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.

journal_name

Metab Eng

journal_title

Metabolic engineering

authors

Lorendeau D,Rinaldi G,Boon R,Spincemaille P,Metzger K,Jäger C,Christen S,Dong X,Kuenen S,Voordeckers K,Verstreken P,Cassiman D,Vermeersch P,Verfaillie C,Hiller K,Fendt SM

doi

10.1016/j.ymben.2016.11.005

subject

Has Abstract

pub_date

2017-09-01 00:00:00

pages

187-197

issue

Pt B

eissn

1096-7176

issn

1096-7184

pii

S1096-7176(16)30217-8

journal_volume

43

pub_type

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