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Fumarate Hydratase Loss Causes Combined Respiratory Chain Defects.

Published version
Peer-reviewed

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Authors

Tyrakis, Petros A 
Yurkovich, Marie E 
Sciacovelli, Marco 
Papachristou, Evangelia K 
Bridges, Hannah R 

Abstract

Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid (TCA) cycle mutated in hereditary and sporadic cancers. Despite recent advances in understanding its role in tumorigenesis, the effects of FH loss on mitochondrial metabolism are still unclear. Here, we used mouse and human cell lines to assess mitochondrial function of FH-deficient cells. We found that human and mouse FH-deficient cells exhibit decreased respiration, accompanied by a varying degree of dysfunction of respiratory chain (RC) complex I and II. Moreover, we show that fumarate induces succination of key components of the iron-sulfur cluster biogenesis family of proteins, leading to defects in the biogenesis of iron-sulfur clusters that affect complex I function. We also demonstrate that suppression of complex II activity is caused by product inhibition due to fumarate accumulation. Overall, our work provides evidence that the loss of a single TCA cycle enzyme is sufficient to cause combined RC activity dysfunction.

Description

Keywords

cancer, fumarate, fumarate hydratase, iron-sulphur clusters, mitochondria, oncometabolites, succination, Animals, Cell Line, Tumor, Cell Respiration, Electron Transport Complex I, Electron Transport Complex II, Fumarate Hydratase, Fumarates, Humans, Iron-Sulfur Proteins, Mice

Journal Title

Cell Rep

Conference Name

Journal ISSN

2211-1247
2211-1247

Volume Title

21

Publisher

Elsevier BV
Sponsorship
MRC (unknown)
Medical Research Council (MC_U105663141)
Medical Research Council (MC_UU_12022/6)
MRC (MC_UU_00015/2)
Medical Research Council (MC_UU_00015/7)