Background Mitochondrial transplantation has been recently explored for treatment of very ill cardiac patients. However, little is known about the intracellular consequences of mitochondrial transplantation. This study aims to assess the bioenergetics consequences of mitochondrial transplantation into normal cardiomyocytes in the short and long term. Methods and Results We first established the feasibility of autologous, non‐autologous, and interspecies mitochondrial transplantation. Then we quantitated the bioenergetics consequences of non‐autologous mitochondrial transplantation into cardiomyocytes up to 28 days using a Seahorse Extracellular Flux Analyzer. Compared with the control, we observed a statistically significant improvement in basal respiration and ATP production 2‐day post‐transplantation, accompanied by an increase in maximal respiration and spare respiratory capacity, although not statistically significantly. However, these initial improvements were short‐lived and the bioenergetics advantages return to the baseline level in subsequent time points. Conclusions This study, for the first time, shows that transplantation of non‐autologous mitochondria from healthy skeletal muscle cells into normal cardiomyocytes leads to short‐term improvement of bioenergetics indicating “supercharged” state. However, over time these improved effects disappear, which suggests transplantation of mitochondria may have a potential application in settings where there is an acute stress.

Mitochondrial Transplantation is emerging as a novel cellular biotherapy to alleviate mitochondrial damage and dysfunction. Mitochondria play a crucial role in establishing cellular homeostasis and providing cell with the energy necessary to accomplish its function. Owing to its endosymbiotic origin, mitochondria share many features with their bacterial ancestors. Unlike the nuclear DNA, which is packaged into nucleosomes and protected from adverse environmental effects; mitochondrial DNA are more prone to harsh environmental effects, in particular that of the reactive oxygen species (ROS). Mitochondrial damage and dysfunction are implicated in many diseases ranging from metabolic diseases to cardiovascular and neurodegenerative diseases, among others. While it was once thought that transplantation of mitochondria would not be possible due to its semi-autonomous nature and reliance on the nucleus, recent advances have shown that it is possible to transplant viable functional intact mitochondria from autologous, allogenic, and xenogeneic sources into different cell types. Moreover, current research suggests that the transplantation could positively modulate bioenergetics and improve disease outcome. Mitochondrial transplantation techniques and consequences of transplantation in cardiomyocytes are the theme of this review. First, we outline the different mitochondrial isolation and transfer techniques. Second, we detail the consequences of mitochondrial transplantation in the cardiovascular system, more specifically in the context of cardiomyopathies and ischemia. Lastly, we elaborate our vision on how mitochondrial transplantation may mitigate other cardiac conditions secondary to mitochondrial damage and dysfunction, such as atherosclerosis and ST-elevated myocardial infarction.