Tissue Distribution of S‐(2‐Succino)cysteine (2SC), a Biomarker of Mitochondrial Stress in Obesity and Diabetes

Abstract

S-(2-succino)cysteine (2SC) is a chemical modification of proteins produced by reaction of fumarate with thiol groups in protein, a process known as succination. We propose to use the name S-(2-succino)cysteine (instead of S-(2-succinyl)cysteine) from this point on. This is to distinguish protein succination (in which fumarate forms a thioether linkage with cysteine residues) from succinylation (in which an ester, thioester or amide bond would be formed). Succination of proteins is increased in muscle of type 1 diabetic rats and in adipose tissue in type 2 diabetic mice. The increase in 2SC is a direct result of tissue accumulation of fumarate in response to nutrient excess and resultant mitochondrial stress in diabetes. In this study, we examine the breadth of succination of tissue proteins in the db/db type 2 model of diabetes. We also determined the extent of succination in epididymal adipocytes of type 1 (Akita, streptozotocin (STZ)) and type 2 (ob/ob, db/db) diabetic mice, in diet-induced obese (DIO) mice, and in the adipose tissue of ground squirrels in various stages of hibernation. While succination was not increased in most tissues (brain, heart, kidney, liver, skeletal muscle) in the db/db model of diabetes, it was increased in all adipose beds of type 2 diabetic and DIO mice in comparison to their controls. Succination was not increased in adipocytes of type 1 diabetic mice. Adipose tissue from hibernating (HIB) 13-lined ground squirrels was also studied to determine if obesity in the absence of hyperglycemia affected succination of proteins. There were no differences in succination of proteins in brown or white adipose tissue over the torpor-arousal cycle. We conclude that 2SC is a biomarker of nutrient excess and mitochondrial stress in adipose tissue, increasing under the hyperglycemic and insulin resistant conditions associated with type 2 diabetes and obesity.