p53 Opens the Mitochondrial Permeability Transition Pore to Trigger Necrosis

Abstract

Summary Ischemia-associated oxidative damage leading to necrosis is a major cause of catastrophic tissue loss in human health. Elucidating its signaling mechanism is of paramount importance. p53 is a central stress sensor responding to multiple insults including oxidative stress to orchestrate apoptotic and autophagic types of cell death. Whether p53 can also activate oxidative stress-induced necrosis is unknown. Here we uncover a role of 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 critical 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.

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