Dual loss of succinate dehydrogenase (SDH) and complex I activity is necessary to recapitulate the metabolic phenotype of SDH mutant tumors

Abstract

Mutations in succinate dehydrogenase (SDH) are associated with tumor development and neurodegenerative diseases. Only in tumors, loss of SDH activity is accompanied with the loss of complex I activity. Yet, it remains unknown whether the metabolic phenotype of SDH mutant tumors is driven by loss of complex I function, and whether this contributes to the peculiarity of tumor development versus neurodegeneration. We addressed this question by decoupling loss of SDH and complex I activity in cancer cells and neurons. We found that sole loss of SDH activity was not sufficient to recapitulate the metabolic phenotype of SDH mutant tumors, because it failed to decrease mitochondrial respiration and to activate reductive glutamine metabolism. These metabolic phenotypes were only induced upon the additional loss of complex I activity. Thus, we show that complex I function defines the metabolic differences between SDH mutation associated tumors and neurodegenerative diseases, which could open novel therapeutic options against both diseases.

Keywords: (13)C metabolic flux analysis; 3-nitropropionic acid (PubChem CID: 1678); Ataxia; Atpenin A5 (PubChem CID: 54676868); CB-839 (PubChem CID: 71577426); Complex I of the electron transport chain; Gastrointestinal stromal tumors; Leigh syndrome; Leukodystrophy; Mitochondrial respiration; Paraganglioma; Pyruvate carboxylase; Reductive glutamine metabolism; SDH mutations; Succinate dehydrogenase; rotenone (PubChem CID: 6758).