Intravenous Transplantation of an Ischemic-specific Peptide-TPP-mitochondrial Compound Alleviates Myocardial Ischemic Reperfusion Injury

[Image: see text] It is known that mitochondrial dysfunction is a critical factor involved in myocardial ischemia–reperfusion injury. Mitochondrial transplantation has been suggested as an effective therapeutic strategy to protect against myocardial ischemia–reperfusion injury. However, its clinical translation remains limited because it requires the local injection of mitochondria into the myocardium. Here, a polypeptide, CSTSMLKAC (PEP), bound to triphenylphosphonium cations (TPP+) effectively binds mitochondria to form a PEP–TPP–mitochondrial compound. Further investigation of this compound has revealed that the ischemia-sensing properties of PEP promote its translocation into the ischemic myocardium. Additionally, the targeting peptide, PEP, readily dissociates from the PEP–TPP–mitochondrial compound, allowing for the transplanted mitochondria to be efficiently internalized by cardiomyocytes or transferred to cardiomyocytes by endothelial cells. Mitochondrial transplantation promotes cardiomyocyte energetics and mechanical contraction, subsequently reducing cellular apoptosis, macrophage infiltration, and the pro-inflammatory response, all of which lead to attenuation of ischemia–reperfusion injury. Thus, this study provides promising evidence that the PEP–TPP–mitochondrial compound effectively promotes intravenous mitochondrial transplantation into the ischemic myocardium and subsequently ameliorates myocardial ischemia–reperfusion injury.