Siow 2022 J Cell Sci
| Siow WX, Kabiri Y, Tang R, Chao YK, Plesch E, Eberhagen C, Flenkenthaler F, Fröhlich T, Bracher F, Grimm C, Biel M, Zischka H, Vollmar AM, Bartel K (2022) Lysosomal TRPML1 regulates mitochondrial function in hepatocellular carcinoma cells. https://doi.org/10.1242/jcs.259455 |
» J Cell Sci 135:jcs259455. PMID: 35274126 Open Access
Siow Wei Xiong, Kabiri Yaschar, Tang Rachel, Chao Yu-Kai, Plesch Eva, Eberhagen Carola, Flenkenthaler Florian, Froehlich Thomas, Bracher Franz, Grimm Christian, Biel Martin, Zischka Hans, Vollmar Angelika M, Bartel Karin (2022) J Cell Sci
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 • Bioblast editor: Plangger M • O2k-Network Lab: DE Munich Zischka H
Labels: MiParea: Respiration
Pathology: Cancer
Organism: Mouse Tissue;cell: Liver Preparation: Permeabilized cells
Regulation: Ion;substrate transport Coupling state: LEAK, OXPHOS Pathway: N, S, ROX HRR: Oxygraph-2k
2023-06
