Iron addicted colorectal cancers exploit Heme-Complex II axis to resist oxidative cell death

Area of Science:

• Oncology
• Cell Biology
• Biochemistry

Background:

• Colorectal cancer (CRC) cells exhibit high iron dependency for proliferation.
• High intracellular iron is generally cytotoxic, posing a question about CRC cell survival in iron-rich environments.
• Ferroptosis, an iron-dependent cell death, is a known pathway, but its role in iron-induced cell death in CRC in vivo is not fully understood.

Purpose of the Study:

• To investigate the mechanisms by which colorectal cancer cells tolerate and exploit iron-rich environments.
• To identify novel pathways involved in buffering iron-induced oxidative stress in CRC.
• To explore the role of the heme-succinate dehydrogenase (SDH)-Coenzyme Q (CoQ) axis in CRC cell survival.

Main Methods:

• Multi-omics profiling
• CRISPR screening
• In vivo mouse models
• Biochemical assays

Main Results:

• A novel heme-dependent succinate dehydrogenase (SDH)-Coenzyme Q (CoQ) axis was identified in CRC cells.
• This axis enables CRC cells to buffer iron-induced oxidative stress by reducing CoQ.
• Reduced CoQ acts as a radical-trapping antioxidant, detoxifying lipid reactive oxygen species (ROS) at mitochondrial and plasma membranes.
• This pathway operates independently of, or in parallel with, canonical ferroptosis regulators.

Conclusions:

• Colorectal cancer cells co-opt metabolic pathways, including the SDH-CoQ axis, for survival under toxic iron conditions.
• This heme-SDH-CoQ pathway is crucial for detoxifying iron-induced oxidative stress in CRC.
• The findings reveal new therapeutic vulnerabilities in colorectal cancer related to iron metabolism and oxidative stress management.