SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease
Philipp Gut, Sanna Matilainen, Jesse G. Meyer, Pieti W. Pallijeff, J. Wall Richard, Christopher J. Carroll, Liliya Euro, Christopher B. Jackson, Pirjo Isohanni, Berge A. Minassian, Reem A. Alkhater, Elsebet Østergaard, Gabriele Civiletto, Alice Parisi, Jonathan Thévenet, 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
Abstract
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.