Bioenergetics Consequences of Mitochondrial Transplantation in Cardiomyocytes.

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

Intracellular Consequences of Mitochondrial Transplantation

Mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells, which plays a vital role in cellular metabolism and homeostasis. As the powerhouse of the cell, the clinical manifestations of mitochondrial damage and dysfunction are devastating. While there has been much new interest and research on therapies involving mitochondria to mitigate diseases ranging from cancer and cardiovascular diseases to neurodegenerative diseases such as Parkinson and Alzheimer, the intracellular consequences of mitochondrial transplantation are not well-studied or well-understood. In this work, we show that autologous, non-autologus, and interspecies mitochondrial transplantation are feasible using a variety microscopy technique. Moreover, we show that non-autologous transplantation of healthy mitochondria from skeletal muscle cells into normal cardiomyocytes leads to improved bioenergetics acutely. Using a metabolic flux analyzer, we measured the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), after sequential treatment with Oligomycin, FCCP, Rotenone/Antimycin A post-transplantation, and compared the values to the control groups with no transplantation event at four time points of post 2-day, 7-day, 14-day , and 28-day. This was followed by mitochondrial genome sequencing studies to investigate whether transplanted mitochondria are truly adopted by the cell or not. This work delineates the potential of mitochondrial transplantation for clinical application in settings where there is an acute stress that would benefit from a boost in cellular bioenergetics. Given the observed bioenergetic profile of mitochondrial transplantation in normal cells, one of the remaining questions is whether the post-transplantation bioenergetics profile will be any different in cells with mitochondrial dysfunction. Future studies are crucial in determining the possible advantages of mitochondrial transplantation, if any, in mitigating mitochondrial diseases and other mitochondrial dysfunctions, as a cellular biotherapy

Intracellular Consequences of Mitochondrial Transplantation

Mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells, which plays a vital role in cellular metabolism and homeostasis. As the powerhouse of the cell, the clinical manifestations of mitochondrial damage and dysfunction are devastating. While there has been much new interest and research on therapies involving mitochondria to mitigate diseases ranging from cancer and cardiovascular diseases to neurodegenerative diseases such as Parkinson and Alzheimer, the intracellular consequences of mitochondrial transplantation are not well-studied or well-understood. In this work, we show that autologous, non-autologus, and interspecies mitochondrial transplantation are feasible using a variety microscopy technique. Moreover, we show that non-autologous transplantation of healthy mitochondria from skeletal muscle cells into normal cardiomyocytes leads to improved bioenergetics acutely. Using a metabolic flux analyzer, we measured the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), after sequential treatment with Oligomycin, FCCP, Rotenone/Antimycin A post-transplantation, and compared the values to the control groups with no transplantation event at four time points of post 2-day, 7-day, 14-day , and 28-day. This was followed by mitochondrial genome sequencing studies to investigate whether transplanted mitochondria are truly adopted by the cell or not. This work delineates the potential of mitochondrial transplantation for clinical application in settings where there is an acute stress that would benefit from a boost in cellular bioenergetics. Given the observed bioenergetic profile of mitochondrial transplantation in normal cells, one of the remaining questions is whether the post-transplantation bioenergetics profile will be any different in cells with mitochondrial dysfunction. Future studies are crucial in determining the possible advantages of mitochondrial transplantation, if any, in mitigating mitochondrial diseases and other mitochondrial dysfunctions, as a cellular biotherapy

Prospects of mitochondrial transplantation in clinical medicine: Aspirations and challenges.

Mitochondria, known as the powerhouse of the cell, are at the center of healthy physiology and provide cells with energy in the form of ATP. These unique organelles are also implicated in many pathological conditions affecting a variety of organs in various systems. Recently, mitochondrial transplantation, inspired by mitochondria's endosymbiotic origin, has been attempted as a potential biotherapy in mitigating a variety of pathological conditions. Mitochondrial transplantation consists of the process of isolation, transfer, and uptake of exogenous, intact mitochondria into damaged cells. Here, we discuss mitochondrial transplantation in the context of clinical medicine practiced in neurology, cardiology, pulmonary medicine, and oncology, among others. We outline the role of mitochondria in various pathologies and discuss the state-of-the-art research that potentially form the basis of new therapeutics for the treatment of a variety of diseases due to mitochondrial dysfunction. Lastly, we explore some of the challenges associated with mitochondrial transplantation that must be addressed before mitochondrial transplantation becomes a viable therapeutic option in clinical settings

Mitochondrial transplantation in cardiomyocytes: foundation, methods, and outcomes.

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. 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 their semiautonomous 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. We outline the different mitochondrial isolation and transfer techniques. Finally, we detail the consequences of mitochondrial transplantation in the cardiovascular system, more specifically in the context of cardiomyopathies and ischemia

Bioenergetics Consequences of Mitochondrial Transplantation in Cardiomyocytes.

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