Publications by authors named "Simon Schwörer"

7 Publications

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Mitochondrial NADP(H) generation is essential for proline biosynthesis.

Science 2021 05 22;372(6545):968-972. Epub 2021 Apr 22.

Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

The coenzyme nicotinamide adenine dinucleotide phosphate (NADP) and its reduced form (NADPH) regulate reductive metabolism in a subcellularly compartmentalized manner. Mitochondrial NADP(H) production depends on the phosphorylation of NAD(H) by NAD kinase 2 (NADK2). Deletion of in human cell lines did not alter mitochondrial folate pathway activity, tricarboxylic acid cycle activity, or mitochondrial oxidative stress, but rather led to impaired cell proliferation in minimal medium. This growth defect was rescued by proline supplementation. NADK2-mediated mitochondrial NADP(H) generation was required for the reduction of glutamate and hence proline biosynthesis. Furthermore, mitochondrial NADP(H) availability determined the production of collagen proteins by cells of mesenchymal lineage. Thus, a primary function of the mitochondrial NADP(H) pool is to support proline biosynthesis for use in cytosolic protein synthesis.
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http://dx.doi.org/10.1126/science.abd5491DOI Listing
May 2021

Proline biosynthesis is a vent for TGFβ-induced mitochondrial redox stress.

EMBO J 2020 04 5;39(8):e103334. Epub 2020 Mar 5.

Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

The production and secretion of matrix proteins upon stimulation of fibroblasts by transforming growth factor-beta (TGFβ) play a critical role in wound healing. How TGFβ supports the bioenergetic cost of matrix protein synthesis is not fully understood. Here, we show that TGFβ promotes protein translation at least in part by increasing the mitochondrial oxidation of glucose and glutamine carbons to support the bioenergetic demand of translation. Surprisingly, we found that in addition to stimulating the entry of glucose and glutamine carbon into the TCA cycle, TGFβ induced the biosynthesis of proline from glutamine in a Smad4-dependent fashion. Metabolic manipulations that increased mitochondrial redox generation promoted proline biosynthesis, while reducing mitochondrial redox potential and/or ATP synthesis impaired proline biosynthesis. Thus, proline biosynthesis acts as a redox vent, preventing the TGFβ-induced increase in mitochondrial glucose and glutamine catabolism from generating damaging reactive oxygen species (ROS) when TCA cycle activity exceeds the ability of oxidative phosphorylation to convert mitochondrial redox potential into ATP. In turn, the enhanced synthesis of proline supports TGFβ-induced production of matrix proteins.
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http://dx.doi.org/10.15252/embj.2019103334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156964PMC
April 2020

Transsulfuration Activity Can Support Cell Growth upon Extracellular Cysteine Limitation.

Cell Metab 2019 11 10;30(5):865-876.e5. Epub 2019 Oct 10.

Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Cysteine acts both as a building unit for protein translation and as the limiting substrate for glutathione synthesis to support the cellular antioxidant system. In addition to transporter-mediated uptake, cellular cysteine can also be synthesized from methionine through the transsulfuration pathway. Here, we investigate the regulation of transsulfuration and its role in sustaining cell proliferation upon extracellular cysteine limitation, a condition reported to occur in human tumors as they grow in size. We observed constitutive expression of transsulfuration enzymes in a subset of cancer cell lines, while in other cells, these enzymes are induced following cysteine deprivation. We show that both constitutive and inducible transsulfuration activities contribute to the cellular cysteine pool and redox homeostasis. The rate of transsulfuration is determined by the cellular capacity to conduct methylation reactions that convert S-adenosylmethionine to S-adenosylhomocysteine. Finally, our results demonstrate that transsulfuration-mediated cysteine synthesis is critical in promoting tumor growth in vivo.
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http://dx.doi.org/10.1016/j.cmet.2019.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961654PMC
November 2019

Author Correction: Epigenetic stress responses induce muscle stem-cell ageing by Hoxa9 developmental signals.

Nature 2019 Aug;572(7769):E11-E15

Leibniz-Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745, Jena, Germany.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41586-019-1455-1DOI Listing
August 2019

Cancer Metabolism Drives a Stromal Regenerative Response.

Cell Metab 2019 03 14;29(3):576-591. Epub 2019 Feb 14.

Memorial Sloan Kettering Cancer Center, Cancer Biology and Genetics Program, New York, NY 10065, USA. Electronic address:

The metabolic reprogramming associated with malignant transformation has led to a growing appreciation of the nutrients required to support anabolic cell growth. Less well studied is how cancer cells satisfy those demands in vivo, where they are dispersed within a complex microenvironment. Tumor-associated stromal components can support tumor growth by providing nutrients that supplement those provided by the local vasculature. These non-malignant stromal cells are phenotypically similar to those that accumulate during wound healing. Owing to their immediate proximity, stromal cells are inevitably affected by the metabolic activity of their cancerous neighbors. Until recently, a role for tumor cell metabolism in influencing the cell fate decisions of neighboring stromal cells has been underappreciated. Here, we propose that metabolites consumed and released by tumor cells act as paracrine factors that regulate the non-malignant cellular composition of a developing tumor by driving stromal cells toward a regenerative response that supports tumor growth.
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http://dx.doi.org/10.1016/j.cmet.2019.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692899PMC
March 2019

Epigenetic stress responses induce muscle stem-cell ageing by Hoxa9 developmental signals.

Nature 2016 12 30;540(7633):428-432. Epub 2016 Nov 30.

Leibniz-Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.

The functionality of stem cells declines during ageing, and this decline contributes to ageing-associated impairments in tissue regeneration and function. Alterations in developmental pathways have been associated with declines in stem-cell function during ageing, but the nature of this process remains poorly understood. Hox genes are key regulators of stem cells and tissue patterning during embryogenesis with an unknown role in ageing. Here we show that the epigenetic stress response in muscle stem cells (also known as satellite cells) differs between aged and young mice. The alteration includes aberrant global and site-specific induction of active chromatin marks in activated satellite cells from aged mice, resulting in the specific induction of Hoxa9 but not other Hox genes. Hoxa9 in turn activates several developmental pathways and represents a decisive factor that separates satellite cell gene expression in aged mice from that in young mice. The activated pathways include most of the currently known inhibitors of satellite cell function in ageing muscle, including Wnt, TGFβ, JAK/STAT and senescence signalling. Inhibition of aberrant chromatin activation or deletion of Hoxa9 improves satellite cell function and muscle regeneration in aged mice, whereas overexpression of Hoxa9 mimics ageing-associated defects in satellite cells from young mice, which can be rescued by the inhibition of Hoxa9-targeted developmental pathways. Together, these data delineate an altered epigenetic stress response in activated satellite cells from aged mice, which limits satellite cell function and muscle regeneration by Hoxa9-dependent activation of developmental pathways.
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http://dx.doi.org/10.1038/nature20603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5415306PMC
December 2016

Comparison of the uptake of methacrylate-based nanoparticles in static and dynamic in vitro systems as well as in vivo.

J Control Release 2015 Oct 12;216:158-68. Epub 2015 Aug 12.

Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstrasse 10, 07743 Jena, Germany; Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany. Electronic address:

Polymer-based nanoparticles are promising drug delivery systems allowing the development of new drug and treatment strategies with reduced side effects. However, it remains a challenge to screen for new and effective nanoparticle-based systems in vitro. Important factors influencing the behavior of nanoparticles in vivo cannot be simulated in screening assays in vitro, which still represent the main tools in academic research and pharmaceutical industry. These systems have serious drawbacks in the development of nanoparticle-based drug delivery systems, since they do not consider the highly complex processes influencing nanoparticle clearance, distribution, and uptake in vivo. In particular, the transfer of in vitro nanoparticle performance to in vivo models often fails, demonstrating the urgent need for novel in vitro tools that can imitate aspects of the in vivo situation more accurate. Dynamic cell culture, where cells are cultured and incubated in the presence of shear stress has the potential to bridge this gap by mimicking key-features of organs and vessels. Our approach implements and compares a chip-based dynamic cell culture model to the common static cell culture and mouse model to assess its capability to predict the in vivo success more accurately, by using a well-defined poly((methyl methacrylate)-co-(methacrylic acid)) and poly((methyl methacrylate)-co-(2-dimethylamino ethylmethacrylate)) based nanoparticle library. After characterization in static and dynamic in vitro cell culture we were able to show that physiological conditions such as cell-cell communication of co-cultured endothelial cells and macrophages as well as mechanotransductive signaling through shear stress significantly alter cellular nanoparticle uptake. In addition, it could be demonstrated by using dynamic cell cultures that the in vivo situation is simulated more accurately and thereby can be applied as a novel system to investigate the performance of nanoparticle systems in vivo more reliable.
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http://dx.doi.org/10.1016/j.jconrel.2015.08.008DOI Listing
October 2015