Role of Mitochondria in Ferroptosis

By Minghui Gao, Junmei Yi, Jiajun Zhu, Alexander M. Minikes, Prashant Monian, Craig B. Thompson, Xuejun Jiang. Molecules and Cells, 2018

1,811 citations recorded by the source corpus.

Summary Ferroptosis is a regulated necrosis process driven by iron-dependent lipid peroxidation. Although ferroptosis and cellular metabolism interplay with each other, whether mitochondria are involved in ferroptosis is under debate. Here we demonstrate that mitochondria play a crucial role in cysteine deprivation-induced ferroptosis but not in that induced by inhibiting glutathione peroxidase-4 (GPX4), the most downstream component of the ferroptosis pathway. Mechanistically, cysteine deprivation leads to mitochondrial membrane potential hyperpolarization and lipid peroxide accumulation. Inhibition of mitochondrial TCA cycle or electron transfer chain (ETC) mitigated mitochondrial membrane potential hyperpolarization, lipid peroxide accumulation, and ferroptosis. Blockage of glutaminolysis had the same inhibitory effect, which was counteracted by supplying downstream TCA cycle intermediates. Importantly, loss of function of fumarate hydratase, a tumor suppressor and TCA cycle component, confers resistance to cysteine deprivation-induced ferroptosis. Collectively, this work demonstrates the crucial role of mitochondria in cysteine deprivation-induced ferroptosis and implicates ferroptosis in tumor suppression.

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/1b1ad842923d9bc9d8e769178cd784bd85e39769

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. Guido Kroemer
2. D. Tang
3. R. Kang
4. Xin Chen
5. Xuejun Jiang
6. Jiajun Zhu
7. Brent R. Stockwell
8. Qing-zhang Tuo

In Molecular Biology

1. Guido Kroemer
2. D. Tang
3. R. Kang
4. Xin Chen
5. Brent R. Stockwell
6. D. Klionsky
7. Jiao Liu
8. Xuejun Jiang

In Pulmonary and Respiratory Medicine

1. D. Tang
2. R. Kang
3. Guido Kroemer
4. Brent R. Stockwell
5. Xin Chen
6. Jiao Liu
7. D. Klionsky
8. Xuejun Jiang

Citations in the corpus

• The interaction between ferroptosis and lipid metabolism in cancer (2020, background): “The PUFA-OOH is the main source of LPO.”
• Ferroptosis in infection, inflammation, and immunity (2021, background): “mitochondria (Gao et al., 2019) and dipeptidyl peptidase 4”
• Mitochondria ROS and mitophagy in acute kidney injury (2022, background): “Thus, inhibition VDAC caused mitochondrial TCA cycle inhibition which mitigate mitochondrial membrane potential hyperpolarization, lipid peroxide accumulation and triggers a mitophagy-dependent ROS increase leading to ferroptosis (summarized in Figure 4) [39,133,134].”
• Ferroptosis as a target for protection against cardiomyopathy (2019, background): “(48) reported that mitochondria are important for cysteine deprivation-induced ferroptosis but not in glutathione peroxidase-4 (GPX4) inhibition-induced ferroptosis.”
• Emerging mechanisms and disease relevance of ferroptosis (2020, background): “More recently, it was demonstrated that the normal metabolic function of mitochondria, including the tricarboxylic acid (TCA) cycle in which fumarase is a key component, facilitates ferroptotic cell death in response to cysteine starvation (Figure 3) [59].”