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

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 () and Eric Verdin ()
Additional contact information
Philipp Gut: Gladstone Institutes and University of California
Sanna Matilainen: University of Helsinki
Jesse G. Meyer: Buck Institute for Research on Aging
Pieti Pällijeff: University of Helsinki
Joy Richard: EPFL Innovation Park
Christopher J. Carroll: St. George’s, University of London
Liliya Euro: University of Helsinki
Christopher B. Jackson: University of Helsinki
Pirjo Isohanni: University of Helsinki
Berge A. Minassian: Institute of Medical Science University of Toronto
Reem A. Alkhater: Johns Hopkins Aramco Healthcare
Elsebet Østergaard: Copenhagen University Hospital Rigshospitalet
Gabriele Civiletto: EPFL Innovation Park
Alice Parisi: EPFL Innovation Park
Jonathan Thevenet: EPFL Innovation Park
Matthew J. Rardin: Buck Institute for Research on Aging
Wenjuan He: Gladstone Institutes and University of California
Yuya Nishida: Gladstone Institutes and University of California
John C. Newman: Gladstone Institutes and University of California
Xiaojing Liu: Duke University School of Medicine
Stefan Christen: EPFL Innovation Park
Sofia Moco: EPFL Innovation Park
Jason W. Locasale: Duke University School of Medicine
Birgit Schilling: Buck Institute for Research on Aging
Anu Suomalainen: University of Helsinki
Eric Verdin: Gladstone Institutes and University of California

Nature Communications, 2020, vol. 11, issue 1, 1-14

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.

Date: 2020
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DOI: 10.1038/s41467-020-19743-4

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