Longevity Briefs: Can We Fix Ageing Mitochondria?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

The genetic revolution is here – humans now have the power to introduce new genes, turn off existing ones, or even edit our own genomes. However, there’s one place that gene editing technology still struggles to reach: the mitochondrion. Mitochondria are cellular power plants, responsible for using nutrients like glucose (sugar) to generate ATP, the cell’s universal fuel. Mitochondria have a fascinating evolutionary history, as they were once separate organisms that became permanent components of complex cells. As such, they still have some of their own DNA (mtDNA) that encodes essential mitochondrial proteins. Unfortunately, this DNA is less protected against damage than the DNA in the nucleus, which means that mitochondria rapidly accumulate genetic damage during ageing and begin to function poorly. This has severe consequences for the rest of the cell and contributes to the development of age-related diseases. Inherited mutations in mtDNA can also cause mitochondrial diseases.

It is possible that in the (relatively distant) future, we could replace or introduce healthy copies of mutated mitochondrial genes. We do have gene editing technology that works on mtDNA, but it is far behind the more developed Crispr-Cas9, which is too large to enter the mitochondria. Fortunately, progress is being made towards alternative approaches, though editing mitochondrial DNA offers its own unique challenges.

The discovery:

In this study, researchers investigated the potential of a gene editing system called DdCBE (double-stranded DNA deaminase toxin A-derived cytosine base editor) to edit mtDNA in human liver organoids. Organoids are miniature, three-dimensional and simplified versions of an organ that can be grown in a lab to mimic the structure and function of the real organ. Here, the researchers used DdCBE to introduce a mutation into a gene called MT-CYB. While this specific mutation is not known to be a cause of disease in humans, other mutations in the same gene are. This strategy was successful – organoids receiving the edit had cells that produced less ATP.

Not every mitochondrion within a given cell will be edited. By introducing mutations into single cells and then developing them into organoids, researchers were able to develop organoids with varying proportions of mutated mitochondria, allowing them to make comparisons. For example, they could see the difference between an organoid in which 10% of mitochondria were mutated and one in which 50% were mutated.

The next step was to see if real mitochondrial mutations could be corrected. Researchers took fibroblast cells from a patient with the m.4291T>C mutation (which causes kidney disorders) and were able to successfully correct this mutation with DdCBE in around 80% of mitochondria. This improved mitochondrial membrane potential (a marker of function) but did not affect ATP production much.

Finally, the researchers were able to refine the delivery method of DdCBE to significantly improve the percentage of cells that were successfully edited.

The implications:

The first and most immediate implication of this research is in disease modelling. Better methods of mtDNA editing will allow scientists to produce cells or tissues carrying human mtDNA diseases and then test treatment options. However, such technology could also be used to correct existing mitochondrial mutations or even age-related mutations that lead to mitochondrial dysfunction in old age. A significant challenge to this approach is that the editing technology needs to reach not only a sufficient number of cells, but also to make a sufficient number of edits within each of those cells.

It terms of slowing ageing and the onset of age-related diseases, gene editing is not the only solution. It may be easier to simply deliver entirely new mitochondria to aged cells. Another more far-fetched but permanent solution would be to genetically alter the human species, by moving the remaining mitochondrial genes into the nucleus where they will be better protected. Most mitochondrial genes have already become part of the human genome under evolutionary pressures, so this strategy would merely be ‘finishing the job’. Until these things become possible, healthy lifestyle practices like good diet, exercise and stress management can slow down mtDNA damage, though it cannot be prevented entirely.