title: The succinated proteome.
abstract: The post-translational modifications (PTMs) of cysteine residues include oxidation, S-glutathionylation, S-nitrosylation, and succination, all of which modify protein function or turnover in response to a changing intracellular redox environment. Succination is a chemical modification of cysteine in proteins by the Krebs cycle intermediate, fumarate, yielding S-(2-succino)cysteine (2SC). Intracellular fumarate concentration and succination of proteins are increased by hyperpolarization of the inner mitochondrial membrane, in concert with mitochondrial, endoplasmic reticulum (ER) and oxidative stress in 3T3 adipocytes grown in high glucose medium and in adipose tissue in obesity and diabetes in mice. Increased succination of proteins is also detected in the kidney of a fumarase deficient conditional knock-out mouse which develops renal cysts. A wide range of proteins are subject to succination, including enzymes, adipokines, cytoskeletal proteins, and ER chaperones with functional cysteine residues. There is also some overlap between succinated and glutathionylated proteins, suggesting that the same low pKa thiols are targeted by both. Succination of adipocyte proteins in diabetes increases as a result of nutrient excess derived mitochondrial stress and this is inhibited by uncouplers, which discharge the mitochondrial membrane potential (ΔΨm) and relieve the electron transport chain. 2SC therefore serves as a biomarker of mitochondrial stress or dysfunction in chronic diseases, such as obesity, diabetes, and cancer, and recent studies suggest that succination is a mechanistic link between mitochondrial dysfunction, oxidative and ER stress, and cellular progression toward apoptosis. In this article, we review the history of the succinated proteome and the challenges associated with measuring this non-enzymatic PTM of proteins by proteomics approaches.
authors.affiliation: Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Merkley
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Metz
authors.forename: Richard D
authors.initials: RD
authors.lastname: Smith
authors.forename: John W
authors.initials: JW
authors.lastname: Baynes
authors.forename: Norma
authors.initials: N
authors.lastname: Frizzell
mesh_terms: D000818:Animals; D002952:Citric Acid Cycle; D003545:Cysteine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism; D005650:Fumarates / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism; D018384:Oxidative Stress; D020543:Proteome / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D005650:Fumarates; D020543:Proteome; D003545:Cysteine
keywords: chemical modification of proteins; cysteine; diabetes; fumarate; succination