ARTICLE: Removing mutant mtDNA from cells

2-Deoxy-D-glucose couples mitochondrial DNA replication with mitochondrial fitness and promotes the selection of wild-type over mutant mitochondrial DNA
Boris Pantic, Daniel Ives, Mara Mennuni, Diego Perez-Rodriguez, Uxoa Fernandez-Pelayo, Amaia Lopez de Arbina, Mikel Muñoz-Oreja, Marina Villar-Fernandez, Thanh-mai Julie Dang, Lodovica Vergani, Iain G Johnston, Robert DS Pitceathly, Robert McFarland, Michael G Hanna, Robert W Taylor, Ian J Holt, Antonella Spinazzola
Nature Communications 12 1 (2021)

This is an exciting one! As we've discussed before, mitochondrial DNA (mtDNA) molecules exist in large populations in our cells, encoding vital machinery. Devastating diseases can result when a high proportion of a cell's mtDNA molecules are mutated, but cells can deal with a low proportion of mutant mtDNA. So, it'd be great if we had a way to decrease the proportion of mutant mtDNA in cells -- below the threshold for disease.

Perhaps we do! We recently played a supporting role in a project with Antonella Spinazzola and Ian Holt, looking at what happens when cells containing a mixture of mutant and normal mtDNA are treated with chemicals. They found that a molecule called 2DG (for short) slows down the replication of mutant mtDNA in cells. As mtDNA is constantly replicating, this preferential inhibition of mutant means that normal mtDNA comes to dominate the cellular population over time. We showed this population shifting over time in a variety of human cell lines and growth media, including several chosen to model in vivo behaviour.

The project showed that 2DG compromises mitochondrial respiration much more in mutant than in wildtype mitochondria. This is likely why mutant replication was so challenged -- poorly functioning mitochondria are less likely to replicate. Restricting glutamine and glucose together had the same effect (though is perhaps harder to achieve in a therapeutic context). 2DG is in trials for epilepsy treatment, so may represent a path to new therapies addressing mtDNA disease. There's a press release here with some more commentary.