Dataset Information

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

ABSTRACT:

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 PGC1? and PPAR? 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.

SUBMITTER: Bartel K

PROVIDER: S-EPMC6664539 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Publications

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

Bartel Karin K Pein Helmut H Popper Bastian B Schmitt Sabine S Janaki-Raman Sudha S Schulze Almut A Lengauer Florian F Koeberle Andreas A Werz Oliver O Zischka Hans H Müller Rolf R Vollmar Angelika M AM von Schwarzenberg Karin K

Cell communication and signaling : CCS 20190729 1

<h4>Background</h4>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.<h4>Methods</h4>LC-MS/MS analysis was performed to investigate l ...[more]

PMID: 31358011

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Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

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