Considering that ~26 million Americans have diabetes and an estimated 79 million have prediabetes, it is critical that we understand the role of expanding adipose tissue mass in the development of systemic metabolic dysfunction. However, many of the biochemical mechanisms underlying adipose tissue dysfunction remain unclear. Previously, we have detected S-(2-succinol)cysteine (2SC), also termed protein succination, a new chemical post-translational modification of proteins. 2SC is formed by reaction of the Krebs cycle intermediate fumarate with reactive cysteine residues in protein. Both fumarate and succination of proteins appear to be selectively increased in adipocytes in diabetes, impairing protein structure and function. The increase in fumarate develops as a result of excess fuel supply, accumulation of ATP and NADH, inner mitochondrial membrane (IMM) hyperpolarization and consequently feedback inhibition of the Krebs cycle. This proposal hypothesizes that the increase in protein succination is a novel mechanistic link between mitochondrial stress and the accumulation of misfolded proteins, contributing to endoplasmic reticulum (ER) stress in the adipocyte in diabetes. In addition, we propose that the succination of redox-active proteins modulates redox stress in diabetes. This project has 3 specific aims: (1) To examine the impact of fumarate accumulation and selective succination in the adipocyte; (2) To determine if succination mechanistically links mitochondrial and ER stress in the adipocyte; and (3) To examine the reactivity of fumarate with protein selenocysteines as a novel redox modulator. We plan to use a novel knockout mouse with selective fumarate accumulation in the adipose tissue. Upon completion of these studies, we will demonstrate the significant contribution of adipocyte protein succination to metabolic dysfunction in diabetes, with important implications for the development of novel therapeutic avenues for the treatment of mitochondrial diseases.

Public Health Relevance

The expansion of adipose tissue is associated with the development of insulin resistance and Type 2 diabetes. Given that ~26 million Americans have diabetes and an estimated 79 million have prediabetes, the role of expanding adipose tissue mass in the development of systemic metabolic dysfunction has received increased attention. However, many of the biochemical mechanisms underlying adipocyte metabolic dysfunction remain unclear. We will explore the early metabolic changes in the adipocyte and anticipate that these studies will lead to better targeted therapies for the early treatment of diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
High Priority, Short Term Project Award (R56)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Haft, Carol R
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University of South Carolina at Columbia
Schools of Medicine
United States
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Manuel, Allison M; Walla, Michael D; Faccenda, Adam et al. (2017) Succination of Protein Disulfide Isomerase Links Mitochondrial Stress and Endoplasmic Reticulum Stress in the Adipocyte During Diabetes. Antioxid Redox Signal 27:1281-1296
Piroli, Gerardo G; Manuel, Allison M; Clapper, Anna C et al. (2016) Succination is Increased on Select Proteins in the Brainstem of the NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) Knockout Mouse, a Model of Leigh Syndrome. Mol Cell Proteomics 15:445-61
Yang, Hao; Wu, Jiang W; Wang, Shu P et al. (2016) Adipose-Specific Deficiency of Fumarate Hydratase in Mice Protects Against Obesity, Hepatic Steatosis, and Insulin Resistance. Diabetes 65:3396-3409
Jeong, Ha-Won; Choi, Ran Hee; McClellan, Jamie L et al. (2016) Tribbles 3 inhibits brown adipocyte differentiation and function by suppressing insulin signaling. Biochem Biophys Res Commun 470:783-91