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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

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p53 opens the mitochondrial permeability transition pore to trigger necrosis

Angelina V Vaseva1, Natalie D Marchenko, Kyungmin Ji

  • 1Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA.

Cell
|June 26, 2012
PubMed

Insights

This study reveals that p53 protein triggers necrosis during oxidative stress by interacting with cyclophilin D in mitochondria. Blocking this interaction protects against stroke, highlighting a new therapeutic target for ischemia.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Neuroscience

Background:

  • Ischemia causes oxidative damage and necrosis, leading to significant tissue loss.
  • p53 protein is a key stress sensor involved in apoptosis and autophagy.
  • The role of p53 in oxidative stress-induced necrosis remains unclear.

Purpose of the Study:

  • To investigate whether p53 can activate necrosis in response to oxidative stress.
  • To elucidate the signaling mechanism of p53-mediated necrosis.
  • To determine the role of the p53-cyclophilin D interaction in stroke pathology.

Main Methods:

  • Studied p53 localization and function under oxidative stress conditions.
  • Investigated the interaction between p53 and cyclophilin D (CypD) in mitochondria.
  • Utilized mouse models of brain ischemia/reperfusion injury.
  • Assessed the effects of p53 reduction and cyclosporine A treatment on stroke outcomes.

Main Results:

  • p53 accumulates in the mitochondrial matrix upon oxidative stress, triggering the mitochondrial permeability transition pore (PTP) opening and necrosis.
  • A physical interaction between p53 and CypD is essential for PTP opening and necrosis.
  • Formation of a p53-CypD complex was observed during brain ischemia/reperfusion injury.
  • Reducing p53 levels or inhibiting the p53-CypD interaction with cyclosporine A conferred protection against stroke.

Conclusions:

  • The mitochondrial p53-CypD axis is a critical mediator of oxidative stress-induced necrosis.
  • This axis plays a significant role in the pathology of stroke.
  • Targeting the p53-CypD interaction may offer a novel therapeutic strategy for stroke and other ischemia-related conditions.

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