Abstract：
:Ischemia-associated oxidative damage leading to necrosis is a major cause of catastrophic tissue loss, and elucidating its signaling mechanism is therefore of paramount importance. p53 is a central stress sensor responding to multiple insults, including oxidative stress to orchestrate apoptotic and autophagic cell death. Whether p53 can also activate oxidative stress-induced necrosis is, however, unknown. Here, we uncover a role for p53 in activating necrosis. In response to oxidative stress, p53 accumulates in the mitochondrial matrix and triggers mitochondrial permeability transition pore (PTP) opening and necrosis by physical interaction with the PTP regulator cyclophilin D (CypD). Intriguingly, a robust p53-CypD complex forms during brain ischemia/reperfusion injury. In contrast, reduction of p53 levels or cyclosporine A pretreatment of mice prevents this complex and is associated with effective stroke protection. Our study identifies the mitochondrial p53-CypD axis as an important contributor to oxidative stress-induced necrosis and implicates this axis in stroke pathology.
journal_name
Celljournal_title
Cellauthors
Vaseva AV,Marchenko ND,Ji K,Tsirka SE,Holzmann S,Moll UMdoi
10.1016/j.cell.2012.05.014subject
Has Abstractpub_date
2012-06-22 00:00:00pages
1536-48issue
7eissn
0092-8674issn
1097-4172pii
S0092-8674(12)00593-4journal_volume
149pub_type
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