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Cited by 83Metabolism and Genetic DisordersMitochondrial Function and PathologySirtuins and Resveratrol in Medicine

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

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Gut, Philipp, Matilainen, Sanna, Meyer, Jesse G., Pällijeff, Pieti, Richard, Joy, Carroll, Christopher J., Euro, Liliya, Jackson, Christopher B. +18 more·2020·Nature Communications
DOI 10.1038/s41467-020-19743-4PMC PMC7684291
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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.

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Authors
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., Liu, X., Christen, S., Moco, S., Locasale, J. W., Schilling, B., Suomalainen, A., & Verdin, E.
Affiliations
  • Gladstone Institutes (US)
  • University of Helsinki (FI)
  • Buck Institute for Research on Aging (US)
  • École Polytechnique Fédérale de Lausanne (CH)
  • University of London (GB)
  • University of Toronto (CA)
  • Saudi Aramco Medical Services Organization (SA)
  • Copenhagen University Hospital (DK)
  • Amgen (United States) (US)
  • North Carolina State University (US)
  • Duke University (US)
Corresponding author
  • Gut, Philipp
  • Schilling, Birgit
  • Suomalainen, Anu
  • Verdin, Eric
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-11-23
Volume
11
Issue
1
Pages
5927-5927
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-19743-4
PMC
PMC7684291
OpenAlex
W3110110283
Cited by
83
References
7
Citations by year
2026: 15 · 2025: 25 · 2024: 14 · 2023: 11 · 2022: 14 · 2021: 4
FWCI
4.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • St George's Online Research Archive (St George's University of London) (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Työväentutkimus Vuosikirja (submittedVersion)
Funders
  • Helsingin Yliopisto
  • Buck Institute for Research on Aging
  • Academy of Finland
  • Sigrid Juséliuksen Säätiö
  • National Institutes of Health (1s10od016281-01)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R24DK085610, DK085610)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
Keywords
SUCLA2, succinylation, SIRT5, mitochondrial encephalomyopathy, TCA cycle, post-translational modification, zebrafish model, fibroblasts, myotubes
MeSH terms
Acyl Coenzyme A, Animals, Cells, Cultured, Female, Humans, Infant, Lysine, Male, Mitochondria, Mutation, Succinate-CoA Ligases, Zebrafish, Survival Analysis, Mice, Knockout, Mitochondrial Diseases, Sirtuins, Proteomics, Mice

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