Faulty mitochondria – the “batteries” that power our body’s cells – could in the future be repaired using gene-editing techniques. Scientists at the University of Cambridge have shown that it is possible to modify the mitochondrial genome in living mice, paving the way for new treatments for incurable mitochondrial disorders.
Our cells contain mitochondria, which provide the energy necessary for the functioning of our cells. Each of these mitochondria is encoded by a tiny amount of mitochondrial DNA. Mitochondrial DNA represents only 0.1% of the entire human genome and is transmitted exclusively from mother to child.
Defects in our mitochondrial DNA can affect the proper functioning of mitochondria, leading to mitochondrial diseases, serious and often fatal conditions that affect approximately 1 in 5,000 people. The diseases are incurable and largely incurable.
There are usually around 1,000 copies of mitochondrial DNA in each cell, and the percentage of these that are damaged or mutated will determine whether or not a person will suffer from mitochondrial disease. Usually more than 60% of a cell’s mitochondria must be defective for disease to occur, and the more defective mitochondria a person has, the more severe their disease will be. If the percentage of defective DNA could be reduced, the disease could potentially be cured.
A cell that contains a mixture of healthy and defective mitochondrial DNA is described as “heteroplasmic”. If a cell does not contain healthy mitochondrial DNA, it is “homoplasmic”.
In 2018, a team from the University of Cambridge’s MRC Mitochondrial Biology Unit applied an experimental gene therapy treatment in mice and were able to successfully target and eliminate damaged mitochondrial DNA in heteroplasmic cells, allowing mitochondria with healthy DNA to take their place.
Our earlier approach was very promising and was the first time anyone was able to modify mitochondrial DNA in a living animal. But it would only work in cells with enough healthy mitochondrial DNA to copy itself and replace those that were defective and deleted. It wouldn’t work in cells whose entire mitochondria had faulty DNA.”
Dr Michal Minczuk, University of Cambridge
In their latest breakthrough, published today in Nature Communication, Dr. Minczuk and his colleagues used a biological tool known as a mitochondrial base editor to modify the mitochondrial DNA of living mice. The treatment is delivered into the mouse’s bloodstream using a modified virus, which is then taken up by its cells. The tool looks for a unique sequence of base pairs – combinations of the A, C, G and T molecules that make up DNA. It then modifies the base of the DNA, in this case a C into a T. This would in principle allow the tool to correct certain “spelling errors” responsible for the dysfunction of the mitochondria.
There is currently no suitable mouse model for mitochondrial DNA diseases. The researchers therefore used healthy mice to test the mitochondrial base editors. However, this shows that it is possible to edit mitochondrial DNA genes in a living animal.
Pedro Silva-Pinheiro, a postdoctoral researcher in Dr Minczuk’s lab and first author of the study, said: “This is the first time anyone has been able to modify DNA base pairs in the mitochondria of a living animal. This shows that in principle we can go in and correct misspellings in faulty mitochondrial DNA, producing healthy mitochondria that allow cells to function properly.”
A pioneering approach in the UK known as mitochondrial replacement therapy – sometimes referred to as ‘three-person IVF’ – replaces defective mitochondria from a mother with those from a healthy donor. However, this technique is complex and even standard IVF is successful less than one in three cycles.
Dr Minczuk added: “There is clearly a long way to go before our work can lead to a cure for mitochondrial diseases. But it does show that there is potential for a future treatment that removes the complexity of mitochondrial replacement therapy and allows for defective mitochondria. to be repaired in children and adults.”
Silva-Pinheiro, P., et al. (2022) In vivo mitochondrial base editing via adeno-associated virus delivery to mouse post-mitotic tissue. Communication Nature. doi.org/10.1038/s41467-022-28358-w.