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 - 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 -