Since the discovery of mutations in succinate dehydrogenase (SDH) complex early this century, it has been shown that tumours underpinned by deficiencies in this metabolic enzyme will demonstrate altered cell metabolism. However, the precise nature of these changes remains poorly described. The metabolic network within cells is highly redundant, with multiple pathways capable of synthesising the required building blocks for cell growth. By the very fact that SDH-deficient cells form tumours, we know that cells have found a way around this mutation. However, it is likely that this metabolic re-wiring has compromised their redundancy. Investigations that pinpoint the enzymes required in the SDH-deficient metabolic network may therefore lead to the identification of novel specific targets for tumours with SDH mutations.
Aspartate is a key amino acid, required for the synthesis of all nucleotides and proteins its synthesis is therefore critical for cellular anabolism. We recently showed that cells lacking Sdhb are deficient in aspartate a direct consequence of loss of SDH activity. SDH-deficient cells instead become reliant on the activity of pyruvate carboxylase (PC), a mitochondrial enzyme, for the majority of aspartate synthesis. We therefore showed that knockdown of PC activity results in lethality in SDH-deficient cells but has little effect on wild-type cells.
Interestingly, we have also observed perturbations in the metabolism of other amino acids, including proline and alanine, suggesting that there may be multiple opportunities for novel therapeutic targets through the investigation of this class of metabolites.