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

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Gut , P , Matilainen , S , Meyer , J G , Pallijeff , P , Richard , J , Carroll , C J , Euro , L , Jackson , C B , Isohanni , P , Minassian , B A , Alkhater , R A , Ostergaard , E , Civiletto , G , Parisi , A , Thevenet , J , Rardin , M J , He , W , Nishida , Y , Newman , J C , Liu , X , Christen , S , Moco , S , Locasale , J W , Schilling , B , Suomalainen , A & Verdin , E 2020 , ' SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease ' , Nature Communications , vol. 11 , no. 1 , 5927 . https://doi.org/10.1038/s41467-020-19743-4

Title: SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease
Author: Gut, Philipp; Matilainen, Sanna; Meyer, Jesse G.; Pallijeff, Pieti; Richard, Joy; Carroll, Christopher J.; Euro, Liliya; Jackson, Christopher B.; Isohanni, Pirjo; Minassian, Berge A.; Alkhater, Reem A.; Ostergaard, Elsebet; Civiletto, Gabriele; Parisi, Alice; Thevenet, Jonathan; Rardin, Matthew J.; He, Wenjuan; Nishida, Yuya; Newman, John C.; Liu, Xiaojing; Christen, Stefan; Moco, Sofia; Locasale, Jason W.; Schilling, Birgit; Suomalainen, Anu; Verdin, Eric
Contributor: University of Helsinki, STEMM - Stem Cells and Metabolism Research Program
University of Helsinki, Research Programs Unit
University of Helsinki, Clinicum
University of Helsinki, HUS Children and Adolescents
University of Helsinki, HUS Helsinki and Uusimaa Hospital District
Date: 2020-11-23
Language: eng
Number of pages: 14
Belongs to series: Nature Communications
ISSN: 2041-1723
URI: http://hdl.handle.net/10138/324423
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-beta (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.
Subject: HIGH-RESOLUTION METABOLOMICS
DATA-INDEPENDENT ACQUISITION
QUANTITATIVE PROTEOMICS
ACETYLATION
ENCEPHALOMYOPATHY
DEFICIENCY
ACYLATION
SIRT5
METABOLISM
DESUCCINYLATION
3111 Biomedicine
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