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.
authors: Department of Medical Biochemistry, Semmelweis University, Tuzolto Street 37-47, Budapest 1094, Hungary MTA-SE Lendület Neurobiochemistry Research Group, Budapest 1094, Hungary.
authors: Gergely
authors: G
authors: Kacso
authors: Department of Medical Biochemistry, Semmelweis University, Tuzolto Street 37-47, Budapest 1094, Hungary MTA-SE Lendület Neurobiochemistry Research Group, Budapest 1094, Hungary.
authors: Dora
authors: D
authors: Ravasz
authors: Department of Medical Biochemistry, Semmelweis University, Tuzolto Street 37-47, Budapest 1094, Hungary MTA-SE Lendület Neurobiochemistry Research Group, Budapest 1094, Hungary.
authors: Judit
authors: J
authors: Doczi
authors: Department of Medical Biochemistry, Semmelweis University, Tuzolto Street 37-47, Budapest 1094, Hungary MTA-SE Lendület Neurobiochemistry Research Group, Budapest 1094, Hungary.
authors: Beáta
authors: B
authors: Németh
authors: Department of Medical Biochemistry, Semmelweis University, Tuzolto Street 37-47, Budapest 1094, Hungary MTA-SE Lendület Neurobiochemistry Research Group, Budapest 1094, Hungary.
authors: Ory
authors: O
authors: Madgar
authors: Monique and Jacques Roboh Department of Genetic Research and the Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors: Ann
authors: A
authors: Saada
authors: Monique and Jacques Roboh Department of Genetic Research and the Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors: Polina
authors: P
authors: Ilin
authors: Monique and Jacques Roboh Department of Genetic Research and the Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors: Chaya
authors: C
authors: Miller
authors: Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen 2100, Denmark.
authors: Elsebet
authors: E
authors: Ostergaard
authors: Department of Medical Biochemistry, Semmelweis University, Tuzolto Street 37-47, Budapest 1094, Hungary MTA-SE Lendület Ion Channel Research Group, Budapest 1094, Hungary.
authors: Iordan
authors: I
authors: Iordanov
authors: Department of Medical Biochemistry, Semmelweis University, Tuzolto Street 37-47, Budapest 1094, Hungary MTA-SE Lendület Neurobiochemistry Research Group, Budapest 1094, Hungary.
authors: Daniel
authors: D
authors: Adams
authors: Department of Medical Biochemistry, Semmelweis University, Tuzolto Street 37-47, Budapest 1094, Hungary MTA-SE Lendület Neurobiochemistry Research Group, Budapest 1094, Hungary.
authors: Zsuzsanna
authors: Z
authors: Vargedo
authors: Institute of Resource Development and Analysis, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
authors: Masatake
authors: M
authors: Araki
authors: Institute of Resource Development and Analysis, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
authors: Kimi
authors: K
authors: Araki
authors: Institute of Resource Development and Analysis, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
authors: Mai
authors: M
authors: Nakahara
authors: Institute of Resource Development and Analysis, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
authors: Haruka
authors: H
authors: Ito
authors: Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest 1083, Hungary.
authors: Aniko
authors: A
authors: Gál
authors: Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest 1083, Hungary.
authors: Mária J
authors: MJ
authors: Molnár
authors: MTA-SE Lendület Hereditary Endocrine Tumours Research Group, Budapest 1088, Hungary.
authors: Zsolt
authors: Z
authors: Nagy
authors: MTA-SE Lendület Hereditary Endocrine Tumours Research Group, Budapest 1088, Hungary.
authors: Attila
authors: A
authors: Patocs
authors: Department of Medical Biochemistry, Semmelweis University, Tuzolto Street 37-47, Budapest 1094, Hungary MTA-SE Laboratory for Neurobiochemistry, Budapest 1094, Hungary.
authors: Vera
authors: V
authors: Adam-Vizi
authors: Department of Medical Biochemistry, Semmelweis University, Tuzolto Street 37-47, Budapest 1094, Hungary MTA-SE Lendület Neurobiochemistry Research Group, Budapest 1094, Hungary.
authors: Christos
authors: C
authors: Chinopoulos
mesh_terms: D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D066298:In Vitro Techniques; D053078:Membrane Potential, Mitochondrial / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D013389:Succinate-CoA Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D012333:RNA, Messenger; C116917:acylcarnitine; D013389:Succinate-CoA Ligases; C000593354:Sucla2 protein, mouse; D002331:Carnitine
keywords: inborn error of metabolism; mitochondrial dysfunction; mouse genetics; mtDNA