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J. Biol. Chem., Vol. 282, Issue 47, 34219-34228, November 23, 2007

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Succination of Protein Thiols during Adipocyte Maturation

A BIOMARKER OF MITOCHONDRIAL STRESS^*

Ryoji Nagai¹, Jonathan W. Brock, Matthew Blatnik, John E. Baatz, Jennifer Bethard, Michael D. Walla, Suzanne R. Thorpe, John W. Baynes², and Norma Frizzell¹

From the Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208 and Children's Research Hospital and Department of Pharmacology, Medical University of South Carolina, Charleston, South Carolina 29243

Although obesity is a risk factor for development of type 2 diabetes and chemical modification of proteins by advanced glycoxidation and lipoxidation end products is implicated in the development of diabetic complications, little is known about the chemical modification of proteins in adipocytes or adipose tissue. In this study we show that S-(2-succinyl)cysteine (2SC), the product of chemical modification of proteins by the Krebs cycle intermediate, fumarate, is significantly increased during maturation of 3T3-L1 fibroblasts to adipocytes. Fumarate concentration increased 5-fold during adipogenesis in medium containing 30 mM glucose, producing a 10-fold increase in 2SC-proteins in adipocytes compared with undifferentiated fibroblasts grown in the same high glucose medium. The elevated glucose concentration in the medium during adipocyte maturation correlated with the increase in 2SC, whereas the concentration of the advanced glycoxidation and lipoxidation end products, N-(carboxymethyl)lysine and N-(carboxyethyl)lysine, was unchanged under these conditions. Adipocyte proteins were separated by one- and two-dimensional electrophoresis and 60 2SC-proteins were detected using an anti-2SC polyclonal antibody. Several of the prominent and well resolved proteins were identified by matrix-assisted laser desorption ionization time-of-flight/time-of-flight mass spectrometry. These include cytoskeletal proteins, enzymes, heat shock and chaperone proteins, regulatory proteins, and a fatty acid-binding protein. We propose that the increase in fumarate and 2SC is the result of mitochondrial stress in the adipocyte during adipogenesis and that 2SC may be a useful biomarker of mitochondrial stress in obesity, insulin resistance, and diabetes.

Received for publication, April 27, 2007 , and in revised form, July 26, 2007.

^* This work was supported by NIDDK, National Institutes of Health Research Grant DK-19971. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Chemistry and Biochemistry, 631 Sumter St. (GSRC), University of South Carolina, Columbia, SC 29208. Tel.:/Fax: 803-777-7272; E-mail: john.baynes{at}sc.edu.

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