Protein Succination: a Mechanistic Mediator of Adipocyte Dysfunction in Diabetes



 DESCRIPTION (provided by applicant): 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.