p53 Opens the Mitochondrial Permeability Transition Pore to Trigger Necrosis in Response to Oxidative Damage

Abstract

p53, originally discovered as the most important tumor suppressor in human cancer, has been known for decades for its major function as a central stress sensor that responds to multiple cellular insults to regulate a broad array of cellular processes such as cell cycle arrest, senescence, and genome stability. In the last 15 years the role of p53 to orchestrate apoptotic cell death in response to cellular insult has been well established. All these p53 programs are highly effective to prevent genetically damaged and potentially mutagenic cells from propagating to daughter cells and become tumorigenic. Hence, p53 has been called the “guardian of the genome.” p53 induces apoptosis by transcriptional activation of numerous pro-apoptotic target genes and by a transcription-independent mitochondrion-based apoptotic p53 program. In the latter case, p53 protein directly activates the intrinsic apoptosis pathway by interacting with both the anti- and pro-apoptotic multi-domain members of the Bcl2 family to induce Bax/Bak lipid pore formation and subsequent mitochondrial outer membrane permeabilization. However, whether p53 can also activate programmed necrosis was unknown. We recently uncovered an entirely new, unsuspected role of p53 in activating oxidative stress-induced necrosis. In response to oxidative stress, p53 accumulates in the mitochondrial matrix and triggers mitochondrial permeability transition pore (mPTP) opening and necrosis by physical interaction with the critical mPTP regulator cyclophilin D (CypD). Oxidative damage-induced necrosis, which is the underlying pathophysiology of ischemia/reperfusion injury, is a major cause of catastrophic tissue loss in human health. Intriguingly, our data show that a robust pathologic p53–CypD complex forms during acute stroke (ischemia/reperfusion injury) in the brain. In contrast, reduction of p53 levels or cyclosporine A pretreatment of mice (a potent inhibitor of CypD) prevents this complex from forming and correlates with effective stroke protection. Our study identifies a novel mitochondrial p53–CypD axis as an important contributor to ischemia-induced necrosis and implicates this axis in stroke pathology.