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

Nat Commun. 2015 Nov 2;6:8784. doi: 10.1038/ncomms9784.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aspartic Acid / metabolism
  • Electron Transport Complex II / genetics
  • Electron Transport Complex II / metabolism*
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Neuroendocrine Tumors / enzymology*
  • Neuroendocrine Tumors / genetics
  • Neuroendocrine Tumors / metabolism
  • Oxidative Phosphorylation
  • Paraganglioma / enzymology*
  • Paraganglioma / genetics
  • Paraganglioma / metabolism
  • Pyruvic Acid / metabolism*
  • Succinate Dehydrogenase / genetics
  • Succinate Dehydrogenase / metabolism*

Substances

  • Membrane Proteins
  • SDHD protein, human
  • Aspartic Acid
  • Pyruvic Acid
  • Electron Transport Complex II
  • SDHD protein, mouse
  • Succinate Dehydrogenase