The Role of Insulin-Like Growth Factor Binding Protein 3 in Mitochondrial Homeostasis




Stuard, Whitney Leigh

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The insulin-like growth factor (IGF) family includes three extracellular ligands and their cognate receptors, along with six IGF-binding proteins (IGFBPs 1-6). Of these, Insulin-like growth factor binding protein-3 (IGFBP-3) is expressed in corneal epithelial cells (CECs) and is present in human tear fluid. IGFBP-3 is a highly glycosylated secretory protein with known roles in growth and survival. In circulation, IGFBP-3 binds IGF-1 to inhibit activation of the IGF-1 receptor, thereby extending the half-life of IGF-1. IGFBP-3 also plays key roles in apoptosis, DNA repair, cell cycle control, the induction of autophagy, angiogenesis, hypoxia, and insulin resistance. However, the exact function of IGFBP-3 is cell and context-dependent. Prior studies in our lab have demonstrated that expression of IGFBP-3 is increased in response to hyperglycemia and hypoxia, suggesting a potential role for IGFBP-3 in the corneal epithelial stress response. Using a combination of contemporary cellular, molecular, and biochemical approaches, we now provide new data showing that IGFBP-3 stabilizes mitochondria in CECs through alterations in mitochondrial morphology and mitophagy. This occurs through activation of the mechanistic target of the rapamycin (mTOR) signaling pathway. Taken together, these data highlight a new role for IGFBP-3 in the regulation of mitochondrial and metabolic homeostasis in the corneal epithelium. We next explored the pathophysiological role of IGFBP-3 in mitochondrial respiration, homeostasis, and mitophagy in CECs subject to hyperosmolar stress, as seen in Dry Eye Disease. Unlike hyperglycemia, hyperosmolar stress due to an increase in levels of salt downregulates IGFBP-3 in vitro. The loss of IGFBP-3 in response to hyperosmolar stress is associated with a shift towards a more respiratory phenotype and an increase in mitochondrial fission. In contrast, co-treatment with recombinant human IGFBP-3 induced robust mitochondrial fusion and maintained metabolic activity. The decrease in intracellular IGFBP-3 in response to hyperosmolarity was further confirmed in the mouse corneal epithelium in vivo using an aqueous-deficient dry eye model. These data confirm a novel role for IGFBP-3 in metabolic and mitochondrial homeostasis.

General Notes

Pages 15-102 are misnumbered as pages 14-101, pages 103-155 are misnumbered as pages 100-152, and pages 156-192 are misnumbered as pages 151-187.

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