Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations

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Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations. / Kacso, Gergely; Ravasz, Dora; Doczi, Judit; Németh, Beáta; Madgar, Ory; Saada, Ann; Ilin, Polina; Miller, Chaya; Ostergaard, Elsebet; Iordanov, Iordan; Adams, Daniel; Vargedo, Zsuzsanna; Araki, Masatake; Araki, Kimi; Nakahara, Mai; Ito, Haruka; Gál, Aniko; Molnár, Mária J; Nagy, Zsolt; Patocs, Attila; Adam-Vizi, Vera; Chinopoulos, Christos.

In: Biochemical Journal, Vol. 473, No. 20, 15.10.2016, p. 3463-3485.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Kacso, G, Ravasz, D, Doczi, J, Németh, B, Madgar, O, Saada, A, Ilin, P, Miller, C, Ostergaard, E, Iordanov, I, Adams, D, Vargedo, Z, Araki, M, Araki, K, Nakahara, M, Ito, H, Gál, A, Molnár, MJ, Nagy, Z, Patocs, A, Adam-Vizi, V & Chinopoulos, C 2016, 'Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations', Biochemical Journal, vol. 473, no. 20, pp. 3463-3485. https://doi.org/10.1042/BCJ20160594

APA

Kacso, G., Ravasz, D., Doczi, J., Németh, B., Madgar, O., Saada, A., ... Chinopoulos, C. (2016). Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations. Biochemical Journal, 473(20), 3463-3485. https://doi.org/10.1042/BCJ20160594

Vancouver

Kacso G, Ravasz D, Doczi J, Németh B, Madgar O, Saada A et al. Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations. Biochemical Journal. 2016 Oct 15;473(20):3463-3485. https://doi.org/10.1042/BCJ20160594

Author

Kacso, Gergely ; Ravasz, Dora ; Doczi, Judit ; Németh, Beáta ; Madgar, Ory ; Saada, Ann ; Ilin, Polina ; Miller, Chaya ; Ostergaard, Elsebet ; Iordanov, Iordan ; Adams, Daniel ; Vargedo, Zsuzsanna ; Araki, Masatake ; Araki, Kimi ; Nakahara, Mai ; Ito, Haruka ; Gál, Aniko ; Molnár, Mária J ; Nagy, Zsolt ; Patocs, Attila ; Adam-Vizi, Vera ; Chinopoulos, Christos. / Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations. In: Biochemical Journal. 2016 ; Vol. 473, No. 20. pp. 3463-3485.

Bibtex

@article{e29f14045f534588b4819f78a88517b1,
title = "Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations",
abstract = "Succinate-CoA ligase (SUCL) is a heterodimer enzyme composed of Suclg1 α-subunit and a substrate-specific Sucla2 or Suclg2 β-subunit yielding ATP or GTP, respectively. In humans, the deficiency of this enzyme leads to encephalomyopathy with or without methylmalonyl aciduria, in addition to resulting in mitochondrial DNA depletion. We generated mice lacking either one Sucla2 or Suclg2 allele. Sucla2 heterozygote mice exhibited tissue- and age-dependent decreases in Sucla2 expression associated with decreases in ATP-forming activity, but rebound increases in cardiac Suclg2 expression and GTP-forming activity. Bioenergetic parameters including substrate-level phosphorylation (SLP) were not different between wild-type and Sucla2 heterozygote mice unless a submaximal pharmacological inhibition of SUCL was concomitantly present. mtDNA contents were moderately decreased, but blood carnitine esters were significantly elevated. Suclg2 heterozygote mice exhibited decreases in Suclg2 expression but no rebound increases in Sucla2 expression or changes in bioenergetic parameters. Surprisingly, deletion of one Suclg2 allele in Sucla2 heterozygote mice still led to a rebound but protracted increase in Suclg2 expression, yielding double heterozygote mice with no alterations in GTP-forming activity or SLP, but more pronounced changes in mtDNA content and blood carnitine esters, and an increase in succinate dehydrogenase activity. We conclude that a partial reduction in Sucla2 elicits rebound increases in Suclg2 expression, which is sufficiently dominant to overcome even a concomitant deletion of one Suclg2 allele, pleiotropically affecting metabolic pathways associated with SUCL. These results as well as the availability of the transgenic mouse colonies will be of value in understanding SUCL deficiency.",
author = "Gergely Kacso and Dora Ravasz and Judit Doczi and Be{\'a}ta N{\'e}meth and Ory Madgar and Ann Saada and Polina Ilin and Chaya Miller and Elsebet Ostergaard and Iordan Iordanov and Daniel Adams and Zsuzsanna Vargedo and Masatake Araki and Kimi Araki and Mai Nakahara and Haruka Ito and Aniko G{\'a}l and Moln{\'a}r, {M{\'a}ria J} and Zsolt Nagy and Attila Patocs and Vera Adam-Vizi and Christos Chinopoulos",
note = "{\circledC} 2016 The Author(s).",
year = "2016",
month = "10",
day = "15",
doi = "10.1042/BCJ20160594",
language = "English",
volume = "473",
pages = "3463--3485",
journal = "Biochemical Journal",
issn = "0264-6021",
publisher = "Portland Press Ltd.",
number = "20",

}

RIS

TY - JOUR

T1 - Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations

AU - Kacso, Gergely

AU - Ravasz, Dora

AU - Doczi, Judit

AU - Németh, Beáta

AU - Madgar, Ory

AU - Saada, Ann

AU - Ilin, Polina

AU - Miller, Chaya

AU - Ostergaard, Elsebet

AU - Iordanov, Iordan

AU - Adams, Daniel

AU - Vargedo, Zsuzsanna

AU - Araki, Masatake

AU - Araki, Kimi

AU - Nakahara, Mai

AU - Ito, Haruka

AU - Gál, Aniko

AU - Molnár, Mária J

AU - Nagy, Zsolt

AU - Patocs, Attila

AU - Adam-Vizi, Vera

AU - Chinopoulos, Christos

N1 - © 2016 The Author(s).

PY - 2016/10/15

Y1 - 2016/10/15

N2 - Succinate-CoA ligase (SUCL) is a heterodimer enzyme composed of Suclg1 α-subunit and a substrate-specific Sucla2 or Suclg2 β-subunit yielding ATP or GTP, respectively. In humans, the deficiency of this enzyme leads to encephalomyopathy with or without methylmalonyl aciduria, in addition to resulting in mitochondrial DNA depletion. We generated mice lacking either one Sucla2 or Suclg2 allele. Sucla2 heterozygote mice exhibited tissue- and age-dependent decreases in Sucla2 expression associated with decreases in ATP-forming activity, but rebound increases in cardiac Suclg2 expression and GTP-forming activity. Bioenergetic parameters including substrate-level phosphorylation (SLP) were not different between wild-type and Sucla2 heterozygote mice unless a submaximal pharmacological inhibition of SUCL was concomitantly present. mtDNA contents were moderately decreased, but blood carnitine esters were significantly elevated. Suclg2 heterozygote mice exhibited decreases in Suclg2 expression but no rebound increases in Sucla2 expression or changes in bioenergetic parameters. Surprisingly, deletion of one Suclg2 allele in Sucla2 heterozygote mice still led to a rebound but protracted increase in Suclg2 expression, yielding double heterozygote mice with no alterations in GTP-forming activity or SLP, but more pronounced changes in mtDNA content and blood carnitine esters, and an increase in succinate dehydrogenase activity. We conclude that a partial reduction in Sucla2 elicits rebound increases in Suclg2 expression, which is sufficiently dominant to overcome even a concomitant deletion of one Suclg2 allele, pleiotropically affecting metabolic pathways associated with SUCL. These results as well as the availability of the transgenic mouse colonies will be of value in understanding SUCL deficiency.

AB - Succinate-CoA ligase (SUCL) is a heterodimer enzyme composed of Suclg1 α-subunit and a substrate-specific Sucla2 or Suclg2 β-subunit yielding ATP or GTP, respectively. In humans, the deficiency of this enzyme leads to encephalomyopathy with or without methylmalonyl aciduria, in addition to resulting in mitochondrial DNA depletion. We generated mice lacking either one Sucla2 or Suclg2 allele. Sucla2 heterozygote mice exhibited tissue- and age-dependent decreases in Sucla2 expression associated with decreases in ATP-forming activity, but rebound increases in cardiac Suclg2 expression and GTP-forming activity. Bioenergetic parameters including substrate-level phosphorylation (SLP) were not different between wild-type and Sucla2 heterozygote mice unless a submaximal pharmacological inhibition of SUCL was concomitantly present. mtDNA contents were moderately decreased, but blood carnitine esters were significantly elevated. Suclg2 heterozygote mice exhibited decreases in Suclg2 expression but no rebound increases in Sucla2 expression or changes in bioenergetic parameters. Surprisingly, deletion of one Suclg2 allele in Sucla2 heterozygote mice still led to a rebound but protracted increase in Suclg2 expression, yielding double heterozygote mice with no alterations in GTP-forming activity or SLP, but more pronounced changes in mtDNA content and blood carnitine esters, and an increase in succinate dehydrogenase activity. We conclude that a partial reduction in Sucla2 elicits rebound increases in Suclg2 expression, which is sufficiently dominant to overcome even a concomitant deletion of one Suclg2 allele, pleiotropically affecting metabolic pathways associated with SUCL. These results as well as the availability of the transgenic mouse colonies will be of value in understanding SUCL deficiency.

U2 - 10.1042/BCJ20160594

DO - 10.1042/BCJ20160594

M3 - Journal article

VL - 473

SP - 3463

EP - 3485

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 20

ER -

ID: 174013123