Mitochondrial ROS-induced metabolic alterations differentially regulate ferroptosis sensitivity

Area of Science:

• Cellular Biology
• Biochemistry
• Metabolism

Background:

• Ferroptosis is an iron-catalyzed, lipid peroxidation-dependent cell death process.
• Mitochondrial reactive oxygen species (mtROS) are critical for ferroptosis execution, but the precise mechanisms are not fully understood.

Purpose of the Study:

• To investigate mtROS-dependent metabolic alterations influencing ferroptosis sensitivity.
• To elucidate the role of glutathione and coenzyme Q10 (CoQ) biosynthesis in mtROS-mediated ferroptosis.

Main Methods:

• Hepatocyte model and RNA-sequencing (RNA-seq) analysis were employed.
• Gene silencing and overexpression of Coenzyme Q10 biosynthesis genes (CoQ8A) were performed.
• The involvement of farnesoid X receptor (FXR) and retinoid X receptors (RXRs) was assessed.

Main Results:

• Elevated mtROS and lipid peroxidation suppressed glycolysis, fatty acid oxidation, and the citric acid cycle.
• mtROS impaired glutathione biosynthesis and downregulated CoQ biosynthesis genes, including CoQ8A.
• Silencing CoQ8A increased ferroptosis, while its overexpression decreased ferroptosis susceptibility.

Conclusions:

• mtROS promotes ferroptosis, partly by inhibiting glutathione and CoQ biosynthesis.
• CoQ8A acts as a key regulator of ferroptosis susceptibility.
• mtROS-mediated CoQ8A downregulation is dependent on FXR and RXR signaling pathways.