title: Succination of thiol groups in adipose tissue proteins in diabetes: succination inhibits polymerization and secretion of adiponectin.
abstract: S-(2-Succinyl)cysteine (2SC) is formed by reaction of the Krebs cycle intermediate fumarate with cysteine residues in protein, a process termed succination of protein. Both fumarate and succination of proteins are increased in adipocytes cultured in high glucose medium (Nagai, R., Brock, J. W., Blatnik, M., Baatz, J. E., Bethard, J., Walla, M. D., Thorpe, S. R., Baynes, J. W., and Frizzell, N. (2007) J. Biol. Chem. 282, 34219-34228). We show here that succination of protein is also increased in epididymal, mesenteric, and subcutaneous adipose tissue of diabetic (db/db) mice and that adiponectin is a major target for succination in both adipocytes and adipose tissue. Cys-39, which is involved in cross-linking of adiponectin monomers to form trimers, was identified as a key site of succination of adiponectin in adipocytes. 2SC was detected on two of seven monomeric forms of adiponectin immunoprecipitated from adipocytes and epididymal adipose tissue. Based on densitometry, 2SC-adiponectin accounted for approximately 7 and 8% of total intracellular adiponectin in cells and tissue, respectively. 2SC was found only in the intracellular, monomeric forms of adiponectin and was not detectable in polymeric forms of adiponectin in cell culture medium or plasma. We conclude that succination of adiponectin blocks its incorporation into trimeric and higher molecular weight, secreted forms of adiponectin. We propose that succination of proteins is a biomarker of mitochondrial stress and accumulation of Krebs cycle intermediates in adipose tissue in diabetes and that succination of adiponectin may contribute to the decrease in plasma adiponectin in diabetes.
authors: Department of Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina 29208, USA.
authors: Norma
authors: N
authors: Frizzell
authors: Mathur
authors: M
authors: Rajesh
authors: Matthew J
authors: MJ
authors: Jepson
authors: Ryoji
authors: R
authors: Nagai
authors: James A
authors: JA
authors: Carson
authors: Suzanne R
authors: SR
authors: Thorpe
authors: John W
authors: JW
authors: Baynes
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D052242:Adiponectin / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002952:Citric Acid Cycle; D003545:Cysteine / Q000031:analogs & derivatives / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D015415:Biomarkers; C511650:S-(2-succinyl)cysteine; D003545:Cysteine