Fumarate Hydratase Loss Causes Combined Respiratory Chain Defects

Abstract

Summary: 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. : Tyrakis et al. show that fumarate accumulation in fumarate hydratase-deficient cells leads to the inhibition of respiratory chain (RC) complex II and the succination of proteins involved in the biogenesis of Fe-S clusters required for RC complex I function, enabling these cells to resist insults that target mitochondria. Keywords: fumarate hydratase, fumarate, mitochondria, cancer, oncometabolites, succination, iron-sulphur clusters