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Mitochondria research

Study could lead to advancements in rare disease treatment

Published on: 7 December 2021

A new study has solved the old enigma in mitochondrial DNA disorders and advances the prospect of enhanced treatments for patients.

An international team involving Newcastle University has identified small molecules that purge cells of mutant mitochondrial DNA molecules thereby restoring mitochondrial function.

Mitochondria are known as the powerhouses of the cell, and their small circles of DNA are essential to produce energy from the food we eat. Consequently, mutant mitochondrial DNAs are responsible for a variety of devastating and incurable human diseases.

An international team report in Nature Communications the identification of small molecules that purge cells of mutant mitochondrial DNA molecules thereby restoring mitochondrial function.

Exceptionally, this is akin to a 'gene therapy' with small molecules. The findings are of considerable importance as they represent a possible treatment for the future.

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Pioneering study

Professor Robert Taylor, from the Wellcome Centre for Mitochondrial Research, Newcastle University, said: “In identifying the cellular metabolic constraints that can influence mitochondrial DNA replication, this groundbreaking study not only resolves a long-standing conundrum in the molecular pathology of mitochondrial disease, but offers an exciting opportunity for rapid translation of this discovery into real patient benefit through repurposing a compound that has already been tested in human subjects.”

More than 30 years ago, researchers at the Queen Square Institute of Neurology (QS IoN), who have led this study, identified the first human diseases caused by mutations in the DNA inside the mitochondria.

Since then, hundreds of mutations in the mitochondrial DNA (mtDNA) have been associated with a variety of diseases affecting almost every organ of the body, at any stage of life. Current treatments are only symptomatic and there are no disease-modifying therapies for mtDNA diseases.

A team at the Wellcome Centre for Mitochondrial Research, Newcastle University, along with Antonella Spinazzola of QS IoN and the surviving member of the original team, Ian Holt, have discovered a means to counteract mitochondria that harbour mutant mtDNAs.

A typical cell contains hundreds of mitochondria each with several copies of mtDNA. Many patients with mitochondrial DNA disorders carry a mixture of mutant and normal mtDNAs, and it has long been a puzzle why the mutant mitochondria persist and even thrive.

The new study shows that the defective mitochondria ‘steal’ energy and other resources from the rest of the cell; as such, they behave like parasites. However, when resources (nutrients) are in short supply, and each and every mitochondrion has to ‘fight for itself’, the defective mitochondria are disadvantaged.

This insight enabled the researchers to demonstrate that healthy mitochondria can be selected with chemicals that restrict nutrient metabolism and dramatically inhibit the replication of the mutant mtDNAs.

The small molecules targeting nutrient metabolism are potential new drugs that are equivalent to a gene therapy, in that they act specifically on the mutant mDNAs, albeit without directly interacting with them.

New findings

Experts, including Professors Robert Taylor and Bobby McFarland from Newcastle University, are already building on the new findings, setting up an experimental medicine study as the next step towards developing the small molecules as treatments for these currently incurable diseases.

Professor Antonella Spinazzola, senior author of the study, from QS IoN, said: “Discovering that nutrient levels can have such a dramatic effect on the replication of mutant mtDNA, and that we can manipulate them with the small molecules, represent two major steps towards understanding and developing treatments for a group of human diseases we have been wrestling with for decades.”

Co-senior author, Professor Ian Holt, added: “As well as achieving our long-term goal of identifying potential drugs that specifically inhibit the replication of mutant mitochondrial DNAs, we have opened up a new area of research: the regulation of mitochondrial DNA metabolism, and thus mitochondrial energy production and cell function, via the manipulation of nutrients”.

Reference: 2-Deoxy-D-glucose couples mitochondrial DNA replication with mitochondrial fitness and promotes the selection of wild-type over mutant mitochondrial DNA. Boris Pantic et al. Nature Communications. Doi: 10.1038/s41467-021-26829-0


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