of Nur77 with cell death. Cytosporone B (Csn-B), an agonist for Nur77, and Nur77 knockdown were adopted in the 6-hydroxydopamine (OHDA)-lesioned PC12 cells to investigate the mechanisms underlying Nur77-mediated injury. The 6-OHDA incubation caused Nur77 translocation from the nucleus to cytosol and Endoplasm reticulum (ER) and induced co-localization of Tom20/Nur77 and Protein Disulfide Isomerase (PDI)/Nur77. Nur77 activation further decreased cell viability, aggravated intracellular LDH release, intracellular Ca 2+, ROS levels, apoptosis, ER tress and, mitochondrial transmembrane potential (Δ Ψm) decline. In addition, Nur77 activation significantly enhanced the efficiency of autophagy as indicated by an up-regulation of Beclin-1/LC-3 and downregulation of p62, and aggravated mitochondrial dysfunctions and ER stress as shown by increased HSP60/Cytochrome C (Cyt C) and CHOP-ATF3 levels respectively. These changes could be partially reversed by Nur77 knockdown. Moreover, Nur77 activation upregulated PINK1 and downregulated Parkin levels. We conclude that Nur77 exacerbates PC12 cell death at least partially by aggravating the mitochondrial impairment and ER stress and enhancing autophagy. We propose that Nur77 is likely a critical target in the PD therapy.

Original languageEnglish
Article number34403
JournalScientific Reports
Volume6
DOIs
StatePublished - 29 Sep 2016

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Reticulum
Endoplasmic Reticulum Stress
Oxidopamine
PC12 Cells
Autophagy
Wounds and Injuries
Nuclear Receptor Subfamily 4, Group A, Member 1
Cell Death
Down-Regulation
Apoptosis
Protein Disulfide-Isomerases
Cytochromes
Membrane Potentials
Cytosol
Cell Survival
Up-Regulation
In Vitro Techniques
Therapeutics

Cite this

Gao, Huimin ; Chen, Zhaoyu ; Fu, Yongmei ; Yang, Xiaoyan ; Weng, Ruihui ; Wang, Rui ; Lu, Jianjun ; Pan, Mengqiu ; Jin, Kunlin ; McElroy, Chris ; Tang, Beisha ; Xia, Ying ; Wang, Qing. / Nur77 exacerbates PC12 cellular injury in vitro by aggravating mitochondrial impairment and endoplasmic reticulum stress. In: Scientific Reports. 2016 ; Vol. 6.
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abstract = "The nuclear orphan receptor, Nur77 plays important roles in neuroimflammation, apoptosis, and dopaminergic neurodegeneration. We conducted a further mechanistic investigation into the association of Nur77 with cell death. Cytosporone B (Csn-B), an agonist for Nur77, and Nur77 knockdown were adopted in the 6-hydroxydopamine (OHDA)-lesioned PC12 cells to investigate the mechanisms underlying Nur77-mediated injury. The 6-OHDA incubation caused Nur77 translocation from the nucleus to cytosol and Endoplasm reticulum (ER) and induced co-localization of Tom20/Nur77 and Protein Disulfide Isomerase (PDI)/Nur77. Nur77 activation further decreased cell viability, aggravated intracellular LDH release, intracellular Ca 2+, ROS levels, apoptosis, ER tress and, mitochondrial transmembrane potential (Δ Ψm) decline. In addition, Nur77 activation significantly enhanced the efficiency of autophagy as indicated by an up-regulation of Beclin-1/LC-3 and downregulation of p62, and aggravated mitochondrial dysfunctions and ER stress as shown by increased HSP60/Cytochrome C (Cyt C) and CHOP-ATF3 levels respectively. These changes could be partially reversed by Nur77 knockdown. Moreover, Nur77 activation upregulated PINK1 and downregulated Parkin levels. We conclude that Nur77 exacerbates PC12 cell death at least partially by aggravating the mitochondrial impairment and ER stress and enhancing autophagy. We propose that Nur77 is likely a critical target in the PD therapy.",
author = "Huimin Gao and Zhaoyu Chen and Yongmei Fu and Xiaoyan Yang and Ruihui Weng and Rui Wang and Jianjun Lu and Mengqiu Pan and Kunlin Jin and Chris McElroy and Beisha Tang and Ying Xia and Qing Wang",
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Gao, H, Chen, Z, Fu, Y, Yang, X, Weng, R, Wang, R, Lu, J, Pan, M, Jin, K, McElroy, C, Tang, B, Xia, Y & Wang, Q 2016, 'Nur77 exacerbates PC12 cellular injury in vitro by aggravating mitochondrial impairment and endoplasmic reticulum stress', Scientific Reports, vol. 6, 34403. https://doi.org/10.1038/srep34403

Nur77 exacerbates PC12 cellular injury in vitro by aggravating mitochondrial impairment and endoplasmic reticulum stress. / Gao, Huimin; Chen, Zhaoyu; Fu, Yongmei; Yang, Xiaoyan; Weng, Ruihui; Wang, Rui; Lu, Jianjun; Pan, Mengqiu; Jin, Kunlin; McElroy, Chris; Tang, Beisha; Xia, Ying; Wang, Qing.

In: Scientific Reports, Vol. 6, 34403, 29.09.2016.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Nur77 exacerbates PC12 cellular injury in vitro by aggravating mitochondrial impairment and endoplasmic reticulum stress

AU - Gao, Huimin

AU - Chen, Zhaoyu

AU - Fu, Yongmei

AU - Yang, Xiaoyan

AU - Weng, Ruihui

AU - Wang, Rui

AU - Lu, Jianjun

AU - Pan, Mengqiu

AU - Jin, Kunlin

AU - McElroy, Chris

AU - Tang, Beisha

AU - Xia, Ying

AU - Wang, Qing

PY - 2016/9/29

Y1 - 2016/9/29

N2 - The nuclear orphan receptor, Nur77 plays important roles in neuroimflammation, apoptosis, and dopaminergic neurodegeneration. We conducted a further mechanistic investigation into the association of Nur77 with cell death. Cytosporone B (Csn-B), an agonist for Nur77, and Nur77 knockdown were adopted in the 6-hydroxydopamine (OHDA)-lesioned PC12 cells to investigate the mechanisms underlying Nur77-mediated injury. The 6-OHDA incubation caused Nur77 translocation from the nucleus to cytosol and Endoplasm reticulum (ER) and induced co-localization of Tom20/Nur77 and Protein Disulfide Isomerase (PDI)/Nur77. Nur77 activation further decreased cell viability, aggravated intracellular LDH release, intracellular Ca 2+, ROS levels, apoptosis, ER tress and, mitochondrial transmembrane potential (Δ Ψm) decline. In addition, Nur77 activation significantly enhanced the efficiency of autophagy as indicated by an up-regulation of Beclin-1/LC-3 and downregulation of p62, and aggravated mitochondrial dysfunctions and ER stress as shown by increased HSP60/Cytochrome C (Cyt C) and CHOP-ATF3 levels respectively. These changes could be partially reversed by Nur77 knockdown. Moreover, Nur77 activation upregulated PINK1 and downregulated Parkin levels. We conclude that Nur77 exacerbates PC12 cell death at least partially by aggravating the mitochondrial impairment and ER stress and enhancing autophagy. We propose that Nur77 is likely a critical target in the PD therapy.

AB - The nuclear orphan receptor, Nur77 plays important roles in neuroimflammation, apoptosis, and dopaminergic neurodegeneration. We conducted a further mechanistic investigation into the association of Nur77 with cell death. Cytosporone B (Csn-B), an agonist for Nur77, and Nur77 knockdown were adopted in the 6-hydroxydopamine (OHDA)-lesioned PC12 cells to investigate the mechanisms underlying Nur77-mediated injury. The 6-OHDA incubation caused Nur77 translocation from the nucleus to cytosol and Endoplasm reticulum (ER) and induced co-localization of Tom20/Nur77 and Protein Disulfide Isomerase (PDI)/Nur77. Nur77 activation further decreased cell viability, aggravated intracellular LDH release, intracellular Ca 2+, ROS levels, apoptosis, ER tress and, mitochondrial transmembrane potential (Δ Ψm) decline. In addition, Nur77 activation significantly enhanced the efficiency of autophagy as indicated by an up-regulation of Beclin-1/LC-3 and downregulation of p62, and aggravated mitochondrial dysfunctions and ER stress as shown by increased HSP60/Cytochrome C (Cyt C) and CHOP-ATF3 levels respectively. These changes could be partially reversed by Nur77 knockdown. Moreover, Nur77 activation upregulated PINK1 and downregulated Parkin levels. We conclude that Nur77 exacerbates PC12 cell death at least partially by aggravating the mitochondrial impairment and ER stress and enhancing autophagy. We propose that Nur77 is likely a critical target in the PD therapy.

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