Many mitochondrial disorders are caused by mutations in the mitochondrial DNA (mtDNA), but most affected patients carry a mix of mutated and normal mitochondrial DNAs, and the disease only manifests when those dysfunctional DNAs reach very high levels.
Researchers have long been trying to identify ways to eliminate the mutants whilst allowing the ‘good’ mitochondrial DNA to thrive. And whilst mitochondrial conditions have proven untreatable until now, the prospects for therapies have improved with the more recent understanding that the fate of mitochondrial genomes is influenced by the availability of fuel.
The article that’s just been published by Antonella and her team in the journal Trends in Pharmacological Sciences explores scientific methods to effectively ‘starve’ the mutant mitochondrial DNA of nutrients in order to disable them, whilst ensuring that the good mtDNA can continue to function as normal.
It’s a comprehensive review of the growing prospects for using small molecule drugs (i.e. drugs generally administered as a pill) to treat mitochondrial dysfunction. It highlights the recent advances Antonella’s team have made in understanding the role nutrient metabolism plays in the balance of ‘good’ and ‘bad’ mitochondria, whilst outlining outstanding questions in the area.
Mitochondrial DNA mutations are affected by changes in how cells in the body metabolise nutrients like glucose, fatty acids and amino acids. One possible strategy being investigated uses small molecule drugs to alter nutrient availability to reduce the levels of the mutated DNA and alleviate symptoms.
An example included in the review was limiting glucose and glutamine availability. This has been shown to reduce the level of mutant mtDNA, thereby restoring mitochondrial function. This metabolic approach could be a potential therapeutic strategy in the future.
A number of drugs are currently being examined for this purpose, and one of them is 2-DG, which was the subject of Prof Spinazzola’s previous study. That study proved that 2-DG prevented the replication of the mutant mtDNA whilst promoting the growth of mitochondria with normal copies of the DNA, leading to restoration of mitochondrial function.
The Principal Investigators of the review, Antonella and her colleague Ian Holt, explained that follow-up studies are well under way, and they expect to publish on the wider potential of small molecule drugs in the near future.
The pair also expressed their gratitude to The Lily Foundation and allied organisations for supporting the development of such treatments for mitochondrial disorders.
More research is needed into understanding how metabolic changes can drive mtDNA selection, but the potential for tailored treatments that address mitochondrial disorders based on these insights should give hope to mito patients everywhere.