Impairment of angiogenesis by fatty acid synthase inhibition involves mTOR malonylation

Blood vessel formation (angiogenesis) is crucial in physiology, but also contributes to pathologies (eg cancer, ocular disease). Various vascular (growth) factors controlling angiogenesis have been identified, a prominent example being the key endothelial cell (EC) growth factor VEGF. However, the host lab recently identified an entirely novel regulation of angiogenesis, relying on metabolic rewiring of the ECs to ensure generation of energy (eg for migration), biomass (eg for proliferation), or redox control (eg in quiescent ECs). Rewiring of metabolic fluxes requires activity shifts of metabolic pathway enzymes, to which posttranslational modifications (PTMs) like phosphorylation, acetylation and succinylation, can contribute. Several metabolic pathway enzymes are succinylated / acetylated, but the consequences of these PTMs for enzymatic activity and flux through the pathways are unexplored. Here, I postulate that succinylation / acetylation co-regulate metabolic enzyme activity and metabolic fluxes in ECs. I will test this hypothesis via the identification of these PTMs of metabolic enzymes, analysis of the impact on metabolic fluxes using state-of-the-art 13C-metabolic flux analysis (MFA), and of the effect on EC sprouting. This unique combinatorial and multidisciplinary approach promises to provide unprecedented insight into whether metabolic flux levels are influenced by succinylation / acetylation in ECs constituting a novel mechanism regulating vessel sprouting.status: publishe