For a long time, metabolism has been viewed as a static series of biochemical reactions. Recent research however reveals that cellular metabolism is indeed highly dynamic, and is implicated in many biologically important phenomena, such as ageing, cellular robustness, and adaptation to ever changing environments. These properties bring metabolism center-stage both for developing therapies against cancer and neurodegenerative disorders and for understanding the ageing process.
We investigate regulatory functions of the metabolic network and how its dynamics are maintained. A model situation where the metabolome has regulatory function is the adaptation to stress conditions. When cells are exposed to oxidants, when cells age or when a cancer cell starts proliferation, their metabolism changes. We found that under those conditions the metabolic network can reconfigure very quickly, and that metabolism can temporarily adjust without requiring regulation at the transcriptome and proteome layer. There is also evidence that these quick metabolic adjustments can be involved in the induction of transcriptional stress responses.
We address these questions often in the yeast Saccharomyces cerevisiae. Working with this single-cellular eukaryote removes some complexity from our investigations, as a plethora of genetic and biochemical techniques are available, reducing bias from altered metabolic activity that is found in cell culture systems, allowing us to work with hundreds of mutants in parallel. To study the metabolic network, we use quantitative mass spectrometry coupled to high-pressure and/or nano-flow liquid chromatography for targeted analysis of proteins and small molecules.
1. How flexible are metabolic pathways? How do they interact with the regulation of cellular macromolecules?
2. How are metabolic transitions, e.g. the change from oxidation to non-oxidative metabolism regulated?
3. Why do cells age? Which metabolic processes are involed? Can we modulate ageing by changing these processes?
Lab members: Floriana Capuano, Nana-Maria Grüning, Jakob Vowinckel, Markus Keller, Anna Stincone, Tauqeer Alam, Maria V Olin-Sandoval, Kate Campbell, Michael Muelleder
Selected, recent publications
Tpo1-mediated spermine and spermidine export controls cell cycle delay and times antioxidant protein expression during the oxidative stress response.
Krüger A, Vowinckel J, Mülleder M, Grote P, Capuano F, Bluemlein K, Ralser M.
EMBO Reports. 2013 Oct 18. doi: 10.1038/embor.2013.165.
A prototrophic deletion mutant collection for yeast metabolomics and systems biology. Michael Mülleder, Floriana Capuano, Pınar Pir, Stefan Christen, Uwe Sauer, Stephen G Oliver & Markus Ralser. Nature Biotechnology 2012, pp1176 - 1178, doi:10.1038/nbt.2442
Pyruvate kinase triggers a metabolic feedback loop that controls redox metabolism in respiring cells. Grüning NM, Rinnerthaler M, Bluemlein K, Mülleder M, Wamelink MM, Lehrach H, Jakobs C, Breitenbach M, Ralser M.
Cell Metabolism. 2011 Sep 7;14(3):415-27. PmID: 21907146
Monitoring protein expression in whole-cell extracts by targeted label- and standard-free LC-MS/MS. Katharina Bluemlein and Markus Ralser.
Nature Protocols, 2011, 6:6, 859-869, doi:10.1038/nprot.2011.333 Abstract