Evaluation the Effect of Mitochondrial transplantation in combination with mitochondrial boosters, MitoQ and melatonin, as a surviving strategy to counteract myocardial reperfusion injury of aged rats

Abstract

Myocardial ischemia-reperfusion (IR) injury poses a severe threat to cardiac health, particularly in the aging population, where susceptibility to such damage is significantly heightened due to age-related decline in mitochondrial function, thus highlighting mitochondria as crucial targets for innovative therapies. This study aims to investigate the combined modality therapy involving mitochondrial transplantation and mitochondrial boosters mitoquinone (MitoQ) and melatonin to address myocardial IR injury in aged rats. Methods: Male Wistar rats (n=108, aged 22-24 months) were randomly assigned to groups with or without IR injury and/or treatments, either alone or in dual and triple combinations. A model of myocardial IR injury was simulated in vivo by occluding and subsequently re-opening the coronary artery. MitoQ (10mg/kg/day for 14 days) was administered intraperitoneally before ischemia, melatonin (10mg/kg) was administered intraperitoneally at reperfusion onset, and mitochondria)(2±0.3(×105 mitochondria in 150μl respiration buffer) were injected intramyocardially also at reperfusion onset. Lastly, changes in hemodynamic indices, levels of creatine kinase(CK)-MB, mitochondrial functional endpoints, and the expression of mitochondrial biogenesis genes (such as sirtuin 1 (SIRT-1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and nuclear respiratory factor 2 (NRF-2)) were assessed. Results: The triple therapy improved myocardial function, reduced CK-MB levels, the ratio of the infarcted area to the area at risk, and enhanced mitochondrial function and the expression of mitochondrial biogenesis genes in aged IR rats. This triple combination approach elicited significant cardioprotection compared to groups receiving single or dual therapies.