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Updated: Aug 15, 2026

Isolation and Functional Analysis of Mitochondria from Cultured Cells and Mouse Tissue
09:27

Isolation and Functional Analysis of Mitochondria from Cultured Cells and Mouse Tissue

Published on: March 23, 2015

Tumor necrosis factor-related apoptosis-inducing ligand alters mitochondrial membrane lipids

Ferry Sandra1, Mauro Degli Esposti, Kenneth Ndebele

  • 1Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.

Cancer Research
|September 17, 2005
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) alters mitochondrial lipids, like cardiolipin, independently of caspases. This lipid change primes mitochondria for apoptosis, enhancing TRAIL

Area of Science:

  • Cellular biology
  • Molecular biology
  • Biochemistry

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers cell death pathways.
  • Mitochondria are crucial in TRAIL-induced apoptosis but their signaling pathways are not fully understood.
  • Mitochondrial lipid alterations are key to overcoming TRAIL resistance.

Purpose of the Study:

  • To investigate the role of mitochondrial lipids in TRAIL-induced apoptosis.
  • To elucidate the mechanism by which TRAIL signaling affects mitochondrial membrane lipids.
  • To understand how lipid homeostasis impacts apoptosis signaling.

Main Methods:

  • Analysis of mitochondrial membrane lipids, including cardiolipin, following TRAIL stimulation.
  • Assessment of caspase activation (caspase-8 and caspase-9) in response to TRAIL.
  • Investigation of phosphatidylcholine homeostasis and diacylglycerol (DAG) levels.
  • Inhibition of lipid-degrading enzymes to study effects on apoptosis.

Main Results:

  • TRAIL signaling alters mitochondrial membrane lipids, notably cardiolipin, independent of caspase activation.
  • This lipid alteration primes mitochondria for Bid-mediated apoptosis.
  • TRAIL induces phosphatidylcholine imbalance, increasing DAG, which activates PKCδ and accelerates caspase-8 cleavage.
  • Preserving phosphatidylcholine homeostasis inhibits caspase-9 activation without significantly affecting caspase-8 activation.

Conclusions:

  • TRAIL signaling directly impacts mitochondrial lipid homeostasis, a crucial step preceding mitochondrial engagement in apoptosis.
  • The observed lipid alterations are independent of caspase activation but prime the mitochondria for apoptosis.
  • This study reveals a novel link between TRAIL, lipid metabolism, and the mitochondrial apoptotic pathway, offering potential targets for cancer therapy.

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