Mutated SUCLG1 causes mislocalization of SUCLG2 protein, morphological alterations of mitochondria and an early-onset severe neurometabolic disorder

C. Chinopoulos, Spyros Batzios, Lambertus P. van den Heuvel, Richard Rodenburg, Roel Smeets, Hans R. Waterham, Marjolein Turkenburg, Jos P. Ruiter, Ronald J.A. Wanders, Judit Doczi, Gergo Horvath, A. Dobolyi, Euthymia Vargiami, Ron A. Wevers, Dimitrios Zafeiriou

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Succinate-CoA ligase (SUCL) is a heterodimer consisting of an alpha subunit encoded by SUCLG1, and a beta subunit encoded by either SUCLA2 or SUCLG2 catalyzing an ATP- or GTP-forming reaction, respectively, in the mitochondrial matrix. The deficiency of this enzyme represents an encephalomyopathic form of mtDNA depletion syndromes. We describe the fatal clinical course of a female patient with a pathogenic mutation in SUCLG1 (c.626C > A, p.Ala209Glu) heterozygous at the genomic DNA level, but homozygous at the transcriptional level. The patient exhibited early-onset neurometabolic abnormality culminating in severe brain atrophy and dystonia leading to death by the age of 3.5 years. Urine and plasma metabolite profiling was consistent with SUCL deficiency which was confirmed by enzyme analysis and lack of mitochondrial substrate-level phosphorylation (mSLP) in skin fibroblasts. Oxygen consumption- but not extracellular acidification rates were altered only when using glutamine as a substrate, and this was associated with mild mtDNA depletion and no changes in ETC activities. Immunoblot analysis revealed no detectable levels of SUCLG1, while SUCLA2 and SUCLG2 protein expressions were largely reduced. Confocal imaging of triple immunocytochemistry of skin fibroblasts showed that SUCLG2 co-localized only partially with the mitochondrial network which otherwise exhibited an increase in fragmentation compared to control cells. Our results outline the catastrophic consequences of the mutated SUCLG1 leading to strongly reduced SUCL activity, mSLP impairment, mislocalization of SUCLG2, morphological alterations in mitochondria and clinically to a severe neurometabolic disease, but in the absence of changes in mtDNA levels or respiratory complex activities.

Original languageEnglish
JournalMolecular Genetics and Metabolism
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Succinate-CoA Ligases
Mitochondria
Mitochondrial DNA
Phosphorylation
Fibroblasts
Skin
Substrates
Proteins
Dystonia
Acidification
Enzymes
Metabolites
Guanosine Triphosphate
Glutamine
Oxygen Consumption
Atrophy
Brain
Adenosine Triphosphate
Immunohistochemistry
Urine

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

Cite this

Mutated SUCLG1 causes mislocalization of SUCLG2 protein, morphological alterations of mitochondria and an early-onset severe neurometabolic disorder. / Chinopoulos, C.; Batzios, Spyros; van den Heuvel, Lambertus P.; Rodenburg, Richard; Smeets, Roel; Waterham, Hans R.; Turkenburg, Marjolein; Ruiter, Jos P.; Wanders, Ronald J.A.; Doczi, Judit; Horvath, Gergo; Dobolyi, A.; Vargiami, Euthymia; Wevers, Ron A.; Zafeiriou, Dimitrios.

In: Molecular Genetics and Metabolism, 01.01.2018.

Research output: Contribution to journalArticle

Chinopoulos, C, Batzios, S, van den Heuvel, LP, Rodenburg, R, Smeets, R, Waterham, HR, Turkenburg, M, Ruiter, JP, Wanders, RJA, Doczi, J, Horvath, G, Dobolyi, A, Vargiami, E, Wevers, RA & Zafeiriou, D 2018, 'Mutated SUCLG1 causes mislocalization of SUCLG2 protein, morphological alterations of mitochondria and an early-onset severe neurometabolic disorder', Molecular Genetics and Metabolism. https://doi.org/10.1016/j.ymgme.2018.11.009
Chinopoulos, C. ; Batzios, Spyros ; van den Heuvel, Lambertus P. ; Rodenburg, Richard ; Smeets, Roel ; Waterham, Hans R. ; Turkenburg, Marjolein ; Ruiter, Jos P. ; Wanders, Ronald J.A. ; Doczi, Judit ; Horvath, Gergo ; Dobolyi, A. ; Vargiami, Euthymia ; Wevers, Ron A. ; Zafeiriou, Dimitrios. / Mutated SUCLG1 causes mislocalization of SUCLG2 protein, morphological alterations of mitochondria and an early-onset severe neurometabolic disorder. In: Molecular Genetics and Metabolism. 2018.
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abstract = "Succinate-CoA ligase (SUCL) is a heterodimer consisting of an alpha subunit encoded by SUCLG1, and a beta subunit encoded by either SUCLA2 or SUCLG2 catalyzing an ATP- or GTP-forming reaction, respectively, in the mitochondrial matrix. The deficiency of this enzyme represents an encephalomyopathic form of mtDNA depletion syndromes. We describe the fatal clinical course of a female patient with a pathogenic mutation in SUCLG1 (c.626C > A, p.Ala209Glu) heterozygous at the genomic DNA level, but homozygous at the transcriptional level. The patient exhibited early-onset neurometabolic abnormality culminating in severe brain atrophy and dystonia leading to death by the age of 3.5 years. Urine and plasma metabolite profiling was consistent with SUCL deficiency which was confirmed by enzyme analysis and lack of mitochondrial substrate-level phosphorylation (mSLP) in skin fibroblasts. Oxygen consumption- but not extracellular acidification rates were altered only when using glutamine as a substrate, and this was associated with mild mtDNA depletion and no changes in ETC activities. Immunoblot analysis revealed no detectable levels of SUCLG1, while SUCLA2 and SUCLG2 protein expressions were largely reduced. Confocal imaging of triple immunocytochemistry of skin fibroblasts showed that SUCLG2 co-localized only partially with the mitochondrial network which otherwise exhibited an increase in fragmentation compared to control cells. Our results outline the catastrophic consequences of the mutated SUCLG1 leading to strongly reduced SUCL activity, mSLP impairment, mislocalization of SUCLG2, morphological alterations in mitochondria and clinically to a severe neurometabolic disease, but in the absence of changes in mtDNA levels or respiratory complex activities.",
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AU - Chinopoulos, C.

AU - Batzios, Spyros

AU - van den Heuvel, Lambertus P.

AU - Rodenburg, Richard

AU - Smeets, Roel

AU - Waterham, Hans R.

AU - Turkenburg, Marjolein

AU - Ruiter, Jos P.

AU - Wanders, Ronald J.A.

AU - Doczi, Judit

AU - Horvath, Gergo

AU - Dobolyi, A.

AU - Vargiami, Euthymia

AU - Wevers, Ron A.

AU - Zafeiriou, Dimitrios

PY - 2018/1/1

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N2 - Succinate-CoA ligase (SUCL) is a heterodimer consisting of an alpha subunit encoded by SUCLG1, and a beta subunit encoded by either SUCLA2 or SUCLG2 catalyzing an ATP- or GTP-forming reaction, respectively, in the mitochondrial matrix. The deficiency of this enzyme represents an encephalomyopathic form of mtDNA depletion syndromes. We describe the fatal clinical course of a female patient with a pathogenic mutation in SUCLG1 (c.626C > A, p.Ala209Glu) heterozygous at the genomic DNA level, but homozygous at the transcriptional level. The patient exhibited early-onset neurometabolic abnormality culminating in severe brain atrophy and dystonia leading to death by the age of 3.5 years. Urine and plasma metabolite profiling was consistent with SUCL deficiency which was confirmed by enzyme analysis and lack of mitochondrial substrate-level phosphorylation (mSLP) in skin fibroblasts. Oxygen consumption- but not extracellular acidification rates were altered only when using glutamine as a substrate, and this was associated with mild mtDNA depletion and no changes in ETC activities. Immunoblot analysis revealed no detectable levels of SUCLG1, while SUCLA2 and SUCLG2 protein expressions were largely reduced. Confocal imaging of triple immunocytochemistry of skin fibroblasts showed that SUCLG2 co-localized only partially with the mitochondrial network which otherwise exhibited an increase in fragmentation compared to control cells. Our results outline the catastrophic consequences of the mutated SUCLG1 leading to strongly reduced SUCL activity, mSLP impairment, mislocalization of SUCLG2, morphological alterations in mitochondria and clinically to a severe neurometabolic disease, but in the absence of changes in mtDNA levels or respiratory complex activities.

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