Abstract 14250: ND-13, a Small DJ-1 Derived Peptide, Confers Cardioprotection by Targeting Mitochondrial Homeostasis

Abstract

Objectives: DJ-1 protein is a multifunctional protein with cardioprotective effects against acute myocardial ischemia-reperfusion injury (IRI). This study aims to elucidate whether ND-13, a small peptide derived from DJ-1, can confer acute cardioprotection after IRI by preserving mitochondrial homeostasis through improvements in mitochondrial respiratory capacity and regulating the balance between mitochondrial fusion/fission. By enhancing mitochondrial respiration and maintaining the integrity of the mitochondrial network, ND-13 may provide a novel therapeutic strategy for cardioprotection in cardiomyocytes following IRI. Methods: In vitro , ex vivo and in vivo murine models of IRI were used to elucidate the cardioprotective effects of ND-13. Infarct size, cardiac function and mitochondrial function were assessed. Results: ND-13 was shown to confer cardioprotection in three distinct models of IRI: (i) in vitro , cardiomyocyte (CM) death was reduced by 42% (64±1% untreated vs 37±2% treated; p≤0.01); (ii) ex vivo Langendorrf, with 43% decrease in infarct size (51±6.4% untreated vs 29±8.8% treated; p≤0.05); (iii) in vivo , with 35% reduction in infarct size (49±6.4% untreated vs 32±5.0% treated; p≤0.0001). CMs treated with ND-13 in the in vitro model of IRI demonstrated a significant increase in mitochondrial respiration rates, (basal: untreated 37±3 vs treated 63±10 pmol/min/cells, p≤0.05; maximal: untreated 286±20 vs treated 494±53 pmol/min/cells, p≤0.001; and spare respiratory capacity: untreated 251±18 vs treated 421±43 pmol/min/cells, p≤0.001) and a significant increase in levels of cytosolic ATP (untreated 4.0 ± 0.3 vs treated 5.6 ± 0.5 μM, p≤0.05). Conclusion: We demonstrate for the first time, cardioprotection with the DJ-1-derived peptide, ND-13, and this beneficial effect appears to be mediated by its mitoprotective actions with enhanced mitochondrial respiratory efficiency and increased ATP production. Upcoming research aims to explore if ND-13 promotes oxidative phosphorylation by directly binding to complexes of the electron transport chain to maximize respiratory function or by enhancing pyruvate dehydrogenase activity, thereby potentially influencing the regulation of the fission/fusion process.