Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Gut, P, Matilainen, S, Meyer, JG, Pällijeff, P, Richard, J, Carroll, CJ, Euro, L, Jackson, CB, Isohanni, P, Minassian, BA, Alkhater, RA, Østergaard, E, Civiletto, G, Parisi, A, Thevenet, J, Rardin, MJ, He, W, Nishida, Y, Newman, JC, Liu, X, Christen, S, Moco, S, Locasale, JW, Schilling, B, Suomalainen, A & Verdin, E 2020, 'SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease', Nature Communications, vol. 11, no. 1, pp. 5927. https://doi.org/10.1038/s41467-020-19743-4

APA

Gut, P., Matilainen, S., Meyer, J. G., Pällijeff, P., Richard, J., Carroll, C. J., Euro, L., Jackson, C. B., Isohanni, P., Minassian, B. A., Alkhater, R. A., Østergaard, E., Civiletto, G., Parisi, A., Thevenet, J., Rardin, M. J., He, W., Nishida, Y., Newman, J. C., ... Verdin, E. (2020). SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease. Nature Communications, 11(1), 5927. https://doi.org/10.1038/s41467-020-19743-4

CBE

Gut P, Matilainen S, Meyer JG, Pällijeff P, Richard J, Carroll CJ, Euro L, Jackson CB, Isohanni P, Minassian BA, Alkhater RA, Østergaard E, Civiletto G, Parisi A, Thevenet J, Rardin MJ, He W, Nishida Y, Newman JC, Liu X, Christen S, Moco S, Locasale JW, Schilling B, Suomalainen A, Verdin E. 2020. SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease. Nature Communications. 11(1):5927. https://doi.org/10.1038/s41467-020-19743-4

MLA

Vancouver

Author

Gut, Philipp ; Matilainen, Sanna ; Meyer, Jesse G ; Pällijeff, Pieti ; Richard, Joy ; Carroll, Christopher J ; Euro, Liliya ; Jackson, Christopher B ; Isohanni, Pirjo ; Minassian, Berge A ; Alkhater, Reem A ; Østergaard, Elsebet ; Civiletto, Gabriele ; Parisi, Alice ; Thevenet, Jonathan ; Rardin, Matthew J ; He, Wenjuan ; Nishida, Yuya ; Newman, John C ; Liu, Xiaojing ; Christen, Stefan ; Moco, Sofia ; Locasale, Jason W ; Schilling, Birgit ; Suomalainen, Anu ; Verdin, Eric. / SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease. In: Nature Communications. 2020 ; Vol. 11, No. 1. pp. 5927.

Bibtex

@article{29ed2a8932f441c3ad2c97d66269888f,
title = "SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease",
abstract = "Mitochondrial acyl-coenzyme A species are emerging as important sources of protein modification and damage. Succinyl-CoA ligase (SCL) deficiency causes a mitochondrial encephalomyopathy of unknown pathomechanism. Here, we show that succinyl-CoA accumulates in cells derived from patients with recessive mutations in the tricarboxylic acid cycle (TCA) gene succinyl-CoA ligase subunit-β (SUCLA2), causing global protein hyper-succinylation. Using mass spectrometry, we quantify nearly 1,000 protein succinylation sites on 366 proteins from patient-derived fibroblasts and myotubes. Interestingly, hyper-succinylated proteins are distributed across cellular compartments, and many are known targets of the (NAD+)-dependent desuccinylase SIRT5. To test the contribution of hyper-succinylation to disease progression, we develop a zebrafish model of the SCL deficiency and find that SIRT5 gain-of-function reduces global protein succinylation and improves survival. Thus, increased succinyl-CoA levels contribute to the pathology of SCL deficiency through post-translational modifications.",
keywords = "Acyl Coenzyme A/metabolism, Animals, Cells, Cultured, Female, Humans, Infant, Lysine/metabolism, Male, Mice, Mice, Knockout, Mitochondria/metabolism, Mitochondrial Diseases/genetics, Mutation, Proteomics, Sirtuins/deficiency, Succinate-CoA Ligases/deficiency, Survival Analysis, Zebrafish",
author = "Philipp Gut and Sanna Matilainen and Meyer, {Jesse G} and Pieti P{\"a}llijeff and Joy Richard and Carroll, {Christopher J} and Liliya Euro and Jackson, {Christopher B} and Pirjo Isohanni and Minassian, {Berge A} and Alkhater, {Reem A} and Elsebet {\O}stergaard and Gabriele Civiletto and Alice Parisi and Jonathan Thevenet and Rardin, {Matthew J} and Wenjuan He and Yuya Nishida and Newman, {John C} and Xiaojing Liu and Stefan Christen and Sofia Moco and Locasale, {Jason W} and Birgit Schilling and Anu Suomalainen and Eric Verdin",
year = "2020",
month = nov,
day = "23",
doi = "10.1038/s41467-020-19743-4",
language = "English",
volume = "11",
pages = "5927",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

RIS

TY - JOUR

T1 - SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease

AU - Gut, Philipp

AU - Matilainen, Sanna

AU - Meyer, Jesse G

AU - Pällijeff, Pieti

AU - Richard, Joy

AU - Carroll, Christopher J

AU - Euro, Liliya

AU - Jackson, Christopher B

AU - Isohanni, Pirjo

AU - Minassian, Berge A

AU - Alkhater, Reem A

AU - Østergaard, Elsebet

AU - Civiletto, Gabriele

AU - Parisi, Alice

AU - Thevenet, Jonathan

AU - Rardin, Matthew J

AU - He, Wenjuan

AU - Nishida, Yuya

AU - Newman, John C

AU - Liu, Xiaojing

AU - Christen, Stefan

AU - Moco, Sofia

AU - Locasale, Jason W

AU - Schilling, Birgit

AU - Suomalainen, Anu

AU - Verdin, Eric

PY - 2020/11/23

Y1 - 2020/11/23

N2 - Mitochondrial acyl-coenzyme A species are emerging as important sources of protein modification and damage. Succinyl-CoA ligase (SCL) deficiency causes a mitochondrial encephalomyopathy of unknown pathomechanism. Here, we show that succinyl-CoA accumulates in cells derived from patients with recessive mutations in the tricarboxylic acid cycle (TCA) gene succinyl-CoA ligase subunit-β (SUCLA2), causing global protein hyper-succinylation. Using mass spectrometry, we quantify nearly 1,000 protein succinylation sites on 366 proteins from patient-derived fibroblasts and myotubes. Interestingly, hyper-succinylated proteins are distributed across cellular compartments, and many are known targets of the (NAD+)-dependent desuccinylase SIRT5. To test the contribution of hyper-succinylation to disease progression, we develop a zebrafish model of the SCL deficiency and find that SIRT5 gain-of-function reduces global protein succinylation and improves survival. Thus, increased succinyl-CoA levels contribute to the pathology of SCL deficiency through post-translational modifications.

AB - Mitochondrial acyl-coenzyme A species are emerging as important sources of protein modification and damage. Succinyl-CoA ligase (SCL) deficiency causes a mitochondrial encephalomyopathy of unknown pathomechanism. Here, we show that succinyl-CoA accumulates in cells derived from patients with recessive mutations in the tricarboxylic acid cycle (TCA) gene succinyl-CoA ligase subunit-β (SUCLA2), causing global protein hyper-succinylation. Using mass spectrometry, we quantify nearly 1,000 protein succinylation sites on 366 proteins from patient-derived fibroblasts and myotubes. Interestingly, hyper-succinylated proteins are distributed across cellular compartments, and many are known targets of the (NAD+)-dependent desuccinylase SIRT5. To test the contribution of hyper-succinylation to disease progression, we develop a zebrafish model of the SCL deficiency and find that SIRT5 gain-of-function reduces global protein succinylation and improves survival. Thus, increased succinyl-CoA levels contribute to the pathology of SCL deficiency through post-translational modifications.

KW - Acyl Coenzyme A/metabolism

KW - Animals

KW - Cells, Cultured

KW - Female

KW - Humans

KW - Infant

KW - Lysine/metabolism

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Mitochondria/metabolism

KW - Mitochondrial Diseases/genetics

KW - Mutation

KW - Proteomics

KW - Sirtuins/deficiency

KW - Succinate-CoA Ligases/deficiency

KW - Survival Analysis

KW - Zebrafish

U2 - 10.1038/s41467-020-19743-4

DO - 10.1038/s41467-020-19743-4

M3 - Journal article

C2 - 33230181

VL - 11

SP - 5927

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

ER -

ID: 61711029