TY  - JOUR
A1  - Bartel, Karin
A1  - Pein, Helmut
A1  - Popper, Bastian
A1  - Schmitt, Sabine
A1  - Janaki-Raman, Sudha
A1  - Schulze, Almut
A1  - Lengauer, Florian
A1  - Koeberle, Andreas
A1  - Werz, Oliver
A1  - Zischka, Hans
A1  - Müller, Rolf
A1  - Vollmar, Angelika M.
A1  - Schwarzenberg, Karin von
T1  - Connecting lysosomes and mitochondria – a novel role for lipid metabolism in cancer cell death
JF  - Cell Communication and Signaling
N2  - 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.
KW  - lysosome
KW  - V-ATPase
KW  - mitochondria
KW  - fission
KW  - apoptosis
KW  - lipid metabolism
KW  - cardiolipin
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221524
VL  - 17
ER  - 
TY  - JOUR
A1  - Mayer, Alexander E.
A1  - Löffler, Mona C.
A1  - Loza Valdés, Angel E.
A1  - Schmitz, Werner
A1  - El-Merahbi, Rabih
A1  - Trujillo-Viera, Jonathan
A1  - Erk, Manuela
A1  - Zhang, Thianzhou
A1  - Braun, Ursula
A1  - Heikenwalder, Mathias
A1  - Leitges, Michael
A1  - Schulze, Almut
A1  - Sumara, Grzegorz
T1  - The kinase PKD3 provides negative feedback on cholesterol and triglyceride synthesis by suppressing insulin signaling
JF  - Science Signaling
N2  - Hepatic activation of protein kinase C (PKC) isoforms by diacylglycerol (DAG) promotes insulin resistance and contributes to the development of type 2 diabetes (T2D). The closely related protein kinase D (PKD) isoforms act as effectors for DAG and PKC. Here, we showed that PKD3 was the predominant PKD isoform expressed in hepatocytes and was activated by lipid overload. PKD3 suppressed the activity of downstream insulin effectors including the kinase AKT and mechanistic target of rapamycin complex 1 and 2 (mTORC1 and mTORC2). Hepatic deletion of PKD3 in mice improved insulin-induced glucose tolerance. However, increased insulin signaling in the absence of PKD3 promoted lipogenesis mediated by SREBP (sterol regulatory element-binding protein) and consequently increased triglyceride and cholesterol content in the livers of PKD3-deficient mice fed a high-fat diet. Conversely, hepatic-specific overexpression of a constitutively active PKD3 mutant suppressed insulin-induced signaling and caused insulin resistance. Our results indicate that PKD3 provides feedback on hepatic lipid production and suppresses insulin signaling. Therefore, manipulation of PKD3 activity could be used to decrease hepatic lipid content or improve hepatic insulin sensitivity.
KW  - Protein kinase D3 (PKD3)
KW  - cholesterol
KW  - diacylglycerol (DAG)
KW  - liver
KW  - metabolism
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250025
ET  - accepted manuscript
ER  -