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.

Links

Publisher Full Text

Authors

Vaseva AV, Marchenko ND, Ji K, Tsirka SE, Holzmann S, Moll UM

Institution

Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA.

Source

Cell 149:7 2012 Jun 22 pg 1536-48

MeSH

Animals
Brain Ischemia
Cell Line, Tumor
Cyclophilins
Embryo, Mammalian
Fibroblasts
Humans
Male
Mice
Mice, 129 Strain
Mitochondrial Membrane Transport Proteins
Necrosis
Oxidative Stress
Reperfusion Injury
Tumor Suppressor Protein p53

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

22726440