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 un...
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Elsevier
2013-03-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124713000727 |
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doaj-dd77064ebe1648f7a88f44f3b46d35fb2020-11-25T01:17:03ZengElsevierCell Reports2211-12472013-03-013368970010.1016/j.celrep.2013.02.013Inhibition of Mitochondrial Aconitase by Succination in Fumarate Hydratase DeficiencyNicola Ternette0Ming Yang1Mahima Laroyia2Mitsuhiro Kitagawa3Linda O’Flaherty4Kathryn Wolhulter5Kaori Igarashi6Kaori Saito7Keiko Kato8Roman Fischer9Alexandre Berquand10Benedikt M. Kessler11Terry Lappin12Norma Frizzell13Tomoyoshi Soga14Julie Adam15Patrick J. Pollard16Central Proteomics Facility, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UKCancer Biology and Metabolism Group, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UKCancer Biology and Metabolism Group, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UKInstitute for Advanced Biosciences, Keio University, 246-2 Mizukami, Tsuruoka, Yamagata 997-0052, JapanCancer Biology and Metabolism Group, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UKCancer Biology and Metabolism Group, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UKInstitute for Advanced Biosciences, Keio University, 246-2 Mizukami, Tsuruoka, Yamagata 997-0052, JapanInstitute for Advanced Biosciences, Keio University, 246-2 Mizukami, Tsuruoka, Yamagata 997-0052, JapanInstitute for Advanced Biosciences, Keio University, 246-2 Mizukami, Tsuruoka, Yamagata 997-0052, JapanCentral Proteomics Facility, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UKBruker Nano GmbH, Östliche Rheinbrückenstraße 49, 76187 Karlsruhe, GermanyCentral Proteomics Facility, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UKHypoxia Biology Group, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UKDepartment of Pharmacology, Physiology & Neuroscience, School of Medicine, University of South Carolina, Columbia, SC 29208, USAInstitute for Advanced Biosciences, Keio University, 246-2 Mizukami, Tsuruoka, Yamagata 997-0052, JapanCancer Biology and Metabolism Group, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UKCancer Biology and Metabolism Group, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK 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. http://www.sciencedirect.com/science/article/pii/S2211124713000727 |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Nicola Ternette Ming Yang Mahima Laroyia Mitsuhiro Kitagawa Linda O’Flaherty Kathryn Wolhulter Kaori Igarashi Kaori Saito Keiko Kato Roman Fischer Alexandre Berquand Benedikt M. Kessler Terry Lappin Norma Frizzell Tomoyoshi Soga Julie Adam Patrick J. Pollard |
| spellingShingle |
Nicola Ternette Ming Yang Mahima Laroyia Mitsuhiro Kitagawa Linda O’Flaherty Kathryn Wolhulter Kaori Igarashi Kaori Saito Keiko Kato Roman Fischer Alexandre Berquand Benedikt M. Kessler Terry Lappin Norma Frizzell Tomoyoshi Soga Julie Adam Patrick J. Pollard Inhibition of Mitochondrial Aconitase by Succination in Fumarate Hydratase Deficiency Cell Reports |
| author_facet |
Nicola Ternette Ming Yang Mahima Laroyia Mitsuhiro Kitagawa Linda O’Flaherty Kathryn Wolhulter Kaori Igarashi Kaori Saito Keiko Kato Roman Fischer Alexandre Berquand Benedikt M. Kessler Terry Lappin Norma Frizzell Tomoyoshi Soga Julie Adam Patrick J. Pollard |
| author_sort |
Nicola Ternette |
| title |
Inhibition of Mitochondrial Aconitase by Succination in Fumarate Hydratase Deficiency |
| title_short |
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_sort |
inhibition of mitochondrial aconitase by succination in fumarate hydratase deficiency |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2013-03-01 |
| 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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| url |
http://www.sciencedirect.com/science/article/pii/S2211124713000727 |
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