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

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.

Citation

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. SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease. Nature communications. 2020 Nov 23;11(1):5927

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PMID: 33230181

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