p53 mediates mitochondria dysfunction-triggered autophagy activation and cell death in rat striatum.
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-alpha (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.
Zhang
Xing-Ding
XD
Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Soochow University School of Medicine, Suzhou, China.
Wang
Ye
Y
Wang
Yan
Y
Zhang
Xuan
X
Han
Rong
R
Wu
Jun-Chao
JC
Liang
Zhong-Qin
ZQ
Gu
Zhen-Lun
ZL
Han
Feng
F
Fukunaga
Kohji
K
Qin
Zheng-Hong
ZH
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D052160:Benzothiazoles / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D008565:Membrane Proteins; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D009498:Neurotoxins / Q000494:pharmacology; D009574:Nitro Compounds / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C533952:Bbc3 protein, rat; D052160:Benzothiazoles; C512709:DRAM1 protein, human; D004791:Enzyme Inhibitors; D018942:Macrolides; D008565:Membrane Proteins; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C057620:bafilomycin A; D014050:Toluene; C025946:3-methyladenine; C121565:pifithrin; D000225:Adenine; C015392:3-nitropropionic acid