PUBLICATION

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

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.
ID
ZDB-PUB-201125-5
Date
2020
Source
Nature communications   11: 5927 (Journal)
Registered Authors
Civiletto, Gabriele, Gut, Philipp, Parisi, Alice, Richard, Joy
Keywords
none
MeSH Terms
  • Acyl Coenzyme A/metabolism*
  • Animals
  • Cells, Cultured
  • Female
  • Humans
  • Infant
  • Lysine/metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Mitochondria/metabolism
  • Mitochondrial Diseases/genetics
  • Mitochondrial Diseases/metabolism
  • Mitochondrial Diseases/pathology*
  • Mutation
  • Proteomics
  • Sirtuins/deficiency
  • Sirtuins/genetics
  • Sirtuins/metabolism
  • Succinate-CoA Ligases/deficiency
  • Succinate-CoA Ligases/genetics*
  • Succinate-CoA Ligases/metabolism
  • Survival Analysis
  • Zebrafish
PubMed
33230181 Full text @ Nat. Commun.
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping