Fumarate Hydratase Loss Causes Combined Respiratory Chain Defects.

TitleFumarate Hydratase Loss Causes Combined Respiratory Chain Defects.
Publication TypeJournal Article
Year of Publication2017
AuthorsTyrakis, PA, Yurkovich, ME, Sciacovelli, M, Papachristou, EK, Bridges, HR, Gaude, E, Schreiner, A, D'Santos, C, Hirst, J, Hernandez-Fernaud, J, Springett, R, Griffiths, JR, Frezza, C
JournalCell Rep
Volume21
Issue4
Pagination1036-1047
Date Published2017 Oct 24
ISSN2211-1247
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.

DOI10.1016/j.celrep.2017.09.092
Alternate JournalCell Rep
Citation Key10.1016/j.celrep.2017.09.092
PubMed ID29069586
PubMed Central IDPMC5668630