Optimal cardioprotection effects of mitochondria transplantation requires donor/recipient metabolic compliances

Background Mitochondrial dysfunction drives metabolic disturbances in cardiac diseases. Mitochondrial transplantation can replace damaged mitochondria and restore cellular metabolism and cardiac function. Although preclinical studies have validated this concept, practical challenges persist. A critical but underexplored question is whether mitochondria from different tissues are equally effective, or whether their tissue-specific metabolic programming influences therapeutic efficacy in the unique metabolic environment of cardiomyocytes. Methods Mitochondria were isolated from heart, liver, and skeletal muscle of 6–8 week C57BL/6 mice using tissue-specific centrifugation. Protein concentration was quantified via Bradford assay for standardized dosing. Isolated mitochondria were injected intramyocardially into mouse models of acute or chronic cardiac disease. Cardiac function was assessed by echocardiography. Mitochondrial metabolic patterns and capacity were evaluated using proteomics, flow cytometry, immunofluorescence, and O2K respirometry. Results Mitochondria were successfully isolated from heart, liver, and skeletal muscle with high yield and purity. Mitochondrial content per tissue mass was higher in heart and skeletal muscle than in liver. Heart-derived mitochondria exhibited significantly greater glucose and fatty acid oxidation (FAO) capacity, as well as higher FAO-related protein expression, compared to liver- or muscle-derived mitochondria. While intramyocardial injection of mitochondria from all three sources restored cardiac function following ischemia/reperfusion (I/R) injury and heart failure, heart-derived mitochondria were most effective. They demonstrated superior restoration of oxidative respiratory capacity, ATP production, and mitigation of oxidative stress in MIRI, leading to reduced infarct size and greater improvement in cardiac function. Conclusions In conclusion, mitochondria from different tissues exhibit distinct metabolic patterns. The heart relies heavily on fatty acid oxidation (FAO), and heart-derived mitochondria possess the inherent enzymatic machinery to meet this demand. Upon transplantation, they integrate structurally and are metabolically "pre-adapted" to utilize fatty acids efficiently, resulting in sustained ATP production, reduced oxidative stress and cell death, and superior cardiac preservation. In contrast, liver- and muscle-derived mitochondria lack this specific optimization. Therefore, achieving optimal cardioprotection requires "donor/recipient metabolic compliance." For acute injuries like ischemia-reperfusion, autologous mitochondria from healthy cardiac tissue offer the most prominent protection. This highlights the importance of donor source selection and supports further investigation of heart-derived mitochondrial transplantation. Future research should focus on optimizing delivery methods, timing, and ex vivo preconditioning to enhance efficacy.