Related Experiment Video
Updated: Aug 25, 2025
Author Spotlight: THP-1 Macrophage Response to LPS/ATP — Unveiling the Pyroptosis, Apoptosis, and Necroptosis Spectrum
Published on: May 3, 2024
Mitochondrion-Mediated Cell Death through Erk1-Alox5 Independent of Caspase-9 Signaling
1Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract:
Mitochondrial disruption leads to the release of cytochrome c to activate caspase-9 and the downstream caspase cascade for the execution of apoptosis. However, cell death can proceed efficiently in the absence of caspase-9 following mitochondrial disruption, suggesting the existence of caspase-9-independent cell death mechanisms. Through a genome-wide siRNA library screening, we identified a network of genes that mediate caspase-9-independent cell death, through ROS production and Alox5-dependent membrane lipid peroxidation. Erk1-dependent phosphorylation of Alox5 is critical for targeting Alox5 to the nuclear membrane to mediate lipid peroxidation, resulting in nuclear translocation of cytolytic molecules to induce DNA damage and cell death. Consistently, double knockouts of caspase-9 and Alox5 in mice, but not deletion of either gene alone, led to significant T cell expansion with inhibited cell death, indicating that caspase-9- and Alox5-dependent pathways function in parallel to regulate T cell death in vivo. This unbiased whole-genome screening reveals an Erk1-Alox5-mediated pathway that promotes membrane lipid peroxidation and nuclear translocation of cytolytic molecules, leading to the execution of cell death in parallel to the caspase-9 signaling cascade.
Insights
A new study reveals a caspase-9-independent cell death pathway involving Erk1 and Alox5. This pathway promotes lipid peroxidation and DNA damage, offering new insights into apoptosis regulation.
Area of Science:
- Cell Biology
- Molecular Biology
- Immunology
Background:
- Mitochondrial disruption typically initiates apoptosis via caspase-9.
- Caspase-9-independent cell death pathways exist but are not fully understood.
Purpose of the Study:
- To identify novel caspase-9-independent cell death mechanisms.
- To elucidate the molecular players and pathways involved in this alternative cell death route.
Main Methods:
- Genome-wide siRNA library screening to identify key genes.
- Analysis of reactive oxygen species (ROS) production and lipid peroxidation.
- Investigating Erk1-dependent phosphorylation and Alox5 localization.
- Utilizing caspase-9 and Alox5 double knockout mouse models.
Main Results:
- A network of genes mediating caspase-9-independent cell death was identified, involving ROS and Alox5-dependent lipid peroxidation.
- Erk1-mediated phosphorylation targets Alox5 to the nuclear membrane, inducing lipid peroxidation.
- This process leads to nuclear translocation of cytolytic molecules, causing DNA damage and cell death.
- Double knockout of caspase-9 and Alox5 in mice inhibited T cell death, leading to T cell expansion.
Conclusions:
- An Erk1-Alox5-mediated pathway executes cell death in parallel to the caspase-9 cascade.
- This pathway involves membrane lipid peroxidation and nuclear translocation of cytolytic molecules.
- The findings highlight a parallel cell death mechanism crucial for regulating T cell homeostasis in vivo.
Related Concept Videos
01:30Overview of Cell Death
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the...
01:17The Extrinsic Apoptotic Pathway
01:31The Intrinsic Apoptotic Pathway
01:30Apoptosis
01:24Caspases
01:07MAPK Signaling Cascades