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

Abstract

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-NH 2 (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.

The Mitochondrial-Targeted Compound SS-31 Re-Energizes Ischemic Mitochondria by Interacting with Cardiolipin

“…9,[40][41][42][43][44] Although it was known that SS-31 concentrates in the IMM and inhibits MPT, 10 its exact mechanism of action remained unclear. Because SS-31 carries a 3+ net charge, we hypothesized that it binds to the anionic phospholipid CL that is uniquely expressed on the IMM.…”

Reactive Oxygen Species: Stuck in the Middle of Neurodegeneration

“…SS peptides concentrate 1000-fold to mitochondria, reduce ROS in neuronal cells, and protect cells against neuronal cell death by tert-butyl hydroperoxide [103]. Additionally, in both mouse and human islet cells where mitochondrial dysfunction is at the center of cell death, SS peptides prevented mitochondrial depolarization and apoptosis [104]. In vivo, SS peptides are protective in a mouse model of ALS, increasing survival and motor performance, and decreasing cell loss [105].…”

Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities

“…Peptides containing tyrosine residues have been found effectively to scavenge oxygen radicals and peroxynitrite and to inhibit lipid peroxidation (304,349). Such peptides reduce intracellular ROS and cell death in neuronal (256) and pancreatic islet cells (309) and recently were reported to reduce skeletal myocyte H 2 O 2 production and to preserve insulin sensitivity in rats fed a high-fat diet (14). Unfortunately, these peptides also possess potent opioid-receptor affinity and activity (285,347,348).…”