Longevity Briefs: Repairing The Cell’s Aged Power Plants With Gene Editing

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.

Why is this research important: Mitochondria are the cellular organs (organelles) that produce the energy the cell needs in order to function. Deep in our evolutionary past, mitochondria were separate single-celled organisms that maintained their own DNA. Since then, most genes associated with the mitochondria have become integrated into the human DNA that resides in the nucleus at the centre of the cell. However, 37 mitochondrial genes still remain within each mitochondrion. This DNA is exposed to much higher levels of damage than the DNA in the nucleus. This causes mutations that decrease the efficiency of the mitochondria with age, which is linked to a cascade of events thought to contribute to the ageing process.

What did the researchers do: In a study published in Nature Communications, researchers used a new tool called a DddA-derived cytosine base editor (DdCBE) in order to edit mitochondrial DNA in live mice. Mitochondrial DNA is hard to edit because it is difficult to get new DNA sequences into the mitochondrion itself. DdCBEs work by targeting and modifying existing ‘genetic letters’ within the DNA code. Researchers delivered DdCBE to the hearts of the mice by packaging them inside an adeno-associated virus (AAV) and introducing them into the bloodstream.

Key takeaway(s) from this research: Researchers were able to successfully install the desired mitochondrial DNA mutations in the cells of adult mice who were treated with DdCBEs. This technology had previously been used to alter mitochondrial DNA in cultured human cells and in mouse embryos, and these alterations were passed on to the mice’s offspring. However, this study is the first to show successful editing of mitochondrial DNA in fully developed mice by delivering DdCBEs using a virus.

This study is a proof of concept that could eventually provide us with a means to alter and correct specific mitochondrial DNA mutations in humans in order to treat mitochondrial diseases. These are diseases (often inherited) in which the mitochondria fail to produce enough energy due to mutations in mitochondrial genes. Using this technology to correct mitochondrial dysfunction during ageing will be more challenging, as this kind of dysfunction isn’t caused by any one specific mutation. Rather, mutations in the mitochondrial DNA during ageing are random, and so even two mitochondria within the same cell will have different mutations

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