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Mitochondrial Targeting with Antioxidant Peptide SS-31 Prevents Mitochondrial Depolarization, Reduces Islet Cell Apoptosis, Increases Islet Cell Yield, and Improves Posttransplantation Function

Dolca A. Thomas^*,, Craig Stauffer^*, Kesheng Zhao, Hua Yang^*, Vijay K. Sharma^*, Hazel H. Szeto and Manikkam Suthanthiran^*,

Departments of ^* Medicine, Transplantation Medicine, and Pharmacology, Weill Medical College of Cornell University, New York-Presbyterian Hospital-Weill Cornell, New York, New York

Address correspondence to: Dr. Dolca A. Thomas, 525 East 68th Street, Box 3, New York, NY 10021. Phone: 212-746-4430; Fax: 212-746-8091; E-mail: dat2003{at}med.cornell.edu

Received for publication August 3, 2006. Accepted for publication October 14, 2006.

Apoptotic cell death is a defined pathway for islet cell demise, and mitochondrial dysfunction contributes to islet cell apoptosis. The hypothesis that the novel peptide d-Arg-2', 6'-dimethyltyrosine-Lys-Phe-NH₂ (SS-31), previously shown to target inner mitochondrial membrane and prevent oxidative damage of neuronal cells and other cell types, optimizes pancreatic islet isolation and improves posttransplantation function in recipients with diabetes was investigated. Herein is demonstrated that SS-31 readily penetrates intact mouse islets, preserves mitochondrial polarization, reduces islet cell apoptosis, and increases islet cell yield. Optimization of islet isolation is demonstrable after SS-31 pretreatment of islet (pancreas) donor mice and with the addition of SS-31 to reagents that are used in the isolation of mouse islets. The supplementation of in vitro culture medium with SS-31 reduced islet cell apoptosis and increased the viability of human islets, as ascertained by dual-parameter flow cytometry analysis. In a stringent marginal islet cell mass transplantation model (200 mouse islets transplanted under the renal capsule of syngeneic diabetic mice) and using islets that were derived from old mice (>24 wk), SS-31 treatment was associated with prompt and sustained normoglycemia, whereas the untreated islet graft recipients remained diabetic. Our data suggest a novel strategy to optimize islet isolation and reduce the need for multiple pancreata to achieve insulin independence in the recipient with type 1 diabetes. Because SS-31 was effective with "extended" islet donors, it is hypothesized that the antioxidant SS-31 may serve to increase the pool of eligible organ donors.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673