TY - JOUR
T1 - Inhibition of Mitochondrial Aconitase by Succination in Fumarate Hydratase Deficiency
AU - Ternette, Nicola
AU - Yang, Ming
AU - Laroyia, Mahima
AU - Kitagawa, Mitsuhiro
AU - O'Flaherty, Linda
AU - Wolhulter, Kathryn
AU - Igarashi, Kaori
AU - Saito, Kaori
AU - Kato, Keiko
AU - Fischer, Roman
AU - Berquand, Alexandre
AU - Kessler, Benedikt M.
AU - Lappin, Terry
AU - Frizzell, Norma
AU - Soga, Tomoyoshi
AU - Adam, Julie
AU - Pollard, Patrick J.
N1 - Funding Information:
We thank Climent Casals-Pascual and David Trudgian for their helpful advice on data analysis. This work was funded by the Wellcome Trust (WT091112MA to P.J.P.), Cancer Research UK (A13349, A14607, and A12027 to P.J.P.), a Grant-in-Aid for scientific research on Innovative Areas, Japan (No. 22134007 to T.S.), and the Yamagata Prefectural Government and City of Tsuruoka. The European Research Council has provided financial support under the European Community's Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no. 310837 to P.J.P. T.S. is a founder of Human Metabolome Technologies, and A.B. is an applications scientist employed by Bruker.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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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U2 - 10.1016/j.celrep.2013.02.013
DO - 10.1016/j.celrep.2013.02.013
M3 - Article
C2 - 23499446
AN - SCOPUS:84875805425
SN - 2211-1247
VL - 3
SP - 689
EP - 700
JO - Cell Reports
JF - Cell Reports
IS - 3
ER -
