Novel Fusion Protein Targeting Mitochondrial DNA Improves Pancreatic Islet Functional Potency and Islet Transplantation Outcomes

Abstract

Long-term graft survival is an ongoing challenge in the field of islet transplantation. With the growing demand for transplantable organs, therapies to improve organ quality and reduce the incidence of graft dysfunction are of paramount importance. We evaluated the protective role of a recombinant DNA repair protein targeted to mitochondria (Exscien I-III), as a therapeutic agent using a rodent model of pancreatic islet transplantation. We first investigated the effect of therapy on isolated rat islets cultured with pro-inflammatory cytokines (interleukin-1 β, interferon γ, and tumor necrosis factor α) for 48 h and documented a significant reduction in apoptosis by flow cytometry, improved viability by immunofluorescence, and conserved functional potency in vitro and in vivo in Exscien I-III-treated islets. We then tested the effect of therapy in systemic inflammation using a rat model of donor brain death (BD) sustained for a 6-h period. Donor rats were allocated to 4 groups: (non-BD + vehicle, non-BD + Exscien I-III, BD + vehicle, and BD + Exscien I-III) and treated with Exscien I-III (4 mg/kg) or vehicle 30 min after BD induction. Sham (non-BD)-operated animals receiving either Exscien I-III or vehicle served as controls. Islets purified from BD + Exscien I-III-treated donors showed a significant increase in glucose-stimulated insulin release in vitro when compared to islets from vehicle-treated counterparts. In addition, donor treatment with Exscien I-III attenuated the effects of BD and significantly improved the functional potency of transplanted islets in vivo. Our data indicate that mitochondrially targeted antioxidant therapy is a novel strategy to protect pancreas and islet quality from the deleterious effects of cytokines in culture and during the inflammatory response associated with donation after BD. The potential for rapid translation into clinical practice makes Exscien I-III an attractive therapeutic option for the management of brain-dead donors or as an additive to islets in culture after isolation setting.

Acetate and Butyrate Improve β-cell Metabolism and Mitochondrial Respiration under Oxidative Stress

“…Pancreatic β-cells are very sensitive to oxidative stress-induced mitochondrial dysfunction due to a relatively weak enzymatic anti-oxidative defense mechanism along with an inefficient repair system for oxidative DNA damage [25,26]. This is a major cause of islet loss in the process toward both type 1 and type 2 diabetes.…”

Metabolism of gut microbiota and its role in state of diabetes mellitus

“…Важным элементом противодиабетического действия КЦЖК является протективный эффект в отношении β-клеток. Одной из главенствующих причин гибели клеток поджелудочной железы при СД 1-го и 2-го типов является их повышенная чувствительность к воздействию продуктов окислительного стресса вследствие их слабых защитных Эндокринология механизмов [39,40]. В исследовании влияния ацетата и бутирата на жизнеспособность β-клеток поджелудочной железы in vitro было выявлено повышение жизнеспособности клеток на 20% под воздействием 1 ммоль ацетата и на 25% под воздействием 1 ммоль бутирата.…”

Neuroligin-2-derived peptide-covered polyamidoamine-based (PAMAM) dendrimers enhance pancreatic β-cells' proliferation and functions

“…[11][12][13] Several β-cell mass protective approaches have been recently developed. This includes, for example, the use of H 2 S, which protects cells from apoptosis induced by high glucose, 14 targeting mitochondrial DNA, 15 developing compounds that protect cells under ER stressinduced autophagy, 16 and many others. 17,18 Regarding T1DM, which is also a life-threatening disease, causing severe complications and increased mortality, there is similarly a need for ways to protect β-cell mass.…”