Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
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 journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
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
C2 - 27496549
VL - 473
SP - 3463
EP - 3485
JO - Biochemical Journal
JF - Biochemical Journal
SN - 0264-6021
IS - 20
ER -
ID: 174013123