Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism

The tricarboxylic acid (TCA) cycle is a central metabolic pathway responsible for supplying reducing potential for oxidative phosphorylation and anabolic substrates for cell growth, repair and proliferation. As such, it might be considered as essential for the ongoing viability and proliferation of a cell or tissue. However, since the first report in 2000 of an inactivating mutation in the TCA cycle enzyme complex, succinate dehydrogenase (SDH) in paraganglioma (PGL), it has become clear that some cells and tissues are not only able to survive with a truncated TCA cycle, but they are also able to support the cell growth and proliferative phenotype observed in tumours. Here, we show that loss of SDH activity leads to changes in the metabolism of non-essential amino acids: in particular, we demonstrate that pyruvate carboxylase is essential to re-fill the depleted pool of aspartate in SDH-deficient cells. Our work demonstrates that the loss of SDH reduces the metabolic plasticity of cells, indicating vulnerabilities that can be targeted therapeutically.