2SC [S-(2-succino)-cysteine] is a chemical modification formed by a Michael addition reaction of fumarate with cysteine residues in proteins. Formation of 2SC, termed ‘succination’ of proteins, increases in adipocytes grown in high-glucose medium and in adipose tissues of Type 2 diabetic mice. However, the metabolic mechanisms leading to increased fumarate and succination of protein in the adipocyte are unknown. Treatment of 3T3 cells with high glucose (30 mM compared with 5 mM) caused a significant increase in cellular ATP/ADP, NADH/NAD+ and Δψm (mitochondrial membrane potential). There was also a significant increase in the cellular fumarate concentration and succination of proteins, which may be attributed to the increase in NADH/NAD+ and subsequent inhibition of tricarboxylic acid cycle NAD+-dependent dehydrogenases. Chemical uncouplers, which dissipated Δψm and reduced the NADH/NAD+ ratio, also decreased the fumarate concentration and protein succination. High glucose plus metformin, an inhibitor of complex I in the electron transport chain, caused an increase in fumarate and succination of protein. Thus excess fuel supply (glucotoxicity) appears to create a pseudohypoxic environment (high NADH/NAD+ without hypoxia), which drives the increase in succination of protein. We propose that increased succination of proteins is an early marker of glucotoxicity and mitochondrial stress in adipose tissue in diabetes.
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Research Article|
June 27 2012
Mitochondrial stress causes increased succination of proteins in adipocytes in response to glucotoxicity
Norma Frizzell;
Norma Frizzell
1
*Department of Pharmacology, Physiology and Neuroscience, School of Medicine, University of South Carolina, Columbia, SC 29208, U.S.A.
1To whom correspondence should be addressed (email norma.frizzell@uscmed.sc.edu).
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Sonia A. Thomas;
Sonia A. Thomas
†Department of Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, U.S.A.
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James A. Carson;
James A. Carson
†Department of Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, U.S.A.
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John W. Baynes
John W. Baynes
*Department of Pharmacology, Physiology and Neuroscience, School of Medicine, University of South Carolina, Columbia, SC 29208, U.S.A.
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Publisher: Portland Press Ltd
Received:
December 12 2011
Revision Received:
April 03 2012
Accepted:
April 24 2012
Accepted Manuscript online:
April 24 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 445 (2): 247–254.
Article history
Received:
December 12 2011
Revision Received:
April 03 2012
Accepted:
April 24 2012
Accepted Manuscript online:
April 24 2012
Citation
Norma Frizzell, Sonia A. Thomas, James A. Carson, John W. Baynes; Mitochondrial stress causes increased succination of proteins in adipocytes in response to glucotoxicity. Biochem J 15 July 2012; 445 (2): 247–254. doi: https://doi.org/10.1042/BJ20112142
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