title: Metabolomics-assisted proteomics identifies succinylation and SIRT5 as important regulators of cardiac function.
abstract: Cellular metabolites, such as acyl-CoA, can modify proteins, leading to protein posttranslational modifications (PTMs). One such PTM is lysine succinylation, which is regulated by sirtuin 5 (SIRT5). Although numerous proteins are modified by lysine succinylation, the physiological significance of lysine succinylation and SIRT5 remains elusive. Here, by profiling acyl-CoA molecules in various mouse tissues, we have discovered that different tissues have different acyl-CoA profiles and that succinyl-CoA is the most abundant acyl-CoA molecule in the heart. This interesting observation has prompted us to examine protein lysine succinylation in different mouse tissues in the presence and absence of SIRT5. Protein lysine succinylation predominantly accumulates in the heart whenSirt5is deleted. Using proteomic studies, we have identified many cardiac proteins regulated by SIRT5. Our data suggest that ECHA, a protein involved in fatty acid oxidation, is a major enzyme that is regulated by SIRT5 and affects heart function.Sirt5knockout (KO) mice have lower ECHA activity, increased long-chain acyl-CoAs, and decreased ATP in the heart under fasting conditions.Sirt5KO mice develop hypertrophic cardiomyopathy, as evident from the increased heart weight relative to body weight, as well as reduced shortening and ejection fractions. These findings establish that regulating heart metabolism and function is a major physiological function of lysine succinylation and SIRT5.
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853;
authors.forename: Sushabhan
authors.initials: S
authors.lastname: Sadhukhan
authors.affiliation: Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710; Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710;
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland;
authors.forename: Dongryeol
authors.initials: D
authors.lastname: Ryu
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853;
authors.forename: Ornella D
authors.initials: OD
authors.lastname: Nelson
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853;
authors.forename: John A
authors.initials: JA
authors.lastname: Stupinski
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853;
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Proteomics & Mass Spectrometry Facility, Institute of Biotechnology, Cornell University, Ithaca, NY 14853;
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Proteomics & Mass Spectrometry Facility, Institute of Biotechnology, Cornell University, Ithaca, NY 14853;
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853;
authors.forename: Robert S
authors.initials: RS
authors.lastname: Weiss
authors.affiliation: Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710; Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710;
authors.forename: Jason W
authors.identifier: http://orcid.org/0000-0002-7766-3502
authors.initials: JW
authors.lastname: Locasale
authors.affiliation: Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; admin.auwerx@epfl.ch hl379@cornell.edu.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853; Howard Hughes Medical Institute, Cornell University, Ithaca, NY 14853 admin.auwerx@epfl.ch hl379@cornell.edu.
authors.forename: Hening
authors.initials: H
authors.lastname: Lin
mesh_terms: D000214:Acyl Coenzyme A / Q000235:genetics / Q000378:metabolism*; D000215:Acylation; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D055432:Metabolomics / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D011499:Protein Processing, Post-Translational; D040901:Proteomics / Q000379:methods; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000214:Acyl Coenzyme A; D005227:Fatty Acids; C542554:SIRT5 protein, mouse; D037761:Sirtuins
keywords: desuccinylation; fatty acid metabolism; hypertrophic cardiomyopathy; lysine succinylation; sirtuin