Diabetes results from insufficient functional ?-cell mass to meet peripheral insulin demands. ?-cells rely upon mitochondrial respiration to generate the energy necessary for insulin biosynthesis, processing, and secretion. Indeed, defects in mitochondrial structure and function have been reported in the ?-cells of patients with type 2 diabetes. Defects in mitochondrial structure and function are characteristic of impairments in mitophagy, a selective form of mitophagy necessary for elimination of dysfunctional mitochondria; however, the role of mitophagy in diabetes pathogenesis is not well understood. We previously discovered a key role for the diabetes susceptibility gene Clec16a in control of glucose homeostasis in humans and mice through its regulation of ?-cell mitophagy. Therefore, our goal is to dissect the mechanistic and physiologic regulation of Clec16a-mediated mitophagy in ?-cells to elucidate its contribution to diabetes pathogenesis. The central hypothesis to be tested is that disruption of Clec16a regulation of its key effectors, the E3 ubiquitin ligase Nrdp1 and the Nrdp1 target Parkin, contribute to ?-cell dysfunction and glucose intolerance. We will test this hypothesis by the following approach:
Specific Aim 1 will directly assess the ?-cell specific implications of Clec16a disease polymorphisms that alter Clec16a structure and its regulation of Nrdp1 stability.
Specific Aim 2 will determine if the type 2 diabets gene Parkin, which recognizes unhealthy mitochondria during mitophagy, serves as the primary downstream effector of Clec16a in ?-cell mitophagy.
Specific Aim 3 will delineate the role of central mediators of mitophagy during ?-cell compensation for diet-induced obesity and in human islets from type 2 diabetic donors. We anticipate obtaining a clear understanding of the importance and translational relevance of mitophagy in ?-cell function from an evaluation of the central effectors crucial to the disposal of unhealthy mitochondria. These results should advance the field of ?-cell biology by defining mitophagy as a fundamental aspect of diabetes pathogenesis and could open new horizons for therapies for patients with diabetes.
Diabetes is a chronic disease that results from inadequate function of insulin-producing ?-cells within the pancreas. The goal of our study is to understand how maintaining the health of ?-cell mitochondria, the power plants of the cell, is important for the prevention of diabetes. Our studies will determine the relevance of clearance of sick and damaged mitochondria to ensure that healthy mitochondria can meet the energy demands needed to ensure ?-cells can control blood sugar.
|Pearson, Gemma; Chai, Biaoxin; Vozheiko, Tracy et al. (2018) Clec16a, Nrdp1, and USP8 Form a Ubiquitin-Dependent Tripartite Complex That Regulates ?-Cell Mitophagy. Diabetes 67:265-277|
|Sas, Kelli M; Kayampilly, Pradeep; Byun, Jaeman et al. (2016) Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications. JCI Insight 1:e86976|
|Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222|