2. Academic Validation
  3. Lysosomal TRPML1 regulates mitochondrial function in hepatocellular carcinoma cells

Lysosomal TRPML1 regulates mitochondrial function in hepatocellular carcinoma cells

  • J Cell Sci. 2022 Mar 15;135(6):jcs259455. doi: 10.1242/jcs.259455.
Wei Xiong Siow 1,  Yaschar Kabiri 2,  Rachel Tang 3,  Yu-Kai Chao 3,  Eva Plesch 4,  Carola Eberhagen 5,  Florian Flenkenthaler 6,  Thomas Fröhlich 6,  Franz Bracher 4,  Christian Grimm 3,  Martin Biel 7,  Hans Zischka 2 5,  Angelika M Vollmar 1,  Karin Bartel 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, Center for Drug Research, Pharmaceutical Biology, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany.
  • 2 Technical University Munich, School of Medicine, Institute of Toxicology and Environmental Hygiene, Biedersteiner Strasse 29, 80802 Munich, Germany.
  • 3 Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, 80336 Munich, Germany.
  • 4 Department of Pharmacy, Center for Drug Research, Pharmaceutical Chemistry, Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
  • 5 Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany.
  • 6 Gene Center, Laboratory for Functional Genome Analysis, Ludwig Maximilians-University Munich, 81377 Munich, Germany.
  • 7 Department of Pharmacy, Center for Drug Research, Pharmacology, Ludwig-Maximilians-University Munich, 81377 Munich, Germany.
PMID: 35274126 DOI: 10.1242/jcs.259455
Abstract

Liver cancers, including hepatocellular carcinoma (HCC), are the second leading cause of Cancer death worldwide, and novel therapeutic strategies are still highly needed. Recently, the endolysosomal cation channel TRPML1 (also known as MCOLN1) has gained focus in Cancer research because it represents an interesting novel target. We utilized the recently developed isoform-selective TRPML1 activator ML1-SA1 and the CRISPR/Cas9 system to generate tools for overactivation and loss-of-function studies on TRPML1 in HCC. After verification of our tools, we investigated the role of TRPML1 in HCC by studying proliferation, Apoptosis and proteomic alterations. Furthermore, we analyzed mitochondrial function in detail by performing confocal and transmission electron microscopy combined with SeahorseTM and Oroboros® functional analysis. We report that TRPML1 overactivation mediated by a novel, isoform-selective small-molecule activator induces Apoptosis by impairing mitochondrial function in a Ca2+-dependent manner. Additionally, TRPML1 loss-of-function deregulates mitochondrial renewal, which leads to proliferation impairment. Thus, our study reveals a novel role for TRPML1 as regulator of mitochondrial function and its modulators as promising molecules for novel therapeutic options in HCC therapy.

Keywords

Ca2+; Cancer; Hepatocellular carcinoma; Lysosome; Mitochondria; Mitophagy; TRPML1.

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