Inhibition of Mitochondrial Aconitase by Succination in Fumarate Hydratase Deficiency
The gene encoding the Krebs cycle enzyme fumarate hydratase (FH) is mutated in hereditary leiomyomatosis and renal cell cancer (HLRCC). Loss of FH activity causes accumulation of intracellular fumarate, which can directly modify cysteine residues to form 2-succinocysteine through succination. We und...
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Published in | Cell reports (Cambridge) Vol. 3; no. 3; pp. 689 - 700 |
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Main Authors | , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
28.03.2013
Cell Press Elsevier |
Subjects | |
Online Access | Get full text |
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Summary: | The gene encoding the Krebs cycle enzyme fumarate hydratase (FH) is mutated in hereditary leiomyomatosis and renal cell cancer (HLRCC). Loss of FH activity causes accumulation of intracellular fumarate, which can directly modify cysteine residues to form 2-succinocysteine through succination. We undertook a proteomic-based screen in cells and renal cysts from Fh1 (murine FH)-deficient mice and identified 94 protein succination targets. Notably, we identified the succination of three cysteine residues in mitochondrial Aconitase2 (ACO2) crucial for iron-sulfur cluster binding. We show that fumarate exerts a dose-dependent inhibition of ACO2 activity, which correlates with increased succination as determined by mass spectrometry, possibly by interfering with iron chelation. Importantly, we show that aconitase activity is impaired in FH-deficient cells. Our data provide evidence that succination, resulting from FH deficiency, targets and potentially alters the function of multiple proteins and may contribute to the dysregulated metabolism observed in HLRCC.
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► Fumarate inhibits Aconitase2 activity via succination of critical cysteine residues ► Endogenous Aconitase2 is succinated and inhibited in FH-deficient cells ► Succination occurs in multiple proteins with roles in diverse cellular processes ► Succination can alter metabolism in FH-deficient cells
Loss-of-function mutations in the tumor suppressor gene fumarate hydratase (FH) predispose to an aggressive type of renal cancer. FH inactivation results in accumulation of the Krebs cycle metabolite fumarate, which can irreversibly modify cysteine residues through succination. Yang, Pollard, and colleagues showed that fumarate-mediated succination occurs on three critical cysteine residues in Aconitase2, leading to its inactivation in FH-deficient cells. Succination targets multiple proteins encompassing diverse cellular pathways, potentially contributing to the oncogenesis in FH-deficient tumors. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work |
ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2013.02.013 |