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Updated: Jan 13, 2026
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Mitochondrial ROS-induced metabolic alterations differentially regulate ferroptosis sensitivity
Abstract:
Ferroptosis is an iron-catalyzed lipid peroxidation (LP)-dependent cell death. Induction of mitochondrial ROS (mtROS) is crucial in the execution of ferroptosis, but the underlying mechanism remains unclear. Through utilizing the hepatocyte model and RNA-seq analysis, we determined mtROS-dependent metabolic changes that modulate ferroptosis sensitivity. Elevated mtROS production and LP suppressed glycolysis, fatty acid oxidation, and citric acid cycle activity, representing adaptive responses that protect cells from ferroptosis. On the other hand, mtROS-driven signaling impaired glutathione biosynthesis and downregulated genes involved in coenzyme Q10 (CoQ) biosynthesis, including those in the mevalonate pathway and CoQ8A, a key stabilizer of the CoQ biosynthetic complex. Importantly, silencing CoQ8A expression enhanced, whereas overexpression of CoQ8A reduced, ferroptosis susceptibility of hepatocytes and various cancer cell types. The mtROS-mediated downregulation of CoQ8A was dependent on farnesoid X receptor (FXR) and retinoid X receptors (RXRs). Collectively, our findings highlight that mtROS promotes ferroptosis, at least in part, by suppressing glutathione and CoQ biosynthesis.
Insights
Mitochondrial reactive oxygen species (mtROS) promote ferroptosis, a cell death pathway. This study reveals mtROS suppresses glutathione and coenzyme Q10 biosynthesis, impacting ferroptosis sensitivity in hepatocytes and cancer cells.
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.
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