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

Gergely Kacso; Dora Ravasz; Judit Doczi; Beáta Németh; Ory Madgar; Ann Saada; Polina Ilin; Chaya Miller; Elsebet Ostergaard; Iordan Iordanov; Daniel Adams; Zsuzsanna Vargedo; Masatake Araki; Kimi Araki; Mai Nakahara; Haruka Ito; Aniko Gál; Mária J Molnár; Zsolt Nagy; Attila Patocs; Vera Adam-Vizi; Christos Chinopoulos

doi:10.1042/BCJ20160594

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

Gergely Kacso, Dora Ravasz, Judit Doczi, Beáta Németh, Ory Madgar, Ann Saada, Polina Ilin, Chaya Miller, Elsebet Ostergaard, Iordan Iordanov, Daniel Adams, Zsuzsanna Vargedo, Masatake Araki, Kimi Araki, Mai Nakahara, Haruka Ito, Aniko Gál, Mária J Molnár, Zsolt Nagy, Attila PatocsVera Adam-Vizi, Christos Chinopoulos

Institut for Klinisk Medicin

12 Citationer (Scopus)

68 Downloads (Pure)

Abstract

Succinate-CoA ligase is a heterodimer enzyme composed of Suclgl -alpha- and a substrate-specific Sucla2 or Suclg2 -beta- 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 were not different between wild type and Sucla2 heterozygote mice unless a submaximal pharmacological inhibition of succinate-CoA ligase 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 substrate-level phosphorylation, 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 succinate-CoA ligase. These results as well as the availability of the transgenic mouse colonies will be of value in understanding succinate-CoA ligase deficiency.

Originalsprog	Engelsk
Tidsskrift	Biochemical Journal
Vol/bind	473
Udgave nummer	20
Sider (fra-til)	3463-3485
Antal sider	23
ISSN	0264-6021
DOI	https://doi.org/10.1042/BCJ20160594
Status	Udgivet - 15 okt. 2016

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10.1042/BCJ20160594Licens: CC BY

Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterationsForlagets udgivne version, 1,92 MBLicens: CC BY

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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, M. J., Nagy, Z., ... 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

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, bind 473, nr. 20, s. 3463-3485. https://doi.org/10.1042/BCJ20160594

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

abstract = "Succinate-CoA ligase is a heterodimer enzyme composed of Suclgl -alpha- and a substrate-specific Sucla2 or Suclg2 -beta- 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 were not different between wild type and Sucla2 heterozygote mice unless a submaximal pharmacological inhibition of succinate-CoA ligase 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 substrate-level phosphorylation, 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 succinate-CoA ligase. These results as well as the availability of the transgenic mouse colonies will be of value in understanding succinate-CoA ligase 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",

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doi = "10.1042/BCJ20160594",

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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

PY - 2016/10/15

Y1 - 2016/10/15

N2 - Succinate-CoA ligase is a heterodimer enzyme composed of Suclgl -alpha- and a substrate-specific Sucla2 or Suclg2 -beta- 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 were not different between wild type and Sucla2 heterozygote mice unless a submaximal pharmacological inhibition of succinate-CoA ligase 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 substrate-level phosphorylation, 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 succinate-CoA ligase. These results as well as the availability of the transgenic mouse colonies will be of value in understanding succinate-CoA ligase deficiency.

AB - Succinate-CoA ligase is a heterodimer enzyme composed of Suclgl -alpha- and a substrate-specific Sucla2 or Suclg2 -beta- 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 were not different between wild type and Sucla2 heterozygote mice unless a submaximal pharmacological inhibition of succinate-CoA ligase 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 substrate-level phosphorylation, 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 succinate-CoA ligase. These results as well as the availability of the transgenic mouse colonies will be of value in understanding succinate-CoA ligase deficiency.

U2 - 10.1042/BCJ20160594

DO - 10.1042/BCJ20160594

M3 - Journal article

C2 - 27496549

SN - 0264-6021

VL - 473

SP - 3463

EP - 3485

JO - Biochemical Journal

JF - Biochemical Journal

IS - 20

ER -

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

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