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Mutated SUCLG1 causes mislocalization of SUCLG2 protein, morphological alterations of mitochondria and an early-onset severe neurometabolic disorder. / Chinopoulos, Christos; Batzios, Spyros; van den Heuvel, Lambertus P. et al.

In: Molecular genetics and metabolism, Vol. 126, No. 1, 2019, p. 43-52.

Research output: Contribution to journal › Article › Academic › peer-review

Harvard

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 2019, 'Mutated SUCLG1 causes mislocalization of SUCLG2 protein, morphological alterations of mitochondria and an early-onset severe neurometabolic disorder', Molecular genetics and metabolism, vol. 126, no. 1, pp. 43-52. https://doi.org/10.1016/j.ymgme.2018.11.009

APA

Chinopoulos, C., Batzios, S., van den Heuvel, L. P., Rodenburg, R., Smeets, R., Waterham, H. R., Turkenburg, M., Ruiter, J. P., Wanders, R. J. A., Doczi, J., Horvath, G., Dobolyi, A., Vargiami, E., Wevers, R. A., & Zafeiriou, D. (2019). Mutated SUCLG1 causes mislocalization of SUCLG2 protein, morphological alterations of mitochondria and an early-onset severe neurometabolic disorder. Molecular genetics and metabolism, 126(1), 43-52. https://doi.org/10.1016/j.ymgme.2018.11.009

Vancouver

Chinopoulos C, Batzios S, van den Heuvel LP, Rodenburg R, Smeets R, Waterham HR et al. Mutated SUCLG1 causes mislocalization of SUCLG2 protein, morphological alterations of mitochondria and an early-onset severe neurometabolic disorder. Molecular genetics and metabolism. 2019;126(1):43-52. Epub 2018. doi: 10.1016/j.ymgme.2018.11.009

Author

Chinopoulos, Christos ; Batzios, Spyros ; van den Heuvel, Lambertus P. et al. / Mutated SUCLG1 causes mislocalization of SUCLG2 protein, morphological alterations of mitochondria and an early-onset severe neurometabolic disorder. In: Molecular genetics and metabolism. 2019 ; Vol. 126, No. 1. pp. 43-52.

BibTeX

@article{507ee48d53e443879a5e726e0c58adca,
title = "Mutated SUCLG1 causes mislocalization of SUCLG2 protein, morphological alterations of mitochondria and an early-onset severe neurometabolic disorder",
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.",
author = "Christos Chinopoulos and Spyros Batzios and {van den Heuvel}, {Lambertus P.} and Richard Rodenburg and Roel Smeets and Waterham, {Hans R.} and Marjolein Turkenburg and Ruiter, {Jos P.} and Wanders, {Ronald J. A.} and Judit Doczi and Gergo Horvath and Arpad Dobolyi and Euthymia Vargiami and Wevers, {Ron A.} and Dimitrios Zafeiriou",
year = "2019",
doi = "10.1016/j.ymgme.2018.11.009",
language = "English",
volume = "126",
pages = "43--52",
journal = "Molecular genetics and metabolism",
issn = "1096-7192",
publisher = "Academic Press Inc.",
number = "1",

}

RIS

TY - JOUR

T1 - Mutated SUCLG1 causes mislocalization of SUCLG2 protein, morphological alterations of mitochondria and an early-onset severe neurometabolic disorder

AU - Chinopoulos, Christos

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, Arpad

AU - Vargiami, Euthymia

AU - Wevers, Ron A.

AU - Zafeiriou, Dimitrios

PY - 2019

Y1 - 2019

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.

AB - 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.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85056734018&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/30470562

U2 - 10.1016/j.ymgme.2018.11.009

DO - 10.1016/j.ymgme.2018.11.009

M3 - Article

C2 - 30470562

VL - 126

SP - 43

EP - 52

JO - Molecular genetics and metabolism

JF - Molecular genetics and metabolism

SN - 1096-7192

IS - 1

ER -

ID: 5759693