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Oxidatively truncated phospholipids are required agents of tumor necrosis factor α (TNFα)-induced apoptosis

Calivarathan Latchoumycandane1, Gopal K Marathe1, Renliang Zhang1

  • 1Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio 44195.

The Journal of Biological Chemistry
|March 22, 2012
PubMed

Insights

Tumor Necrosis Factor alpha (TNFα) triggers cell death by creating oxidized, truncated phospholipids like azelaoyl phosphatidylcholine (Az-PC). These molecules are essential for TNFα-induced apoptosis, linking cell surface signals to mitochondrial damage.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Immunology

Background:

  • Tumor Necrosis Factor alpha (TNFα) induces cell death via reactive oxygen species (ROS) at the cell surface.
  • The precise mechanisms by which ROS communicate with mitochondria and induce apoptosis remain unclear.
  • Oxidation of phospholipids by ROS generates truncated phospholipids, such as azelaoyl phosphatidylcholine (Az-PC), which can initiate intrinsic apoptosis.

Purpose of the Study:

  • To investigate if Az-PC is formed intracellularly during TNFα stimulation.
  • To determine if Az-PC is essential for TNFα-induced cytotoxicity.
  • To elucidate the role of phospholipid oxidation and truncation in TNFα-mediated apoptosis.

Main Methods:

  • Monitoring ROS formation and phospholipid peroxidation in Jurkat cells stimulated with TNFα.
  • Utilizing NADPH oxidase inhibitors and siRNA to block ROS production.
  • Employing mass spectrometry to quantify phospholipid peroxides and Az-PC levels.
  • Assessing the impact of Glutathione peroxidase-4 (GPx4) and PAFAH2 modulation on cell death and phospholipid metabolism.

Main Results:

  • TNFα stimulation led to ROS generation, phospholipid peroxidation, and increased Az-PC levels in Jurkat cells.
  • Inhibition of ROS production or GPx4 activity blocked Az-PC formation and TNFα-induced cell death.
  • GPx4 knockdown enhanced Az-PC formation and apoptosis, while PAFAH2 overexpression prevented Az-PC accumulation and cell death.
  • Phospholipid oxidation and truncation were identified as critical steps connecting TNFα signaling to mitochondrial apoptosis.

Conclusions:

  • Intracellular formation of Az-PC is a key event in TNFα-induced apoptosis.
  • The pathway involving ROS-mediated phospholipid oxidation and truncation is essential for TNFα cytotoxicity.
  • Targeting this phospholipid-centric pathway offers potential therapeutic strategies for diseases involving TNFα-mediated cell death.

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