Inhibition of Mitochondrial Aconitase by Succination in Fumarate Hydratase Deficiency

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

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)689-700
Number of pages12
JournalCell Reports
Volume3
Issue number3
DOIs
Publication statusPublished - 2013

Fingerprint

Fumarate Hydratase
Aconitate Hydratase
Fumarates
Cysteine
Iron
Citric Acid Cycle
Sulfur
Gene encoding
Proteomics
Cysts
Mass Spectrometry
Chelation
Proteins
Metabolism
Mass spectrometry
Kidney
Fumaric aciduria
Enzymes
Genes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ternette, N., Yang, M., Laroyia, M., Kitagawa, M., O'Flaherty, L., Wolhulter, K., ... Pollard, P. J. (2013). Inhibition of Mitochondrial Aconitase by Succination in Fumarate Hydratase Deficiency. Cell Reports, 3(3), 689-700. https://doi.org/10.1016/j.celrep.2013.02.013

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.

In: Cell Reports, Vol. 3, No. 3, 2013, p. 689-700.

Research output: Contribution to journalArticle

Ternette, N, Yang, M, Laroyia, M, Kitagawa, M, O'Flaherty, L, Wolhulter, K, Igarashi, K, Saito, K, Kato, K, Fischer, R, Berquand, A, Kessler, BM, Lappin, T, Frizzell, N, Soga, T, Adam, J & Pollard, PJ 2013, 'Inhibition of Mitochondrial Aconitase by Succination in Fumarate Hydratase Deficiency', Cell Reports, vol. 3, no. 3, pp. 689-700. https://doi.org/10.1016/j.celrep.2013.02.013
Ternette N, Yang M, Laroyia M, Kitagawa M, O'Flaherty L, Wolhulter K et al. Inhibition of Mitochondrial Aconitase by Succination in Fumarate Hydratase Deficiency. Cell Reports. 2013;3(3):689-700. https://doi.org/10.1016/j.celrep.2013.02.013
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. In: Cell Reports. 2013 ; Vol. 3, No. 3. pp. 689-700.
@article{0b1b998c6589459089f78761e3423d23,
title = "Inhibition of Mitochondrial Aconitase by Succination in Fumarate Hydratase Deficiency",
abstract = "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.",
author = "Nicola Ternette and Ming Yang and Mahima Laroyia and Mitsuhiro Kitagawa and Linda O'Flaherty and Kathryn Wolhulter and Kaori Igarashi and Kaori Saito and Keiko Kato and Roman Fischer and Alexandre Berquand and Kessler, {Benedikt M.} and Terry Lappin and Norma Frizzell and Tomoyoshi Soga and Julie Adam and Pollard, {Patrick J.}",
year = "2013",
doi = "10.1016/j.celrep.2013.02.013",
language = "English",
volume = "3",
pages = "689--700",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",

}

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=84875805425&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875805425&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2013.02.013

DO - 10.1016/j.celrep.2013.02.013

M3 - Article

C2 - 23499446

AN - SCOPUS:84875805425

VL - 3

SP - 689

EP - 700

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 3

ER -