TRPML1-induced autophagy inhibition triggers mitochondrial mediated apoptosis
Yucheng Liu1, Xinyan Wang1, Wucheng Zhu1
1Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, 209 Tongshan Rd, Xuzhou, Jiangsu, 221004, China.
Abstract:
Previous studies have demonstrated that autophagy tightly regulates apoptosis. However, the underlying mechanism whereby autophagy regulates apoptosis remains unclear. Here, we discover a "autophagy inhibition-mitochondrial turnover disruption-ROS elevation-DNA damage-p53 transactivation-apoptosis" axis that explicates the process of autophagy modulating apoptosis. We found that autophagy inhibition induced by TRPML1, a cationic channel localized in the lysosome, results in accumulation of damaged mitochondria via blocking the mitophagic flux to lysosomes in human melanoma and glioblastoma cells. The disrupted mitochondria turnover leads to ROS elevation, which in turn causes severe damage to DNA in these cancer cells. Damage to DNA resulted from TRPML1-mediated autophagy inhibition subsequently activates p53, which ultimately triggers mitochondrial mediated apoptosis by modulating pro- and anti-apoptosis proteins in these cancer cells. As a result, by triggering apoptosis, TRPML1-induced autophagy inhibition greatly suppresses growth of human melanoma and glioma both in vitro and in vivo. In summary, our findings define the mechanism underling the regulation of autophagy inhibition in apoptosis and represent TRPML1 as a novel target for potentially treating melanoma and glioblastoma in the clinical setting.
Insights
Autophagy inhibition by TRPML1 disrupts mitochondrial turnover, causing DNA damage and apoptosis in cancer cells. This reveals a novel mechanism for targeting melanoma and glioblastoma.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Autophagy's role in regulating apoptosis is established but not fully understood.
- The precise molecular mechanisms linking autophagy to apoptosis require elucidation.
Purpose of the Study:
- To elucidate the mechanism by which autophagy inhibition modulates apoptosis.
- To identify TRPML1 as a key regulator in this process and evaluate its therapeutic potential.
Main Methods:
- Investigated the effect of TRPML1-induced autophagy inhibition on mitochondrial turnover in human melanoma and glioblastoma cells.
- Assessed reactive oxygen species (ROS) levels, DNA damage, p53 activation, and apoptosis.
- Evaluated the in vitro and in vivo efficacy of TRPML1 inhibition in suppressing tumor growth.
Main Results:
- TRPML1 inhibition blocks mitophagic flux, leading to damaged mitochondria accumulation.
- Disrupted mitochondrial turnover results in elevated ROS and subsequent DNA damage.
- DNA damage activates p53, triggering apoptosis and suppressing tumor growth in melanoma and glioblastoma models.
Conclusions:
- A novel "autophagy inhibition-mitochondrial turnover disruption-ROS elevation-DNA damage-p53 transactivation-apoptosis" axis has been defined.
- TRPML1 is identified as a critical mediator linking autophagy inhibition to apoptosis.
- TRPML1 represents a promising therapeutic target for melanoma and glioblastoma treatment.
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