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Updated: Jan 11, 2026
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Complex II inhibition suppresses RSL3-induced ferroptosis by restoring mitochondrial bioenergetics
Sun Chul Lee1, Soo Kyung Lee1, Hyun Kim2
1Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea; Organelle Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea; Department of Global Medical Science, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
Abstract:
The mitochondrial electron transport chain (ETC) serves as the main site of cellular energy production and a major source of reactive oxygen species (ROS) generation, which can contribute to the lipid peroxidation associated with ferroptosis. However, the critical roles of mitochondria in ferroptosis are still being debated, and the consequences for cell survival vary depending on different ferroptosis inducers or mitochondrial modulators. In the neuroblastoma clonal cells SH-SY5Y, we demonstrated that inhibition of mitochondrial Complex II by 2-thenoyltrifluoroacetone (TTFA) markedly suppressed RSL3-induced ferroptotic lipid peroxidation and cell death. RSL3, a known inhibitor of glutathione peroxidase 4 (GPX4), significantly increased the mitochondrial membrane potential and superoxide production while reducing ATP-linked oxygen consumption. Co-treatment with TTFA effectively attenuated RSL3-induced mitochondrial hyperpolarization, lowered mitochondrial ROS generation, and restored respiratory activities - particularly enhanced ATP-linked oxygen consumption and reduced proton leak. Consistently, TTFA restored ATP production suppressed by RSL3. In contrast, inhibition of Complex I by rotenone did not suppress superoxide production and lipid peroxidation induced by RSL3, although it provided some protection against RSL3-mediated cytotoxicity. These findings suggest that inhibition of Complex II confers protection against ferroptosis by maintaining mitochondrial redox balance and protecting mitochondrial energy metabolism. In addition, our results uncover a novel mitochondrial mechanism underlying RSL3-induced oxidative stress and ferroptosis that can be modulated through targeted regulation of the ETC.
Insights
Inhibiting mitochondrial Complex II protects against ferroptosis by preserving mitochondrial function and energy production. This study reveals a new mitochondrial mechanism in ferroptosis that can be targeted by regulating the electron transport chain (ETC).
Area of Science:
- Cellular Biology
- Mitochondrial Function
- Oxidative Stress
Background:
- Mitochondria are key in cellular energy production and reactive oxygen species (ROS) generation, influencing ferroptosis.
- The precise role of mitochondria in ferroptosis remains debated, with varied outcomes depending on inducers and modulators.
- Ferroptosis, a regulated form of cell death, involves lipid peroxidation and is linked to mitochondrial dysfunction.
Purpose of the Study:
- To investigate the role of mitochondrial Complex II in ferroptosis induced by RSL3 in SH-SY5Y neuroblastoma cells.
- To elucidate the mechanism by which Complex II inhibition affects mitochondrial function, ROS production, and cell death during ferroptosis.
- To explore the potential of targeting the electron transport chain (ETC) for modulating ferroptosis.
Main Methods:
- Utilized SH-SY5Y neuroblastoma cells.
- Administered RSL3 (a GPX4 inhibitor) and 2-thenoyltrifluoroacetone (TTFA, a Complex II inhibitor) or rotenone (a Complex I inhibitor).
- Assessed mitochondrial membrane potential, superoxide production, ATP-linked oxygen consumption, ATP production, and lipid peroxidation.
Main Results:
- TTFA significantly suppressed RSL3-induced ferroptotic lipid peroxidation and cell death.
- RSL3 increased mitochondrial membrane potential and superoxide production while decreasing ATP-linked oxygen consumption.
- TTFA counteracted RSL3 effects by reducing mitochondrial hyperpolarization and ROS, restoring respiratory activity and ATP production. Rotenone showed limited impact on RSL3-induced ROS and lipid peroxidation.
Conclusions:
- Inhibition of mitochondrial Complex II protects against ferroptosis by maintaining mitochondrial redox balance and energy metabolism.
- Targeting Complex II offers a novel strategy to modulate ferroptosis by regulating mitochondrial function.
- The study uncovers a specific mitochondrial mechanism in RSL3-induced ferroptosis involving Complex II and oxidative stress.
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