Metabolic Alterations in Fumarate Hydratase Deficient Cells - - PowerPoint PPT Presentation

Metabolic Alterations in Fumarate Hydratase Deficient Cells

Christian Frezza

1 MRC Cancer Unit, University of Cambridge, Cambridge, UK

* Corresponding author: cf366@MRC-CU.cam.ac.uk

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Graphical Abstract

Metabolic Alterations in Fumarate Hydratase Deficient Cells

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Fe-S cluster biogenesis

Abstract: 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

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f u m a r a t e ( f m

• l / c

e l l )

F h 1

f l / f l

F h 1

• / -

F h 1

• / -

+ p F h 1 l o w F h 1

• / -

+ p F h 1 h i g h

1 2 3 O C R ( p m

• l / m

i n /  g p r o t e i n )

F h 1

f l / f l

F h 1

• /
• F

h 1

• /
• +

p F h 1 l o w F h 1

• /
• +

p F h 1 h i g h

5 1 1 5

Fh1 Fh1

high

4 8 12 16 20 24 28 32 5 10 15 T im e (m in ) O C R (p m o l/m in / g p r o te in )

20 mM A z id e 1 00 M TMPD + 10 mM A s c o rb a te

1 0 2 0 3 0 2 4 6 8 1 0 1 2

T im e (m in )

O C R (p m o l/m in / g p r o te in )

1 0 m M S u ccin ate 2 M A n tim yc in A

10 20 30 5 10 15

T im e (m in )

O C R (p m o l/m in / g p r o te in )

5 m M G lutam ate 5 m M M alate 2 M R otenone

10 20 30 10 20 30 40 T im e (m in ) O C R (p m o l/m in / g p r o te in )

2 M A n tim ycin 0 .5 m M D uroquinol

B o v in e h e a rt m ito c h o n d ria l m e m b ra n e s N A D H :O 2 ( m o le s /m in /m g p r o te in )

c o n tro l 5 m M M M F 0 .0 0 .5 1 .0 1 .5

B o v in e h e a rt m ito c h o n d ria l m e m b ra n e s N A D H :O 2 ( m o le s /m in /m g p r o te in )

c o n tro l 1 0 0 m M fu m a ra te 0 .0 0 .2 0 .4 0 .6 0 .8

Nature Reviews Cancer 12, 564-571 (August 2012)

protein protein

Acknowledgments

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Key Collaborators: Mitochondrial Biology Unit, Cambridge Judy Hirst Hannah Bridges Cancer Research UK Cambridge Institute, Cambridge Petros Tyrakis and Marie Yurkovich Clive D’Santos and Eva Papachristou Marco Sciacovelli Edoardo Gaude