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.
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
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