Summary Mitochondrial inheritance, genome maintenance, and metabolic adaptation depend on organelle fission by Dynamin-Related Protein 1 (DRP1) and its mitochondrial receptors. DRP1 receptors include the paralogs Mitochondrial Dynamics 49 and 51 (MID49/MID51) and Mitochondrial Fission Factor (MFF), but the mechanisms by which these proteins recruit and regulate DRP1 are unknown. Here we present a cryoEM structure of human, full-length DRP1 coassembled with MID49 and an analysis of structure- and disease-based mutations. We report that GTP induces a remarkable elongation and rotation of the G-domain, Bundle-Signaling Element (BSE) and connecting hinge loops of DRP1. In this conformation, a network of multivalent interactions promotes polymerization of a linear DRP1 filament with MID49/MID51. Following coassembly, GTP hydrolysis and exchange lead to MID receptor dissociation, filament shortening and curling of DRP1 oligomers into constricted and closed rings. Together, these views of full-length, receptor- and nucleotide-bound conformations reveal how DRP1 performs mechanical work through nucleotide-driven allostery.

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Glucose stimulates insulin secretion from β-cells by increasing intracellular Ca 2+ . Ca 2+ then binds to synaptotagmin-7 as a major Ca 2+ sensor for exocytosis, triggering secretory granule fusion and insulin secretion. In type-2 diabetes, insulin secretion is impaired; this impairment is ameliorated by glucagon-like peptide-1 (GLP-1) or by GLP-1 receptor agonists, which improve glucose homeostasis. However, the mechanism by which GLP-1 receptor agonists boost insulin secretion remains unclear. Here, we report that GLP-1 stimulates protein kinase A (PKA)-dependent phosphorylation of synaptotagmin-7 at serine-103, which enhances glucose-and Ca 2+-stimulated insulin secretion and accounts for the improvement of glucose homeostasis by GLP-1. A phospho-mimetic synaptotagmin-7 mutant enhances Ca 2+ -triggered exocytosis, whereas a phospho-inactive synaptotagmin-7 mutant disrupts GLP-1 potentiation of insulin secretion. Our findings thus suggest that synaptotagmin-7 is directly activated by GLP-1 signaling and may serve as a drug target for boosting insulin secretion. Moreover, our data reveal, to our knowledge, the first physiological modulation of Ca

Diabetic retinopathy is a progressive disease elicited by chronic exposure to high blood glucose, e.g., hyperglycemia and is generally recognized as a vascular disease like other diabetesrelated diseases. Although the pathogenesis of diabetic retinopathy has not been clearly elucidated, numerous drugs have been developed based on the current understanding of the complicated and intricate biochemical and pathophysiological aspects of the disease. Current therapy for diabetic retinopathy includes laser photocoagulation, surgery, and metabolic control. Future therapies for diabetic retinopathy are based on the pathophysiology of the disease, such as anti-VEGF, anti-angiogenesis, and anti-inflammatory and anti-extracellular matrix pathways. Several clinical trials are ongoing for diabetic macular edema using drug delivery routes including intravitreal injections, subtenon injections and intravenous injection, topical drops, and intravitreal implants. Drug Dev Res 69:1-14, 2008.

Sustained i.v.t. delivery was achieved in a dose-dependent fashion after the i.v.t. injection of a proprietary sirolimus depot-forming ocular formulation. Across the tolerability and safety studies, no significant findings were observed for systemic and ocular tolerability. The human WB levels were well below the daily trough systemic blood level range required for systemic immunosuppression. An i.v.t. injection of sirolimus has a PK and safety profile that is favorable for treating inflammatory conditions of the eye, such as non-infectious uveitis, and warrants further investigation in humans.

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