Journal
METABOLIC ENGINEERING
Volume 43, Issue -, Pages 187-197Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymben.2016.11.005
Keywords
Succinate dehydrogenase; Complex I of the electron transport chain; Mitochondrial respiration; Reductive glutamine metabolism; Pyruvate carboxylase; C-13 metabolic flux analysis; Paraganglioma; Gastrointestinal stromal tumors; Leigh syndrome; Ataxia; Leukodystrophy; SDH mutations
Categories
Funding
- VIB-Marie Curie fellowship
- FWO Flanders
- FWO postdoctoral fellowship
- Marie Curie - CIG
- European Union [PCIG13-GA-2013-617727]
- FWO - Odysseus II, Belgium [G.0.E56.14N]
- Concern Foundation
- FWO - Research Grants, Belgium [1513415N]
- KU-Leuven Methusalem
- Eugene Yourassowsky Schenking
- Bayer Health Care
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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.
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