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

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  • 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
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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 languageEnglish
JournalNature Communications
Volume11
Issue number1
Pages (from-to)5927
ISSN2041-1723
DOIs
Publication statusPublished - 23 Nov 2020

    Research areas

  • 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

ID: 61711029