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

Citations Over TimeTop 10% of 2015 papers

Abstract

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 thought to be essential for cell proliferation and tissue homeostasis. However, since the initial report 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 that they are also able of supporting 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-supply the depleted pool of aspartate in SDH-deficient cells. Our results demonstrate that the loss of SDH reduces the metabolic plasticity of cells, suggesting vulnerabilities that can be targeted therapeutically.

Related Papers

• → Metabolism of hyperpolarized [1‐13C]pyruvate through alternate pathways in rat liver(2016)49 cited
• → Assays of Pyruvate Dehydrogenase Complex and Pyruvate Carboxylase Activity(2011)16 cited
• → Effect of streptozotocin-induced diabetes mellitus on the turnover of rat liver pyruvate carboxylase and pyruvate dehydrogenase(1980)55 cited
• → Dissociation of pyruvate dehydrogenase from the glucagon stimulation of pyruvate carboxylation in rat liver mitochondria(1975)32 cited
• → Intracellular localization of pyruvate carboxylase in mammalian liver(1974)6 cited