Many mitochondrial disorders are caused by mutations in the mitochondrial DNA (mtDNA). Most affected patients carry a mix of mutated and normal mitochondrial DNAs, and the disease only manifests when dysfunctional DNAs reach very high levels.
Researchers have long sought ways to eliminate mutants mtDNA whilst allowing the ‘good’ mitochondrial DNA to thrive. Although mitochondrial disorders have been untreatable until now, recent insights into how fuel availability influences mitochondrial genomes have improved therapy prospects.
Prof Antonella’s ground-breaking research
Antonella Spinazzola, Professor of Neuroscience and Mitochondrial Medicine at UCL Queen Square, and her team have published an article in the journal Trends in Pharmacological Sciences. The article explores scientific methods to ‘starve’ mutant mitochondrial DNA of nutrients in order to disable them, whilst ensuring that the good mtDNA functions as normal.
The review highlights the growing prospects for using small molecule drugs (i.e. drugs generally administered as a pill) to treat mitochondrial dysfunction. Antonella’s team have made significant advances in understanding how nutrient metabolism affects the balance of ‘good’ and ‘bad’ mitochondria, whilst also outlining outstanding questions in the field.
Mitochondrial DNA mutations are influenced by how cells metabolise nutrients like glucose, fatty acids and amino acids. One strategy under investigation uses small molecule drugs to alter nutrient availability, reducing mutated DNA levels and alleviating symptoms.
An example from the review shows that limiting glucose and glutamine availability can reduce mutant mtDNA levels, restoring mitochondrial function. This metabolic approach could be a potential therapeutic strategy in the future.
Several drugs are being examined for this purpose, including 2-Deoxyglucose (2-DG). Prof Spinazzola’s previous study demonstrated that 2-DG prevents the replication of mutant mtDNA whilst promoting the growth of mitochondria with normal DNA, restoring mitochondrial function.
Future research and gratitude
Principal Investigators Antonella Spinazzola and Ian Holt are conducting follow-up studies on the potential of small molecule drugs. They expressed gratitude to The Lily Foundation and allied organisations for supporting the development of such treatments for mitochondrial diseases.
More research is needed to understand how metabolic changes drive mtDNA selection. However, the potential for tailored treatments based on these insights should give hope to mitochondrial disease patients worldwide.