Details

Autor(en) / Beteiligte

• Benzarti, Mohaned
• Neises, Laura
• Oudin, Anais
• Krötz, Christina
• Viry, Elodie
• Gargiulo, Ernesto
• Pulido, Coralie
• Schmoetten, Maryse
• Pozdeev, Vitaly
• Lorenz, Nadia I.
• Ronellenfitsch, Michael W.
• Sumpton, David
• Warmoes, Marc
• Jaeger, Christian
• Lesur, Antoine
• Becker, Björn
• Moussay, Etienne
• Paggetti, Jerome
• Niclou, Simone P.
• Letellier, Elisabeth
• Meiser, Johannes

Titel

PKM2 diverts glycolytic flux in dependence on mitochondrial one-carbon cycle

Ist Teil von

• Cell reports (Cambridge), 2024-03, Vol.43 (3), p.113868-113868, Article 113868

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Galactose is a tool to mimic glycolytic limitation•Glycolytic limitation prioritizes serine synthesis pathway (SSP) through PKM2 block•PKM2 block requires activation of ME to maintain TCA cycle, while PEPCK2 supports SSP•PKM2 block is independent of serine and is linked to mitochondrial 1C metabolism Benzarti et al. demonstrate that glycolytic limitation forces cancer cells to rewire their glycolytic flux toward SSP by PKM2 inhibition. PKM2 inhibition is independent of serine and can be reversed by genetic ablation of mitochondrial 1C cycle enzymes. These findings highlight cellular adaptation mechanisms upon limited carbon supply.