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Metabolic Alterations in Fumarate Hydratase Deficient Cells
Christian Frezza

University of Cambridge

Published: 20 November 2017 by MDPI AG in The 2nd International Electronic Conference on Metabolomics in The 2nd International Electronic Conference on Metabolomics
MDPI AG, 10.3390/iecm-2-04986

Mutations of the tricarboxylic acid cycle (TCA cycle) enzyme fumarate hydratase (FH) cause the hereditary cancer syndrome Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). FH-deficient renal cancers are highly aggressive and metastasise even when small, leading to an abysmal clinical outcome. How these cells survive without FH and how they become transformed is still under investigation. Today, I will show our data on the metabolic reprogramming triggered by the loss of FH, which induces, amongst various changes, the fumarate-mediated succination of the iron-sulfur-cluster proteins ISCU1, NFU1, and Bola1/3. Of note, this post translational modification leads to defects in iron-sulfur cluster biogenesis and complex I deficiency. These results could help to explain the profound alteration of mitochondrial metabolism in cells that lack FH.

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