Mitochondrial Transplantation as a Treatment for Heart Disease

Mitochondria are the power plants of the cell, generating the chemical energy store molecule ATP. The function of mitochondria declines throughout the body with age, and this is particularly impactful in energy-hungry tissues such as the heart. This decline appears to involve changes in mitochondrial shape and dynamics, as well as failing mitophagy, the quality control mechanism responsible for removing worn and damaged mitochondria. This is all clearly the end of a chain of cause and effect involving many other processes, starting with the root causes of aging, and passing through altered epigenetic regulation and expression of necessary proteins.

One possible approach to therapy is to bypass all of the unknowns and transplant functional mitochondria into the patient in large numbers. These are taken up by cells and put to work. This has been shown to produce benefits in animal models, and a few human clinical studies have taken place, but is nonetheless still a form of therapy in the comparatively early stages. There are plenty of unanswered questions, such as how large a fraction of the native mitochondria can be replaced safely at any one time, how long the benefits last before new mitochondria succumb to the aged cellular environment, and whether long-term complications can arise when a different mitochondrial genome is introduced. Still, it is quite an exciting area of development: we should start to see firm answers to these questions over the next decade or so.

With cardiovascular diseases affecting millions of patients, new treatment strategies are urgently needed. The use of stem cell based approaches has been investigated during the last decades and promising effects have been achieved. However, the beneficial effect of stem cells has been found to being partly due to paracrine functions by alterations of their microenvironment and so an interesting field of research, the "stem-less" approaches has emerged over the last years using or altering the microenvironment, for example, via deletion of senescent cells, application of microRNAs or by modifying the cellular energy metabolism via targeting mitochondria.

Using autologous muscle-derived mitochondria for transplantations into the affected tissues has resulted in promising reports of improvements of cardiac functions in vitro and in vivo. However, since the targeted treatment group represents mainly elderly or otherwise sick patients, it is unclear whether and to what extent autologous mitochondria would exert their beneficial effects in these cases. Stem cells might represent better sources for mitochondria and could enhance the effect of mitochondrial transplantations.

Despite previous promising usage of mitochondria for transplantations important considerations regarding significant aging effects of somatic cells, stem cells, and mitochondria as well as factors like safety issues, tissue sources, and possible disease effects deserve further investigations when mitochondrial transplantations are to be used for future applications. Factors influencing stem cell and mitochondria function include age of the cells, probably previous divisions of the cells, heterogeneity of stem cells as well as mitochondria, and likely tissue source and additional diseases. Furthermore after the first positive reports, the time of treatment for the most beneficial effect and repetitions of applications should be further investigated: positive effects have been shown pre ischemia, prior to and during reperfusion as well as after delayed application.

The quantity of mitochondria seems to be less critical as only a small number of mitochondria is needed for improving cardiac functions. The development of further safety and storage solutions for mitochondria could improve applications. Following the first promising reports of stem cell derived mitochondria further research especially considering the differences of autologous (maybe collection in early life stages and asservation for later use) vs. allogeneic vs. syngeneic sources deserve further investigations and will surely lead to exiting new developments during the upcoming years.

Link: https://doi.org/10.3390/ijms22041824

Comments

Interesting. I wonder if this could be feasible with other cell organelles as well.

Posted by: Kel at March 24th, 2021 6:03 PM

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