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SENP3 Promotes an Mff-Primed Bcl-x -Drp1 Interaction Involved in Cell Death Following Ischemia

Chun Guo1, Keri L Hildick2, Juwei Jiang1

  • 1School of Biosciences, University of Sheffield, Sheffield, United Kingdom.

Frontiers in Cell and Developmental Biology
|November 1, 2021
PubMed

Insights

Mitochondrial fission protein SUMOylation regulates cell death during ischemia. SENP3 deSUMOylation enhances Drp1-Bcl-x interaction, promoting cell death, while blocking this interaction reduces cell death.

Area of Science:

  • Cell Biology
  • Mitochondrial Dynamics
  • Ischemic Cell Death

Background:

  • Mitochondrial fission machinery dysregulation is implicated in ischemic cell death.
  • Dynamin-related protein 1 (Drp1) recruitment to Mitochondrial fission factor (Mff) on the mitochondrial outer membrane is crucial for fission.
  • Drp1 SUMOylation and deSUMOylation by SENP3 influence the Drp1-Mff interaction and cell death.

Purpose of the Study:

  • To investigate the role of Drp1 SUMOylation and deSUMOylation in regulating the interaction with Bcl-x .
  • To elucidate the interplay between Mff, Drp1, and Bcl-x in the context of ischemia-reperfusion injury.
  • To determine the therapeutic potential of modulating the Drp1-Bcl-x interaction in ischemic conditions.

Main Methods:

  • Investigated Drp1 SUMOylation and deSUMOylation effects on Drp1-Bcl-x interaction using in vivo and in vitro assays.
  • Utilized oxygen/glucose deprivation (OGD) and reoxygenation models to simulate ischemia.
  • Employed mutant Bcl-x proteins to assess the functional significance of the Drp1-Bcl-x interaction in cell death.

Main Results:

  • Preventing Drp1 SUMOylation and SENP3-mediated deSUMOylation enhance the Drp1-Bcl-x interaction.
  • Mff acts as a priming factor for Drp1 binding to Bcl-x , and Mff can directly interact with Bcl-x .
  • SENP3 levels inversely correlate with Drp1-Bcl-x interaction during OGD and reoxygenation.
  • A Bcl-x mutant defective in Drp1 binding significantly reduces cell death following OGD and reoxygenation.

Conclusions:

  • SENP3-mediated deSUMOlyation promotes an Mff-primed Drp1-Bcl-x interaction.
  • This interaction contributes to cell death following ischemia-reperfusion.
  • Targeting the Drp1-Bcl-x interaction may offer a therapeutic strategy for ischemic conditions.
Keywords:
Bcl-xLDrp1MffSENP3SUMOylationischemia

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