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Siow, W.X.* ; Kabiri, Y.* ; Tang, R.* ; Chao, Y.K.* ; Plesch, E.* ; Eberhagen, C. ; Flenkenthaler, F.* ; Fröhlich, T.* ; Bracher, F.* ; Grimm, C.* ; Biel, M.* ; Zischka, H. ; Vollmar, A.M.* ; Bartel, K.*

Lysosomal TRPML1 regulates mitochondrial function in hepatocellular carcinoma cells.

J. Cell Sci. 135:jcs259455 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Ca2+ ; Cancer ; Hepatocellular Carcinoma ; Lysosome ; Mitochondria ; Mitophagy ; Trpml1
ISSN (print) / ISBN 0021-9533
e-ISSN 1477-9137
Journal Journal of Cell Science
Quellenangaben Volume: 135, Issue: 6, Pages: , Article Number: jcs259455 Supplement: ,
Publisher Company of Biologists
Publishing Place Cambridge
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Toxicology and Pharmacology (TOXI)
Grants Ludwig-Maximilians-Universitat Munchen
Deutsche Forschungsgemeinschaft