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

Philipp Gut; Sanna Matilainen; Jesse G Meyer; Pieti Pällijeff; Joy Richard; Christopher J Carroll; Liliya Euro; Christopher B Jackson; Pirjo Isohanni; Berge A Minassian; Reem A Alkhater; Elsebet Østergaard; Gabriele Civiletto; Alice Parisi; Jonathan Thevenet; Matthew J Rardin; Wenjuan He; Yuya Nishida; John C Newman; Xiaojing Liu; Stefan Christen; Sofia Moco; Jason W Locasale; Birgit Schilling; Anu Suomalainen; Eric Verdin

doi:10.1038/s41467-020-19743-4

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

Philipp Gut, Sanna Matilainen, Jesse G Meyer, Pieti Pällijeff, Joy Richard, Christopher J Carroll, Liliya Euro, Christopher B Jackson, Pirjo Isohanni, Berge A Minassian, Reem A Alkhater, Elsebet Østergaard, Gabriele Civiletto, Alice Parisi, Jonathan Thevenet, Matthew J Rardin, Wenjuan He, Yuya Nishida, John C Newman, Xiaojing LiuStefan Christen, Sofia Moco, Jason W Locasale, Birgit Schilling, Anu Suomalainen, Eric Verdin

Department of Clinical Genetics

66 Citations (Scopus)

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.

Original language	English
Article number	5927
Journal	Nature Communications
Volume	11
Issue number	1
Pages (from-to)	5927
ISSN	2041-1722
DOIs	https://doi.org/10.1038/s41467-020-19743-4
Publication status	Published - 23 Nov 2020

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

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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. Article 5927. https://doi.org/10.1038/s41467-020-19743-4

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, 5927, pp. 5927. https://doi.org/10.1038/s41467-020-19743-4

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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",

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doi = "10.1038/s41467-020-19743-4",

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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

UR - https://www.scopus.com/pages/publications/85096443301

U2 - 10.1038/s41467-020-19743-4

DO - 10.1038/s41467-020-19743-4

M3 - Journal article

C2 - 33230181

SN - 2041-1722

VL - 11

SP - 5927

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5927

ER -

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

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Keywords

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