Lysosomal TRPML1 regulates mitochondrial function in hepatocellular carcinoma cells

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Hepatocellular carcinoma (HCC) is a major global cause of cancer mortality, necessitating novel therapeutic targets.
• The endolysosomal cation channel TRPML1 (MCOLN1) is emerging as a potential target in cancer research.
• Existing therapeutic strategies for HCC remain limited, highlighting the need for innovative approaches.

Purpose of the Study:

• To investigate the role of TRPML1 in hepatocellular carcinoma (HCC) progression and identify its potential as a therapeutic target.
• To develop and validate tools for studying TRPML1 function, including an isoform-selective activator (ML1-SA1) and CRISPR/Cas9-based loss-of-function models.
• To elucidate the mechanisms by which TRPML1 modulates cancer cell behavior, focusing on proliferation, apoptosis, and mitochondrial function.

Main Methods:

• Utilized a novel isoform-selective TRPML1 activator (ML1-SA1) and CRISPR/Cas9 gene editing for TRPML1 overactivation and loss-of-function studies in HCC models.
• Assessed cancer cell proliferation, apoptosis, and proteomic alterations.
• Performed detailed mitochondrial function analysis using confocal and transmission electron microscopy, SeahorseTM, and Oroboros® assays.

Main Results:

• TRPML1 overactivation, induced by ML1-SA1, triggers apoptosis in HCC cells through Ca2+-dependent impairment of mitochondrial function.
• TRPML1 loss-of-function leads to dysregulated mitochondrial renewal, consequently impairing HCC cell proliferation.
• Proteomic analysis revealed significant alterations in response to TRPML1 modulation.

Conclusions:

• TRPML1 plays a critical role in regulating mitochondrial function within hepatocellular carcinoma.
• Modulators of TRPML1 represent promising therapeutic candidates for the treatment of HCC.
• Targeting TRPML1 offers a novel strategy to combat liver cancer by influencing mitochondrial dynamics and cell fate.