Abstract：
:Activated autophagy/mitophagy has been intensively observed in ischemic brain, but its roles remain controversial. Peroxynitrite (ONOO-), as a representative of reactive nitrogen species, is considered as a critical neurotoxic factor in mediating cerebral ischemia-reperfusion (I/R) injury, but its roles in autophagy/mitophagy activation remain unclear. Herein, we hypothesized that ONOO- could induce PINK1/Parkin-mediated mitophagy activation via triggering dynamin-related protein 1 (Drp1) recruitment to damaged mitochondria, contributing to cerebral I/R injury. Firstly, we found PINK1/Parkin-mediated mitophagy activation was predominant among general autophagy, leading to rat brain injury at the reperfusion phase after cerebral ischemia. Subsequently, increased nitrotyrosine was found in the plasma of ischemic stroke patients and ischemia-reperfused rat brains, indicating the generation of ONOO- in ischemic stroke. Moreover, in vivo animal experiments illustrated that ONOO- was dramatically increased, accompanied with mitochondrial recruitment of Drp1, PINK1/Parkin-mediated mitophagy activation, and progressive infarct size in rat ischemic brains at the reperfusion phase. FeTMPyP, a peroxynitrite decomposition catalyst, remarkably reversed mitochondrial recruitment of Drp1, mitophagy activation, and brain injury. Intriguingly, further study revealed that ONOO- induced tyrosine nitration of Drp1 peptide, which might contribute to mitochondrial recruitment of Drp1 for mitophagy activation. In vitro cell experiments yielded consistent results with in vivo animal experiments. Taken together, all above findings support the hypothesis that ONOO--induced mitophagy activation aggravates cerebral I/R injury via recruiting Drp1 to damaged mitochondria.
journal_name
Mol Neurobioljournal_title
Molecular neurobiologyauthors
Feng J,Chen X,Guan B,Li C,Qiu J,Shen Jdoi
10.1007/s12035-017-0859-xsubject
Has Abstractpub_date
2018-08-01 00:00:00pages
6369-6386issue
8eissn
0893-7648issn
1559-1182pii
10.1007/s12035-017-0859-xjournal_volume
55pub_type
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