Mediators of mitophagy in the regulation of beta cell function

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ABSTRACT Diabetes results from insufficient functional β-cell mass to meet peripheral insulin demands. β-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 β-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 type 2 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 β-cell mitophagy. Therefore, our goal is to dissect the mechanistic and physiologic regulation of Clec16a-mediated mitophagy in β-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 β-cell failure in type 2 diabetes. We will test this hypothesis by the following approach: Specific Aim 1 will directly assess the mechanistic implications of Clec16a disease polymorphisms that alter its functional domains. Specific Aim 2 will determine if the mitophagy initiator Parkin, which recognizes unhealthy mitochondria during mitophagy, serves as the primary downstream effector of Clec16a in β-cell mitophagy. Specific Aim 3 will delineate the role of Clec16a during β-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 β-cell function from an evaluation of the central effectors crucial to the disposal of unhealthy mitochondria. These results should advance the field of β-cell biology by defining the role of mitophagy in type 2 diabetes pathogenesis and could open new horizons for therapies for patients with diabetes.