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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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Autores principales: Ternette, Nicola, Yang, Ming, Laroyia, Mahima, Kitagawa, Mitsuhiro, O’Flaherty, Linda, Wolhulter, Kathryn, Igarashi, Kaori, Saito, Kaori, Kato, Keiko, Fischer, Roman, Berquand, Alexandre, Kessler, Benedikt M., Lappin, Terry, Frizzell, Norma, Soga, Tomoyoshi, Adam, Julie, Pollard, Patrick J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617368/
https://www.ncbi.nlm.nih.gov/pubmed/23499446
http://dx.doi.org/10.1016/j.celrep.2013.02.013
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author Ternette, Nicola
Yang, Ming
Laroyia, Mahima
Kitagawa, Mitsuhiro
O’Flaherty, Linda
Wolhulter, Kathryn
Igarashi, Kaori
Saito, Kaori
Kato, Keiko
Fischer, Roman
Berquand, Alexandre
Kessler, Benedikt M.
Lappin, Terry
Frizzell, Norma
Soga, Tomoyoshi
Adam, Julie
Pollard, Patrick J.
author_facet Ternette, Nicola
Yang, Ming
Laroyia, Mahima
Kitagawa, Mitsuhiro
O’Flaherty, Linda
Wolhulter, Kathryn
Igarashi, Kaori
Saito, Kaori
Kato, Keiko
Fischer, Roman
Berquand, Alexandre
Kessler, Benedikt M.
Lappin, Terry
Frizzell, Norma
Soga, Tomoyoshi
Adam, Julie
Pollard, Patrick J.
author_sort Ternette, Nicola
collection PubMed
description 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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spelling pubmed-36173682013-04-05 Inhibition of Mitochondrial Aconitase by Succination in Fumarate Hydratase Deficiency Ternette, Nicola Yang, Ming Laroyia, Mahima Kitagawa, Mitsuhiro O’Flaherty, Linda Wolhulter, Kathryn Igarashi, Kaori Saito, Kaori Kato, Keiko Fischer, Roman Berquand, Alexandre Kessler, Benedikt M. Lappin, Terry Frizzell, Norma Soga, Tomoyoshi Adam, Julie Pollard, Patrick J. Cell Rep Report 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. Cell Press 2013-03-28 /pmc/articles/PMC3617368/ /pubmed/23499446 http://dx.doi.org/10.1016/j.celrep.2013.02.013 Text en © 2013 The Authors https://creativecommons.org/licenses/by/3.0/ Open Access under CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/) license
spellingShingle Report
Ternette, Nicola
Yang, Ming
Laroyia, Mahima
Kitagawa, Mitsuhiro
O’Flaherty, Linda
Wolhulter, Kathryn
Igarashi, Kaori
Saito, Kaori
Kato, Keiko
Fischer, Roman
Berquand, Alexandre
Kessler, Benedikt M.
Lappin, Terry
Frizzell, Norma
Soga, Tomoyoshi
Adam, Julie
Pollard, Patrick J.
Inhibition of Mitochondrial Aconitase by Succination in Fumarate Hydratase Deficiency
title Inhibition of Mitochondrial Aconitase by Succination in Fumarate Hydratase Deficiency
title_full Inhibition of Mitochondrial Aconitase by Succination in Fumarate Hydratase Deficiency
title_fullStr Inhibition of Mitochondrial Aconitase by Succination in Fumarate Hydratase Deficiency
title_full_unstemmed Inhibition of Mitochondrial Aconitase by Succination in Fumarate Hydratase Deficiency
title_short Inhibition of Mitochondrial Aconitase by Succination in Fumarate Hydratase Deficiency
title_sort inhibition of mitochondrial aconitase by succination in fumarate hydratase deficiency
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617368/
https://www.ncbi.nlm.nih.gov/pubmed/23499446
http://dx.doi.org/10.1016/j.celrep.2013.02.013
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