p53 Opens the Mitochondrial Permeability Transition Pore to Trigger Necrosis

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. [Display omitted] ► Necrosis in oxidative stress and ischemia depends on mitochondrial PTP pore opening ► PTP opening is triggered by p53 interaction with CypD in the mitochondrial matrix ► A p53-CypD complex is formed in necrotic brain tissue in a stroke model in mice ► Blocking formation of the p53-CypD complex is associated with stroke protection In addition to regulating apoptosis and autophagic cell death, p53 also promotes necrosis. During ischemic stroke, p53 accumulates in the neuronal mitochondrial matrix and opens the permeability transition pore by binding CypD, causing mitochondria to swell and rupture.