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 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 Electronic supplementary material The online version of this article (10.1186/s12964-019-0399-2) contains supplementary material, which is available to authorized users.

Characterization of New Proteomic Biomarker Candidates in Mucopolysaccharidosis Type IVA

“…Previous reports have described the relationship between lysosomes with other organelles such as the transGolgi reticulum, mitochondrion, vesicles, and cytoskeleton [ 49 , 50 , 51 , 52 , 53 ]. Lysosomal activity is regulated by the activation of mTORC1 and CLEAR promotors [ 49 ].…”

Targeting the Mitochondria-Proteostasis Axis to Delay Aging

“…LC3 family proteins can also interact with the mitochondria-specific lipid cardiolipin, which can act as a biosensor for oxidative damage and an autophagic degradation signal when it translocates to the outer mitochondrial membrane ( Antón et al, 2016 ). Interestingly, mitochondrial cardiolipin content seems to be linked to lysosomal function, at least in vitro ( Chen et al, 2008 ; Bartel et al, 2019 ). However, it is not known if this indirect modulation of mitochondrial cardiolipin also induces mitophagy, as observed during oxidative damage-induced translocation of cardiolipin to the mitochondrial surface.…”

Cardiolipin, the Mitochondrial Signature Lipid: Implication in Cancer

“…More studies on Huh7 cell lines have shown that under lysosomal stress, CL content was decreased, leading to mitochondrial fission. Mitochondrial fission was accompanied by an impaired mitochondrial function associated with mitochondria-induced apoptosis [119]. CLs also have a high affinity with the anticancer drug doxorubicin (Dox).…”