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STING1 Promotes Ferroptosis Through MFN1/2-Dependent Mitochondrial Fusion
Changfeng Li1, Jiao Liu2, Wen Hou3
1Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China.
Abstract:
Ferroptosis is a type of iron-dependent regulated cell death caused by the disruption that occurs when oxidative stress and antioxidant defenses interact, and then driven by lipid peroxidation and subsequent plasma membrane ruptures. The regulation of ferroptosis involves many factors, including the crosstalk between subcellular organelles, such as mitochondria, endoplasmic reticulum (ER), lysosomes, lipid droplets, and peroxisomes. Here, we show that the ER protein STING1 (also known as STING or TMEM173) promotes ferroptosis in human pancreatic cancer cell lines by increasing MFN1/2-dependent mitochondrial fusion, but not mitophagy-mediated mitochondrial removal. The classic ferroptosis inducer erastin, but not sulfasalazine, induces the accumulation of STING1 in the mitochondria, where it binds to MFN1/2 to trigger mitochondrial fusion, leading to subsequent reactive oxygen species production and lipid peroxidation. Consequently, in vitro or xenograft mouse models show that the genetic depletion of STING1 or MFN1/2 (but not the mitophagy regulator PINK1 or PRKN) reduces the sensitivity of pancreatic cancer cells to ferroptosis. These findings not only establish a new mitochondrial fusion-dependent cell death mechanism, but also indicate a potential strategy for enhancing ferroptosis-based therapy.
Insights
The endoplasmic reticulum protein STING1 promotes ferroptosis, a cell death pathway, in pancreatic cancer by enhancing mitochondrial fusion. Inhibiting STING1 or mitochondrial fusion proteins reduces ferroptosis sensitivity in cancer cells.
Area of Science:
- Cell Biology
- Oncology
- Biochemistry
Background:
- Ferroptosis is an iron-dependent regulated cell death characterized by lipid peroxidation and plasma membrane rupture.
- The regulation of ferroptosis involves complex crosstalk between various subcellular organelles, including mitochondria and the endoplasmic reticulum (ER).
- Understanding novel regulators of ferroptosis is crucial for developing targeted cancer therapies.
Purpose of the Study:
- To investigate the role of the ER protein STING1 (also known as STING or TMEM173) in ferroptosis.
- To elucidate the mechanism by which STING1 influences ferroptosis, particularly its interaction with mitochondrial dynamics.
- To evaluate the therapeutic potential of targeting STING1 for enhancing ferroptosis in pancreatic cancer.
Main Methods:
- Utilized human pancreatic cancer cell lines and xenograft mouse models.
- Investigated the effect of ferroptosis inducers (erastin, sulfasalazine) on STING1 localization and mitochondrial dynamics.
- Assessed the impact of genetic depletion of STING1, MFN1/2, PINK1, and PRKN on ferroptosis sensitivity.
Main Results:
- STING1 accumulates in mitochondria and promotes ferroptosis by increasing MFN1/2-dependent mitochondrial fusion, not mitophagy.
- Erastin, but not sulfasalazine, induces STING1 accumulation in mitochondria, leading to fusion, reactive oxygen species production, and lipid peroxidation.
- Genetic depletion of STING1 or MFN1/2 significantly reduces ferroptosis sensitivity in pancreatic cancer cells, while depletion of PINK1 or PRKN does not.
Conclusions:
- Established a novel mitochondrial fusion-dependent cell death mechanism regulated by STING1.
- STING1 acts as a promoter of ferroptosis in pancreatic cancer through modulation of mitochondrial fusion.
- Targeting STING1 or MFN1/2 presents a potential therapeutic strategy for enhancing ferroptosis-based treatments in pancreatic cancer.
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