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Metabolic Alterations in Fumarate Hydratase Deficient Cells
1  University of Cambridge
2  MRC Cancer Unit


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.

Keywords: cancer metabolism, fumarate hydratase, mitochondria
Comments on this paper
Daqiang Pan
Hi Christian,

I am very happy to see your presentation again here. I have a question about the respiratory chain activity in Fh1-deficiency cells. As shown in your results, CII showed almost no activity and CI showed only 30-40% activity, albeit CIII and CIV were less impaired. How can the cells maintain CIII and CIV activity with no/very low CII/I activity? I am looking forward to your reply.

with kind regards,
Christian Frezza
Dear Daqiang Pan
thanks for your question. If you are referring to the Seahorse experiments on slide 21, please consider that with these experiments we isolate each respiratory chain complex using a combination of inhibitors and specific substrates, and we identify how they contribute to oxygen consumption. In other words, when taken in isolation Complex III and IV do not exhibit major defects. However, since both complex I and II exhibit defects in their activity, it is likely that both complex III and IV do not receive electrons from them when working as a complex.

I hope this addresses your question.

Let me know your thoughts

Daqiang Pan
Dear Christian,

Thanks for your reply and I got it now. Furthermore, I'd like to know if it is possible to measure the Fe-S in isolated Complex I-III? I am wondering if Fe-S decreased in all these complexes as CIII was not really functional impaired.


Christian Frezza
Dear Daqiang
the number and function of Fe-S clusters in the respiratory chain complexes vary. For instance, CI has 8 Fe-S clusters, CII has 3, CIII has 1, and CIV doesn't have any. You could measure their abundance in isolated RC complexes using spectroscopy. It is likely that Fe-S clusters are decreased in all these complexes, but the effect of this may be different. indeed, CIII activity was slightly, but not significantly, decreased in our experiments.
Madhu Basetti
Dear Christian,

Many thanks for presenting your keynote address at this conference.

with best regards,

Christian Frezza
Dear Madhu,

thanks to you for this great opportunity!