TY - JOUR
T1 - SUCLA2 mutations cause global protein succinylation contributing to the pathomechanism of a hereditary mitochondrial disease
AU - Gut, Philipp
AU - Matilainen, Sanna
AU - Meyer, Jesse G.
AU - Pällijeff, Pieti
AU - Richard, Joy
AU - Carroll, Christopher J.
AU - Euro, Liliya
AU - Jackson, Christopher B.
AU - Isohanni, Pirjo
AU - Minassian, Berge A.
AU - Alkhater, Reem A.
AU - Østergaard, Elsebet
AU - Civiletto, Gabriele
AU - Parisi, Alice
AU - Thevenet, Jonathan
AU - Rardin, Matthew J.
AU - He, Wenjuan
AU - Nishida, Yuya
AU - Newman, John C.
AU - Liu, Xiaojing
AU - Christen, Stefan
AU - Moco, Sofia
AU - Locasale, Jason W.
AU - Schilling, Birgit
AU - Suomalainen, Anu
AU - Verdin, Eric
N1 - Funding Information:
The authors wish to thank Tuula Manninen, Babette Hollman, Anu Harju and Markus Innilä for technical assistance. We thank Thierry Guillaud, José Sanchez, Eduardo Jiminez, and Noélie Rochat for assistance in the zebrafish facility, John C. Carrol for graphic design and Gary Howard for editing the manuscript. The study was supported by grants from the Academy of Finland, Sigrid Jusélius Foundation, University of Helsinki and Helsinki University Hospital (to A.S.). This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R24 DK085610 E.V.). We acknowledge support from the NIH shared instrumentation grant for the TripleTOF system at the Buck Institute (1S10 OD016281, Buck Institute).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-19743-4
DO - 10.1038/s41467-020-19743-4
M3 - Article
C2 - 33230181
AN - SCOPUS:85096443301
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5927
ER -