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

Date

2016-09-29

Authors

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

ORCID

0000-0002-1336-348X (Jin, Kunlin)

Journal Title

Journal ISSN

Volume Title

Publisher

Springer Nature

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 (DeltaPsim) 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.

Description

Keywords

Citation

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, 6, 34403. https://doi.org/10.1038/srep34403

Rights

© The Author(s) 2016

License

Attribution 4.0 International (CC BY 4.0)