New therapeutic perspectives from the study of the mechanisms of certain mitochondrial diseases

“Modelling POLG mutations in mice unravels a critical role of POLγΒ in regulating phenotypic severity” is the title of the study published in the prestigious international journal «Nature Communications» by the team of researchers led by Carlo Viscomi, associate professor in the Department of Biomedical sciences of the University of Padua and Principal investigator at the Istituto Veneto di Medicina Molecolare (VIMM).

The study has shed light on how mutations in an enzyme that is fundamental to our health, DNA polymerase gamma (POLγ), can cause severe mitochondrial diseases. This enzyme is responsible for DNA replication in mitochondria, the “power stations” of our cells. When POLγ does not function correctly, mitochondrial DNA becomes unstable, with potentially very serious consequences for the body.

Diseases caused by mutations in the POLG gene are highly heterogeneous and often difficult to diagnose because of the complexity of the symptoms: indeed, the same mutation can cause different symptoms in different patients. In addition, there are no cures, so patients can only receive treatments to relieve symptoms.

To try to understand better the mechanisms underlying this variability, the researchers produced mutated versions of the protein to analyse its structure and function, and reproduced the same mutations in murine models to observe the effects on the whole organism.

All the mutations analysed significantly reduce POLγ activity. Using cryoelectron microscopy, the team identified structural differences between the human and murine proteins, particularly in the accessory subunit called POLγB, which has the function of stabilising the enzyme. These differences make the murine enzyme more resistant to mutations than the human one and explain why, in mice, the same mutations cause less severe defects than in humans. Despite this, the murine models retain the essential features of human diseases, such as mitochondrial DNA instability and reduced enzyme activity and stability.

“This study is important for two reasons. On the one hand, it helps us to understand better the molecular mechanisms of diseases caused by mutations in POLG. On the other, it opens up new prospects for the development of drugs or gene therapies capable of correcting or compensating for the defects caused by POLG mutations,” emphasises Carlo Viscomi. “The study also demonstrates how useful animal models are for investigating the mechanisms underlying these rare diseases, while taking into account differences between species. Understanding these differences is essential for advancing research towards increasingly effective and personalised therapies.”