Succination of proteins in diabetes

Abstract

Cysteine is arguably the most reactive amino acid in protein. A wide range of cysteine derivatives is formed in vivo, resulting from oxidation, nitrosation, alkylation and acylation reactions. This review describes succination of proteins, an irreversible chemical modification of cysteine by the Krebs cycle intermediate, fumarate, yielding S-(2-succinyl)cysteine (2SC). Intracellular fumarate concentration and succination of proteins are increased by hyperpolarization of the inner mitochondrial membrane and develop in concert with mitochondrial and oxidative stress in diabetes. Increased succination of glyceraldehyde-3-phosphate dehydrogenase explains the loss in specific activity of this enzyme in muscle of streptozotocin-diabetic rats and increased succination of adiponectin may explain the decreased secretion of adiponectin from adipose tissue in type 2 diabetes. In addition to GAPDH and adiponectin, other succinated proteins identified in adipocytes include cytoskeletal proteins (tubulin, actin) and chaperone proteins in the endoplasmic reticulum. Succination of adipocyte protein in vitro is inhibited by uncouplers of oxidative phosphorylation and by inhibitors of ER stress. 2SC serves as a biomarker of mitochondrial stress and recent studies suggest that succination is the mechanistic link between mitochondrial and ER stress in diabetes.

Oncometabolites: linking altered metabolism with cancer

“…Succination is a distinct process from succinylation, which typically occurs on lysine residues and is considered to be mediated by succinyl coenzyme A, producing a thioester derivative protein product (79). Recently, increases in protein succinylation have also been shown to occur under conditions where succinate levels are elevated and the activity of the desuccinylase SIRT5 is suppressed.…”

Adiponectin suppresses endoplasmic reticulum stress in nonalcoholic steatohepatitis

“…Our findings also indicate that adiponectin suppresses ER stress through the XBP-1, ATF-4 and ACC pathway in the liver of the nSREBP1c/adiponectin transgenic mice. Adiponectin is known to suppress ER stress in obesity and diabetes (16,17). Recent studies have linked ER stress to obesity, insulin action and type 2 diabetes (18,19), and the activation of the UPR is governed by three ER transmembrane proteins: inositol-requiring kinase-1 (IRE1), protein kinase-like ER kinase (PERK) and activating transcription factor-6 (ATF6).…”

The Enlarging List of Phenotypic Characteristics That Might Allow the Clinical Identification of Families at Risk for Type 1 Diabetes

“…The positive association between mitochondrial membrane potential oscillations and fasting plasma glucose within the range from normal to dysglycemic conditions suggested that hyperglycaemic challenge implied increased glucose metabolisation, enhanced oxidant formation and hyperpolarisation of the mitochondrial membrane. It is noteworthy that succination of proteins, which is an irreversible chemical modification of cysteine by the Krebs cycle intermediate fumarate, is increased by hyperpolarisation of the inner mitochondrial membrane and develops in concert with mitochondrial and oxidative stress in diabetes (Frizzell et al, 2011).…”