p53 opens the mitochondrial permeability transition pore to trigger necrosis

By Angelina V. Vaseva, N. Marchenko, K. Ji, S. Tsirka, S. Holzmann, U. Moll. Cell, 2012

729 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a06eb242a302b8126db94b6a9400aa8d5825cab6

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Citations in the corpus

Neuronal Cell Death. (2018, neutral): “There is some evidence that brain ischemia can also cause mPT leading to necrosis by translocation of p53 to mitochondria where it forms a complex with cyclophilin D (688).”
How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? (2017, background): “For example, p53 was reported to open the mitochondrial permeability transition pore to thereby induce necrotic cell death.(98) Moreover, p53 has also been reported to sensitise cells to ferroptosis, a non-apoptotic form of cell death,(99) by repressing expression of SLC7A11, a key component of the ”
Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 (2018, background): “At odds with CYPD, several other proteins that had previously been hypothesized to mediate a non-redundant role within the PTPC turned out to be dispensable for MPT in vivo, based on relatively robust genetic models [373].”
Crosstalk between apoptosis, necrosis and autophagy. (2013, methodology): “Moreover, p53 can directly promote mitochondrial outer membrane permeabilization (MOMP) to trigger apoptosis by modulating the MOMP governing BCL-2 family [55,56].”
Multiple Functions of BCL-2 Family Proteins (2013, background): “Recently, p53 was reported to accumulate in the mitochondrial matrix and trigger mitochondrial permeability transition pore (PTP) opening by interactionwith the PTPregulatorcyclophilin D (CypD) in response to oxidative stress (Vaseva et al. 2012).”
The Cell-Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression. (2016, background): “Interestingly, a recent study suggests that p53 not only regulates mitochondria outer membrane permeability, it also induces permeabilization of the inner mitochondria membrane during oxidative stress (Vaseva et al. 2012).”