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- Title
SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease.
- Authors
Gut, Philipp; Matilainen, Sanna; Meyer, Jesse G.; Pällijeff, Pieti; Richard, Joy; Carroll, Christopher J.; Euro, Liliya; Jackson, Christopher B.; Isohanni, Pirjo; Minassian, Berge A.; Alkhater, Reem A.; Østergaard, Elsebet; Civiletto, Gabriele; Parisi, Alice; Thevenet, Jonathan; Rardin, Matthew J.; He, Wenjuan; Nishida, Yuya; Newman, John C.; Liu, Xiaojing
- 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. The pathomechanism of succinyl-CoA ligase (SCL) deficiency, a hereditary mitochondrial disease, is not fully understood. Here, the authors show that increased succinyl-CoA levels contribute to SCL pathology by causing global protein hyper-succinylation.
- Subjects
RECESSIVE genes; KREBS cycle; GENETIC disorders; MITOCHONDRIAL DNA abnormalities; POST-translational modification; PROTEINS; MASS spectrometry
- Publication
Nature Communications, 2020, Vol 11, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-19743-4