Reduction of Early Reperfusion Injury With the Mitochondria-Targeting Peptide Bendavia

Abstract

We recently showed that Bendavia, a novel mitochondria-targeting peptide, reduced infarction and no-reflow across several experimental models. The purpose of this study was to determine the therapeutic timing and mechanism of action that underlie Bendavia’s cytoprotective property. In rabbits exposed to in vivo ischemia/reperfusion (30/180 min), Bendavia administered 20 min prior to reperfusion (0.05mg/kg/hr, i.v.) reduced myocardial infarct size by ~50% when administered for either 1 or 3 hours of reperfusion. However, when Bendavia perfusion began just 10 min after the onset of reperfusion, the protection against infarction and no–reflow was completely lost, indicating that the mechanism of protection is occurring early in reperfusion. Experiments in isolated mouse liver mitochondria found no discernible effect of Bendavia on blocking the permeability transition pore, and studies in isolated heart mitochondria showed no effect of Bendavia on respiratory rates. As Bendavia significantly lowered reactive oxygen species (ROS) levels in isolated heart mitochondria, the ROS-scavenging capacity of Bendavia was compared to well-known ROS scavengers using in vitro (cell-free) systems that enzymatically generate ROS. Across doses ranging from 1nM to 1mM, Bendavia showed no discernible ROS-scavenging properties, clearly differentiating itself from prototypical scavengers. In conclusion, Bendavia is a promising candidate to reduce cardiac injury when present at onset of reperfusion, but not after reperfusion has already commenced. Given that both infarction and no-reflow are related to increased cellular ROS, Bendavia’s protective mechanism of action likely involves reduced ROS generation (as opposed to augmented scavenging) by endothelial and myocyte mitochondria.

Defective postreperfusion metabolic recovery directly associates with incident delayed graft function

“…24 Given its specificity and the abundance of preclinical data, we chose to include this peptide for the proof-of-principle studies. 38 SS-31 has proven effective in cultured renal tubular cells in which it preserved mitochondrial structure and accelerated ATP recovery upon reperfusion. 22 We extended these findings to human kidney tissue and found that incubation with SS-31 partially preserved respiratory chain complex I integrity upon simulated I/R.…”

Chronic Therapy With Elamipretide (MTP-131), a Novel Mitochondria-Targeting Peptide, Improves Left Ventricular and Mitochondrial Function in Dogs With Advanced Heart Failure

“…Cardiolipin plays a central role in cristae formation, MITO fusion, mtDNA stability and segregation and in the function and organization of the respiratory complexes into supercomplexes for oxidative phosphorylation (10–14). Elamipretide has been shown to enhance ATP synthesis in multiple organs including heart, kidney, neurons and skeletal muscle (15–19). This study, examined the effects of long-term therapy with elamipretide on LV and MITO function in dogs with HF.…”

Keep the fire burning: Current avenues in the quest of treating mitochondrial disorders

“…SS-31 interacts with cardiolipin via electrostatic and hydrophobic interactions, preventing cardiolipin induced conversion from cytochrome c into a peroxidase while protecting the electron transporting function (Szeto, 2014). So far, SS-31 has not been studied in models of primary mitochondrial disorders but beneficial effects were shown under conditions of mtDNA mutation (Dai et al, 2010) and myocardial damage (Brown et al, 2014;Dai et al, 2014;Kloner et al, 2012).…”