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.
Highlights
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
We performed an analysis of the steady-state concentrations of these amino acids using the previously characterized immortalized mouse chromaffin cell lines as a model, which represent the cell type from which PCC arise in patients
It has long been known that succinate dehydrogenase (SDH)-deficient PCC/PGL demonstrate an altered metabolic phenotype: through the inactivation of SDH mitochondria function per se, and via a pseudohypoxic phenotype mediated by the effect of succinate accumulation on the cellular transcriptome[11,12,16]
Summary
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. It was recently shown that loss of another TCA cycle enzyme associated with a hereditary cancer syndrome, fumarate hydratase, led to significant metabolic reprogramming of the mitochondria, which was essential for continued cell viability[18,19] Both genetic and hypoxia-mediated disruption of the TCA cycle has been suggested to result in alterations in cellular metabolic activity, resulting in cells that are more reliant on reductive carboxylation of glutamine for the provision of carbon for anabolic purposes than oxidative TCA cycle metabolism[20,21,22]. We found that, despite the use of reductive carboxylation to metabolize glutamine, SDH-deficient cells are unable to reverse their deficiency
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
