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Nur77 exacerbates PC12 cellular injury in vitro by aggravating mitochondrial impairment and endoplasmic reticulum
Huimin Gao1, Zhaoyu Chen1, Yongmei Fu2
1Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600, Guangzhou, Guangdong 510630, P.R. China.
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 Ca2+, ROS levels, apoptosis, ER tress and, mitochondrial transmembrane potential (ΔΨm) 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.
Insights
Nur77 activation worsens cell death by increasing mitochondrial impairment, ER stress, and autophagy. Nur77 may be a therapeutic target for Parkinson's disease (PD) and neurodegeneration.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- The nuclear orphan receptor Nur77 is implicated in neuroinflammation, apoptosis, and dopaminergic neurodegeneration.
- Understanding Nur77's role in cell death mechanisms is crucial for neurodegenerative disease research.
Purpose of the Study:
- To investigate the mechanisms by which Nur77 influences cell death in a cellular model of Parkinson's disease.
- To explore the impact of Nur77 activation and knockdown on cellular injury.
Main Methods:
- Utilized 6-hydroxydopamine (OHDA)-lesioned PC12 cells.
- Administered Cytosporone B (Csn-B) as a Nur77 agonist and employed Nur77 knockdown.
- Assessed cell viability, LDH release, intracellular calcium and ROS levels, apoptosis, ER stress, and mitochondrial function.
Main Results:
- Nur77 activation led to its translocation to the cytosol and ER, co-localizing with Tom20 and PDI.
- Activated Nur77 decreased cell viability, increased cellular damage markers (LDH, Ca2+, ROS), apoptosis, ER stress, and mitochondrial dysfunction (ΔΨm decline).
- Nur77 activation enhanced autophagy, upregulated PINK1, and downregulated Parkin, with partial reversal by Nur77 knockdown.
Conclusions:
- Nur77 activation exacerbates PC12 cell death by worsening mitochondrial impairment, ER stress, and enhancing autophagy.
- Nur77 plays a significant role in mediating cellular injury in this model.
- Nur77 represents a potential therapeutic target for Parkinson's disease (PD).
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