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Connecting lysosomes and mitochondria - a novel role for lipid metabolism in cancer cell death.
Cell Commun. Signal. 17:87 (2019)
BackgroundThe 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.MethodsLC-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.ResultsOur data reveal that interfering with lysosomal function changes composition and subcellular localization of triacylglycerids accompanied by an upregulation of PGC1 alpha and PPAR alpha 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.ConclusionThis 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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Lysosome ; V-atpase ; Mitochondria ; Fission ; Apoptosis ; Lipid Metabolism ; Cardiolipin; V-atpase Inhibition; Saturated Fatty-acids; Signaling Pathways; Apoptosis; Tfeb; Transformation; Dysfunction; Metastasis; Activation; Mechanism
ISSN (print) / ISBN
1478-811X
e-ISSN
1478-811X
Journal
Cell Communication and Signaling
Quellenangaben
Volume: 17,
Issue: 1,
Article Number: 87
Publisher
BioMed Central
Publishing Place
Campus, 4 Crinan St, London N1 9xw, England
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Reviewing status
Peer reviewed