Cell Reports (Mar 2024)
PKM2 diverts glycolytic flux in dependence on mitochondrial one-carbon cycle
- Mohaned Benzarti,
- Laura Neises,
- Anais Oudin,
- Christina Krötz,
- Elodie Viry,
- Ernesto Gargiulo,
- Coralie Pulido,
- Maryse Schmoetten,
- Vitaly Pozdeev,
- Nadia I. Lorenz,
- Michael W. Ronellenfitsch,
- David Sumpton,
- Marc Warmoes,
- Christian Jaeger,
- Antoine Lesur,
- Björn Becker,
- Etienne Moussay,
- Jerome Paggetti,
- Simone P. Niclou,
- Elisabeth Letellier,
- Johannes Meiser
Affiliations
- Mohaned Benzarti
- Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg; Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg; Molecular Disease Mechanisms Group, Faculty of Science, Technology and Medicine, Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
- Laura Neises
- Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
- Anais Oudin
- NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
- Christina Krötz
- Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
- Elodie Viry
- Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
- Ernesto Gargiulo
- Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
- Coralie Pulido
- Animal Facility, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
- Maryse Schmoetten
- Molecular Disease Mechanisms Group, Faculty of Science, Technology and Medicine, Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
- Vitaly Pozdeev
- Molecular Disease Mechanisms Group, Faculty of Science, Technology and Medicine, Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
- Nadia I. Lorenz
- Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany; German Cancer Consortium, Partner Site Frankfurt/Mainz, Frankfurt am Main, Germany; Frankfurt Cancer Institute (FCI), University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany; University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany
- Michael W. Ronellenfitsch
- Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany; German Cancer Consortium, Partner Site Frankfurt/Mainz, Frankfurt am Main, Germany; Frankfurt Cancer Institute (FCI), University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany; University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany
- David Sumpton
- Cancer Research U.K. Scotland Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK
- Marc Warmoes
- Metabolomics Platform, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg
- Christian Jaeger
- Metabolomics Platform, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg
- Antoine Lesur
- Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
- Björn Becker
- Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
- Etienne Moussay
- Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
- Jerome Paggetti
- Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
- Simone P. Niclou
- Faculty of Science, Technology and Medicine, University of Luxembourg, Belvaux, Luxembourg; NORLUX Neuro-Oncology Laboratory, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
- Elisabeth Letellier
- Molecular Disease Mechanisms Group, Faculty of Science, Technology and Medicine, Department of Life Sciences and Medicine, University of Luxembourg, Belvaux, Luxembourg
- Johannes Meiser
- Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg; Corresponding author
- Journal volume & issue
-
Vol. 43,
no. 3
p. 113868
Abstract
Summary: Modeling tumor metabolism in vitro remains challenging. Here, we used galactose as an in vitro tool compound to mimic glycolytic limitation. In contrast to the established idea that high glycolytic flux reduces pyruvate kinase isozyme M2 (PKM2) activity to support anabolic processes, we have discovered that glycolytic limitation also affects PKM2 activity. Surprisingly, despite limited carbon availability and energetic stress, cells induce a near-complete block of PKM2 to divert carbons toward serine metabolism. Simultaneously, TCA cycle flux is sustained, and oxygen consumption is increased, supported by glutamine. Glutamine not only supports TCA cycle flux but also serine synthesis via distinct mechanisms that are directed through PKM2 inhibition. Finally, deleting mitochondrial one-carbon (1C) cycle reversed the PKM2 block, suggesting a potential formate-dependent crosstalk that coordinates mitochondrial 1C flux and cytosolic glycolysis to support cell survival and proliferation during nutrient-scarce conditions.
