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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)
Verlagsversion Forschungsdaten 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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Ca2+ ; Cancer ; Hepatocellular Carcinoma ; Lysosome ; Mitochondria ; Mitophagy ; Trpml1
ISSN (print) / ISBN 0021-9533
e-ISSN 1477-9137
Zeitschrift Journal of Cell Science
Quellenangaben Band: 135, Heft: 6, Seiten: , Artikelnummer: jcs259455 Supplement: ,
Verlag Company of Biologists
Verlagsort Cambridge
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Molecular Toxicology and Pharmacology (TOXI)
Förderungen Ludwig-Maximilians-Universitat Munchen
Deutsche Forschungsgemeinschaft