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Reviving Cardiomyocytes via Coincubation with Mitochondria


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Posted 24 March 2020 - 07:11 PM


It has been known for a number of years that cells can ingest mitochondria and put them to work. Researchers here demonstrate that mitochondrial function in heart muscle cells can be improved by co-culturing them with free mitochondria harvested from other cells. The hope is that cells produced for transplantation into heart disease patients can be made more vigorous and effective via this means. Further, it is perhaps the case that mitochondria can be delivered in large numbers into the aging heart in order to improve the function of that tissue in situ.

Mitochondria are the power plants of the cell, each cell containing hundreds of these bacteria-like organelles that are essential to cell function. They produce the chemical energy store molecule adenosine triphosphate, used to power cellular processes. Unfortunately, mitochondrial activity declines with age for reasons that appear related to alterations in the mitochondrial dynamics of fusion and fission, and a related failure of the quality control mechanism of mitophagy, which normally acts to recycle worn and damage mitochondria. Cells become overtaken by large mitochondria as a result of too little fission, resistant to mitophagy.

Efforts to restore mitochondrial function remain at a comparatively early stage. The only practical methodologies presently available, such as NAD+ upregulation and mitochondrially targeted antioxidants, do appear to restore mitophagy and mitochondrial function in older tissues to some degree, but the effect sizes are neither large nor reliable, judging from human trials carried out to date. Better therapies are needed, and one possible approach to this challenge is the periodic delivery of new mitochondria. It remains to be seen how long fresh mitochondria will last before succumbing to the same environmental factors that degraded native mitochondria, but initial results here suggest that the benefit is short-lived, on the order of a few days to a week.

Researchers demonstrate the ability to supercharge cells with mitochondrial transplantation

Researchers have shown that they can give cells a short-term boost of energy through mitochondrial transplantation. Researchers first isolated mitochondria by differential centrifugation, followed by transplantation through coincubation. Once the mitochondria had settled in their new host cells, they performed metabolic flux analysis to measure two key parameters: the oxygen consumption rate and the extracellular acidification rate, which provide important information about cellular metabolism and how well the cells are consuming/producing energy. The analyses were conducted at two, seven, 14 and 28 days.

"Regarding the viability of mitochondrial transplantation in different cell lines, we've done a lot of variations, including work with skeletal muscle cells, T-cells, and cardiomyocytes. We even tested the feasibility of transplanting mitochondria from rat cells to commercially available human cells, in our lab, to see if there's a mechanism that prevents such a procedure; we found that transplanting mitochondria between different species is also possible." Next, the team plans to investigate whether the internalized mitochondria establish signaling with the cell's nucleus and whether they'll be adopted by the host on a long-term basis.

Bioenergetics Consequences of Mitochondrial Transplantation in Cardiomyocytes

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. 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.

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.


View the full article at FightAging




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