Down-regulation of Bcl-2 enhances autophagy activation and cell death induced by mitochondrial dysfunction in rat striatum.
In vivo administration of the mitochondrial inhibitor 3-nitropropionic acid (3-NP) produces striatal pathology mimicking Huntington's disease (HD). However, the mechanisms of cell death induced by metabolic impairment are not fully understood. Previous studies showed that 3-NP triggered p53-depedent autophagy activation and cell death. The present study investigated the contribution of the Bcl-2 signaling pathway to autophagy activation and cell death induced by 3-NP. Rat striatum was intoxicated with 3-NP by stereotaxic injection. 3-NP up-regulated the expression of the autophagic protein beclin 1 but down-regulated the expression of the antiapoptotic protein Bcl-2. Pretreatment with the autophagy inhibitor 3-methyladenine (3-MA) significantly inhibited the 3-NP-induced alterations in beclin 1 and Bcl-2 protein levels. Similarly, the 3-NP-induced decline in Bcl-2 was also prevented by the lysosomal inhibitor E64, indicating degradation of Bcl-2 by lysosomes. In agreement with the time course of 3-NP-induced cell death, an increase in the release of cytochrome c from mitochondria was observed. 3-MA also attenuated the 3-NP-induced release of cytochrome c. On the other hand, 3-NP-induced elevations in proapoptotic protein Bax and autophagic protein beclin 1 and LC3-II were significantly enhanced by the Bcl-2-specific inhibitor HA14-1. Furthermore, HA14-1 increased the release of cytochrome c and 3-NP-induced striatal damage. These results suggest that induction of autophagy leads to degradation of Bcl-2. Meanwhile, down-regulation of Bcl-2 amplifies autophagy activation and apoptotic signaling. Bcl-2 thus plays important roles in mitochondria dysfunction-induced apoptotic death of stritatal neurons by modulating both autophagic and apoptotic processes.
Zhang
Xing-Ding
XD
Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Soochow University School of Medicine, Suzhou, China.
Wang
Ye
Y
Wu
Jun-Chao
JC
Lin
Fang
F
Han
Rong
R
Han
Feng
F
Fukunaga
Kohji
K
Qin
Zheng-Hong
ZH
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D000071186:Beclin-1; D001578:Benzopyrans / Q000494:pharmacology; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009498:Neurotoxins / Q000633:toxicity; D009570:Nitriles / Q000494:pharmacology; D009574:Nitro Compounds / Q000633:toxicity; D011422:Propionates / Q000633:toxicity; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013194:Staining and Labeling; D013997:Time Factors; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C512829:Becn1 protein, rat; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D009498:Neurotoxins; D009570:Nitriles; D009574:Nitro Compounds; D011422:Propionates; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; C456800:ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; C025946:3-methyladenine; D045304:Cytochromes c; D000225:Adenine; C015392:3-nitropropionic acid