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Author Spotlight: Detection of Mitophagy in Caenorhabditis elegans and Mammalian Cells Using Organelle-Specific Dyes
Published on: May 19, 2023
Mitophagy contributes to alpha-tocopheryl succinate toxicity in GSNOR-deficient hepatocellular carcinoma
Salvatore Rizza1, Luca Di Leo2, Sara Mandatori3
1Redox Signaling and Oxidative Stress Group, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
Abstract:
The downregulation of the denitrosylating enzyme S-nitrosoglutathione reductase (GSNOR, EC:1.1.1.284), is a feature of hepatocellular carcinoma (HCC). This condition causes mitochondrial rearrangements that sensitize these tumors to mitochondrial toxins, in particular to the mitochondrial complex II inhibitor alpha-tocopheryl succinate (αTOS). It has also been reported the GSNOR depletion impairs the selective degradation of mitochondria through mitophagy; however, if this contributes to GSNOR-deficient HCC cell sensitivity to αTOS and can be applied to anticancer therapies, is still not known. Here, we provide evidence that GSNOR-deficient HCC cells show defective mitophagy which contributes to αTOS toxicity. Mitophagy inhibition by Parkin (EC: 2.3.2.31) depletion enhances αTOS anticancer effects, thus suggesting that this drug could be effective in treating mitophagy-defective tumors.
Insights
Hepatocellular carcinoma (HCC) cells lacking S-nitrosoglutathione reductase (GSNOR) exhibit impaired mitophagy, increasing sensitivity to alpha-tocopheryl succinate (αTOS). This suggests αTOS may treat tumors with defective mitophagy.
Area of Science:
- Biochemistry and Molecular Biology
- Oncology
- Cell Biology
Background:
- Hepatocellular carcinoma (HCC) is characterized by reduced S-nitrosoglutathione reductase (GSNOR) activity.
- GSNOR deficiency leads to mitochondrial dysfunction and sensitizes HCC cells to mitochondrial toxins like alpha-tocopheryl succinate (αTOS).
- GSNOR depletion is linked to impaired mitophagy, but its role in HCC cell sensitivity to αTOS and therapeutic potential remains unclear.
Purpose of the Study:
- To investigate the contribution of defective mitophagy to the sensitivity of GSNOR-deficient HCC cells to αTOS.
- To explore the potential of αTOS as a therapeutic agent for mitophagy-defective tumors.
Main Methods:
- Utilized GSNOR-deficient HCC cell models.
- Assessed mitophagy levels and αTOS sensitivity.
- Investigated the role of Parkin (a mitophagy regulator) in modulating αTOS efficacy.
Main Results:
- GSNOR-deficient HCC cells demonstrated defective mitophagy.
- This mitophagy defect was found to contribute significantly to αTOS-induced toxicity.
- Inhibition of mitophagy via Parkin depletion potentiated the anticancer effects of αTOS.
Conclusions:
- Defective mitophagy is a key factor in the heightened sensitivity of GSNOR-deficient HCC cells to αTOS.
- αTOS shows promise as a therapeutic strategy for cancers exhibiting mitophagy defects.
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