Skip to main content

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

Publication ,  Journal Article
Gut, P; Matilainen, S; Meyer, JG; Pällijeff, P; Richard, J; Carroll, CJ; Euro, L; Jackson, CB; Isohanni, P; Minassian, BA; Alkhater, RA; He, W ...
Published in: Nat Commun
November 23, 2020

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

November 23, 2020

Volume

11

Issue

1

Start / End Page

5927

Location

England

Related Subject Headings

  • Zebrafish
  • Survival Analysis
  • Succinate-CoA Ligases
  • Sirtuins
  • Proteomics
  • Mutation
  • Mitochondrial Diseases
  • Mitochondria
  • Mice, Knockout
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Gut, P., Matilainen, S., Meyer, J. G., Pällijeff, P., Richard, J., Carroll, C. J., … Verdin, E. (2020). SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease. Nat Commun, 11(1), 5927. https://doi.org/10.1038/s41467-020-19743-4
Gut, Philipp, Sanna Matilainen, Jesse G. Meyer, Pieti Pällijeff, Joy Richard, Christopher J. Carroll, Liliya Euro, et al. “SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease.Nat Commun 11, no. 1 (November 23, 2020): 5927. https://doi.org/10.1038/s41467-020-19743-4.
Gut P, Matilainen S, Meyer JG, Pällijeff P, Richard J, Carroll CJ, et al. SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease. Nat Commun. 2020 Nov 23;11(1):5927.
Gut, Philipp, et al. “SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease.Nat Commun, vol. 11, no. 1, Nov. 2020, p. 5927. Pubmed, doi: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. SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease. Nat Commun. 2020 Nov 23;11(1):5927.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

November 23, 2020

Volume

11

Issue

1

Start / End Page

5927

Location

England

Related Subject Headings

  • Zebrafish
  • Survival Analysis
  • Succinate-CoA Ligases
  • Sirtuins
  • Proteomics
  • Mutation
  • Mitochondrial Diseases
  • Mitochondria
  • Mice, Knockout
  • Mice