P53 mediates mitochondria dysfunction-triggered autophagy activation and cell death in rat striatum

Xing Ding Zhang, Ye Wang, Yan Wang, Xuan Zhang, Rong Han, Jun Chao Wu, Zhong Qin Liang, Zhen Lun Gu, Feng Han, Kohji Fukunaga, Zheng Hong Qin

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79 Citations (Scopus)

Abstract

In vivo administration of the mitochondrial inhibitor 3-nitropropionic acid (3-NP) produces striatal pathology mimicking Huntington disease (HD). However, the mechanisms of cell death induced by metabolic impairment are not fully understood. The present study investigated contributions of p53 signaling pathway to autophagy activation and cell death induced by 3-NP. Rat striatum was intoxicated with 3-NP by stereotaxic injection. Morphological and biochemical analyses demonstrated activation of autophagy in striatal cells as evidenced by increased formation of autophagosomes, the expression of active lysosomal cathepsin B and D, microtubule associate protein light chain 3 (LC3) and conversion of LC3-I to LC3-II. 3-NP upregulated the expression of tumor suppressor protein 53 (p53) and its target genes including Bax, p53-upregulated modulator of apoptosis (PUMA) and damage-regulated autophagy modulator (DRAM). 3-NP-induced elevations in pro-apoptotic proteins Bax and PUMA, autophagic proteins LC3-II and DRAM were significantly reduced by the p53 specific inhibitor pifithrin-α (PFT). PFT also significantly inhibited 3-NP-induced striatal damage. Similarly, 3-NP-induced DNA fragmentation and striatal cell death were robustly attenuated by the autophagy inhibitor 3-methyladenine (3-MA) and bafilomycin A1 (BFA). These results suggest that p53 plays roles in signaling both autophagy and apoptosis. Autophagy, at least partially, contributes to neurodegeneration induced by mitochondria dysfunction.

Original languageEnglish
Pages (from-to)339-350
Number of pages12
JournalAutophagy
Volume5
Issue number3
DOIs
Publication statusPublished - 2009 Apr 1

Keywords

  • 3-nitropropionic acid
  • Autophagy
  • DRAM
  • LC3
  • Mitochondria
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Zhang, X. D., Wang, Y., Wang, Y., Zhang, X., Han, R., Wu, J. C., Liang, Z. Q., Gu, Z. L., Han, F., Fukunaga, K., & Qin, Z. H. (2009). P53 mediates mitochondria dysfunction-triggered autophagy activation and cell death in rat striatum. Autophagy, 5(3), 339-350. https://doi.org/10.4161/auto.5.3.8174