MitoCeption as a Method of Artificial Mitochondrial Transfer

Mitochondria are the power plants of the cell, hundreds of bacteria-like organelles that divide like bacteria and are selectively destroyed when damaged by cellular quality control mechanisms. They carry out the energetic chemical reactions needed to package the chemical energy store molecule ATP that is used to power cellular processes. Some of the protein machinery vital to this function is encoded in mitochondrial DNA, a circular genome that resides in mitochondria themselves rather than in the cell nucleus with the majority of a cell's DNA. It is this DNA that is the Achilles' heel of mitochondria, as it is less well protected and repaired than is the case for nuclear DNA. It becomes damaged over time, and this damage leads to dysfunction in mitochondria and the cells that host them, particularly as cellular quality control mechanisms decline in efficiency with advancing age.

This mitochondrial dysfunction that manifests with age is an important component of age-related disease and disruption of normal tissue function. It is better studied in energy hungry tissues such as muscles and the brain, but it is a global phenomenon throughout the body. Evidence strongly implicates loss of mitochondrial function in sarcopenia, the loss of muscle mass and strength that occurs with age, and in all of the common age-related neurodegenerative conditions.

What can be done about this? The SENS approach is to create backups of mitochondrial genes in the cell nucleus, a process known as allotopic expression, with the challenge being that the resultant proteins have to be altered in ways that allow them to be delivered to mitochondria where they are needed. In principle this can eliminate the consequences of damage to mitochondrial DNA. This has been carried out as proof of principle at least for several mitochondrial genes. Other researchers have proposed the use of tools that can selectively destroy mutated mitochondrial DNA. Still others have suggested delivering new mitochondria into cells by exploiting one of a number of mechanisms by which this can happen naturally.

Of these approaches, only allotopic expression has made much progress towards realization, and even that line of work is arguably only at an advanced stage for one mitochondrial gene, via the work at Gensight Biologics. The open access paper here is illustrative of the present state of work on convincing cells to take up new mitochondria: the specific process used only works in cell cultures, and is thus only of potential near term use in rescuing the deteriorated function of cells from an aged patient prior to use in cell therapy. Even that might not be as useful a technique as induced pluripotency, which appears to clear out damaged mitochondria fairly effectively.

There is also the question of whether delivering new mitochondria without clearing out the old, damaged mitochondria will actually help in the long term. Damaged mitochondria can take over cells because their damage grants them either resistance to quality control mechanisms or the ability to replicate more readily than their undamaged peers. In that circumstance, new mitochondria will be quickly outcompeted by the existing damaged population, and whatever benefit is obtained will be short-lived.

Primary allogeneic mitochondrial mix (PAMM) transfer/transplant by MitoCeption to address damage in PBMCs caused by ultraviolet radiation

A substantial number of in vitro and in vivo assays have demonstrated the natural ability of cells to transfer mitochondria amongst each other. This phenomenon is most commonly observed in mitochondrial transfer from healthy mesenchymal stem/stromal cells (MSCs) to damaged cells. The transfer replaces or repairs damaged mitochondria and thereby reduces the percentage of dead cells and restores normal functions. In 1982, researchers introduced a type of artificial mitochondrial transfer or transplant (AMT/T) model using a co-incubation step between the recipient cell and exogenous mitochondria. Their pioneering study demonstrated for the first time that the mitochondrial DNA (mtDNA) of donor cells could be integrated into recipient cells and subsequently transmit hereditary traits and induce functional changes. AMT/T mimics the natural process of mitochondrial transfer, reprograms cellular metabolism, and induces proliferation. The introduction of this model elucidated the possible use of mitochondria as an active therapeutic agent.

Our study tests a modification of the original MitoCeption protocol which reduces the time and complexity of the protocol. We sought to determine if primary allogenic mitochondrial mix (PAMM) MitoCeption could be used to repair peripheral blood mononuclear cells (PBMCs) damaged by ultraviolet radiation (UVR). PAMM is composed of the PBMCs of at least three donors. Our results showed that when PBMCs are exposed to UVR, there is a decrease in metabolic activity, mitochondrial mass, and mtDNA sequence stability as well as an increase in p53 expression and the percentage of dead cells. When PAMM MitoCeption was used on UVR-damaged cells, it successfully transferred mitochondria from different donors to distinct PBMCs populations and repaired the observed UVR damage.

To our knowledge, this study is the first to demonstrate in-vitro that MitoCeption can be used to re-establish mitochondrial function loss caused by UVR exposure. Additionally, we successfully transferred a mix of different PBMC donors to one PAMM that was used to repair damaged cells. Other research groups have successfully transferred mitochondria from one cell donor type to others; however, none of them have mixed mitochondria isolated from different donors for the transfer/transplant. This study elucidates the potential to use mitochondria from different donors (PAMM) to treat UVR stress and possibly other types of damage or metabolic malfunctions in cells, resulting in not only in-vitro but also ex-vivo applications.

Comments

I think Gary Hudson of Oisin said that they might even be able to put mitochondria inside their fusogenix lipid nanoparticles. It would be interesting to see an experiment where they lump a large number of these into ages mice or rats.

Posted by: jimofoz at July 15th, 2019 5:12 PM

A further thought, perhaps a skin cream consisting of lipid nanoparticles containing mitochondria could improve the appearance of sunlight damaged ages skin?

Posted by: jimofoz at July 15th, 2019 5:15 PM

Would love to try it. Fight aging is where I first learned about MitoQ and those have been great for years. But very expensive, would love to know what feelings youthful mitochondria would deliver.

Posted by: arren brandt at July 16th, 2019 5:04 AM

"Even that might not be as useful a technique as induced pluripotency, which appears to clear out damaged mitochondria fairly effectively."
Does this mean that partial reprogramming can partially solve the problem?

Posted by: Barbara T. at July 16th, 2019 3:03 PM

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