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Noxa mitochondrial targeting domain induces necrosis via VDAC2 and mitochondrial catastrophe

Ji-Hye Han1, Junghee Park1, Seung-Hyun Myung1

  • 1Department of Biochemistry and Molecular Biology, Chosun University School of Medicine, 309 Pilmoon-Daero, Dong-Gu, Gwang-Ju, 61452, Korea.

Cell Death & Disease
|July 10, 2019
PubMed

Insights

The Noxa protein's mitochondrial targeting domain (MTD) induces necrotic cell death by interacting with VDAC2. This interaction opens the mitochondrial permeability transition pore (mPTP), causing cell damage.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Medicine

Background:

  • Noxa is a BH3-only protein that triggers apoptosis by binding prosurvival Bcl-2 proteins.
  • The Noxa mitochondrial targeting domain (MTD) induces mitochondrial fragmentation and necrosis.

Purpose of the Study:

  • To investigate the mechanism by which the Noxa MTD induces necrotic cell death.
  • To identify the specific protein interactions and pathways involved in MTD-mediated necrosis.

Main Methods:

  • Utilized an extended MTD (eMTD) peptide in cell culture models.
  • Assessed cell viability, membrane integrity, calcium influx, mitochondrial morphology, and reactive oxygen species (ROS) generation.
  • Investigated the role of VDAC2 and the mitochondrial permeability transition pore (mPTP) using gene silencing and pharmacological inhibitors.

Main Results:

  • The eMTD peptide induced necrotic cell death, characterized by membrane blebbing, calcium influx, mitochondrial swelling, fragmentation, and ROS generation.
  • The MTD domain directly interacts with VDACs, particularly VDAC2.
  • MTD-induced mPTP opening occurred independently of CypD and was inhibited by VDAC2 downregulation or DIDS treatment.

Conclusions:

  • The Noxa MTD domain is a potent inducer of necrotic cell death.
  • MTD-induced necrosis involves VDAC2-mediated opening of the mPTP.
  • This mechanism represents a novel pathway for targeted cell death induction.

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