Journal Article

Connecting lysosomes and mitochondria – a novel role for lipid metabolism in cancer cell death

Zischka, Hans, von Schwarzenberg, Karin, Müller, Rolf, Koeberle, Andreas, Vollmar, Angelika M., Schmitt, Sabine, Pein, Helmut, Bartel, Karin, Janaki-Raman, Sudha, Werz, Oliver, Schulze, Almut, Lengauer, Florian, Popper, Bastian

2019

Overview

Background The understanding of lysosomes has been expanded in recent research way beyond their view as cellular trash can. Lysosomes are pivotal in regulating metabolism, endocytosis and autophagy and are implicated in cancer. Recently it was discovered that the lysosomal V-ATPase, which is known to induce apoptosis, interferes with lipid metabolism in cancer, yet the interplay between these organelles is poorly understood. Methods LC-MS/MS analysis was performed to investigate lipid distribution in cells. Cell survival and signaling pathways were analyzed by means of cell biological methods (qPCR, Western Blot, flow cytometry, CellTiter-Blue). Mitochondrial structure was analyzed by confocal imaging and electron microscopy, their function was determined by flow cytometry and seahorse measurements. Results Our data reveal that interfering with lysosomal function changes composition and subcellular localization of triacylglycerids accompanied by an upregulation of PGC1α and PPARα expression, master regulators of energy and lipid metabolism. Furthermore, cardiolipin content is reduced driving mitochondria into fission, accompanied by a loss of membrane potential and reduction in oxidative capacity, which leads to a deregulation in cellular ROS and induction of mitochondria-driven apoptosis. Additionally, cells undergo a metabolic shift to glutamine dependency, correlated with the fission phenotype and sensitivity to lysosomal inhibition, most prominent in Ras mutated cells. Conclusion This study sheds mechanistic light on a largely uninvestigated triangle between lysosomes, lipid metabolism and mitochondrial function. Insight into this organelle crosstalk increases our understanding of mitochondria-driven cell death. Our findings furthermore provide a first hint on a connection of Ras pathway mutations and sensitivity towards lysosomal inhibitors. Graphical Abstract

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Apoptosis / ATPases / Biochemistry / Biomedical and Life Sciences / Cancer / Cardiolipin / Cell Biology / Cell death / Confocal microscopy / Cytokines and Growth Factors / Electron microscopy / Fission / Flow cytometry / Glutamine / Life Sciences / Lipid metabolism / Lysosome / Lysosomes / Membrane lipids / Microscopy / Mitochondria / Protein-Ligand Interactions / Receptors / V-ATPase