Biology subjects

Bogner-Strauss, J.

Publications and source records attributed to Bogner-Strauss, J..

3 recordsLinked to original sources

bioRxiv2020

Loss of malate-aspartate shuttle component SLC25A12 induces pulmonary metastasis

BackgroundAspartate biosynthesis and its delivery to the cytosol can be crucial for tumor growth in vivo. However, the impact of aspartate synthesis on metastasis has not been studied. We previously described that loss-of-aspartate glutamate carrier 1 (SLC25A12 or AGC1), an important component of the malate-aspartate shuttle, impairs cytosolic aspartate levels, NAD+/NADH ratio, mitochondrial respiration, and tumor growth. Here, we report the impact of AGC1-knockdown on metastasis. ResultsAGC1 expression is positively correlated with worse patient prognosis in many cancers. AGC1-knockdown in mouse lung carcinoma and melanoma cell lines leads to increased pulmonary metastasis following subcutaneous or intravenous injections, respectively. On the other hand, conventional in vitro metastasis assays show no indication of increased metastasis capacity of AGC1-knockdown cells. ConclusionThis study highlights that certain branches of metabolism impact tumor growth and tumor metastasis differently. In addition, it also argues that commonly known metastasis indicators, including EMT genes, cell migration, or colony formation do not always reflect the metastatic capacity in vivo.

cancer biology↗

bioRxiv2020

N-acetylaspartate improves cell survival when glucose is limiting

N-acetylasparate (NAA), previously considered a brain-specific metabolite, is found in several cancers. However, whether it plays a role in tumor growth or survival is not fully understood. We provide evidence that NAA prevents cell death in low-glucose conditions via sustaining intracellular UDP-N-acetylglucosamine (UDP-GlcNac) levels, suppressing endoplasmic reticulum (ER) stress, and enabling continued protein synthesis. NAA production is critical for in vivo tumor growth where lower glucose levels are present than those in cell culture. Furthermore, the breakdown of NAA leads to ER stress and cell death, suggesting that the role of NAA in low-glucose is independent of its catabolism to produce aspartate or acetate. Together, these data suggest NAA can support the growth of some tumors by helping them cope with glucose limitations in vivo. HighlightsEndogenous N-acetylaspartate (NAA) production boosts tumor growth NAA supports cell survival in low glucose via suppressing ER stress Breaking down NAA limits tumor growth and induces ER stress in vivo The role of NAA to rescue low glucose is independent of donating acetate or aspartate In briefCancer cells need N-acetylaspartate to avoid ER stress and cell death when glucose availability is low.

cancer biology↗

bioRxiv2019

Subcellular metabolic pathway kinetics are revealed by correcting for artifactual post harvest metabolism

OBJECTIVEThe dynamic regulation of metabolic pathways can be monitored by stable isotope tracing. Yet, many metabolites are part of distinct processes within different subcellular compartments. Standard isotope tracing experiments relying on analyses in whole cells may not accurately reflect compartmentalized metabolic processes. Analysis of compartmentalized metabolism and the dynamic interplay between compartments can potentially be achieved by stable isotope tracing followed by subcellular fractionation. Although it is recognized that metabolism can take place during biochemical fractionation of cells, a clear understanding of how such post-harvest metabolism impacts the interpretation of subcellular isotope tracing data and methods to correct for this are lacking. We set out to directly assess artifactual metabolism, enabling us to develop and test strategies to correct for it. We apply these techniques to examine the compartment-specific metabolic kinetics of 13C-labeled substrates targeting central metabolic pathways.\n\nMETHODSWe designed a stable isotope tracing strategy to interrogate post-harvest metabolic activity during subcellular fractionation using liquid chromatography-mass spectrometry (LC-MS).\n\nRESULTSWe show that post-harvest metabolic activity occurs rapidly (within seconds) upon cell harvest. With further characterization we reveal that this post-harvest metabolism is enzymatic, and reflects the metabolic capacity of the sub-cellular compartment analyzed; but is limited in the extent of its propagation into downstream metabolites in metabolic pathways. We also propose and test a post-labeling strategy to assess the amount of post-harvest metabolism occurring in an experiment and then to adjust data to account for this. We validate this approach for both mitochondrial and cytosolic metabolic analyses.\n\nCONCLUSIONSOur data indicate that isotope tracing coupled with sub-cellular fractionation can reveal distinct and dynamic metabolic features of cellular compartments, and that confidence in such data can be improved by applying a post-labeling correction strategy. We examine compartmentalized metabolism of acetate and glutamine and show that acetyl-CoA is turned over rapidly in the cytosol and acts as a pacemaker of anabolic metabolism in this compartment.

biochemistry↗