Forskning
Udskriv Udskriv
Switch language
Rigshospitalet - en del af Københavns Universitetshospital
Udgivet

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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

  1. Comprehensive genome-wide association study of different forms of hernia identifies more than 80 associated loci

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Influence of NAFLD and bariatric surgery on hepatic and adipose tissue mitochondrial biogenesis and respiration

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Renal Phenotype in Mitochondrial Diseases: A Multicenter Study

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  5. A novel homoplasmic mt-tRNAGlu m.14701C>T variant presenting with a partially reversible infantile respiratory chain deficiency

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • 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
Vis graf over relationer

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.

OriginalsprogEngelsk
Artikelnummer5927
TidsskriftNature Communications
Vol/bind11
Udgave nummer1
Sider (fra-til)5927
ISSN2041-1723
DOI
StatusUdgivet - 23 nov. 2020

ID: 61711029