Breakthrough molecule offers hope for treating rare mitochondrial diseases

Breakthrough molecule offers hope for treating rare mitochondrial diseases

A medical breakthrough could lead to the first treatment for rare but serious diseases in which genetic defects disrupt cellular energy production. Researchers at the University of Gothenburg have identified a molecule that makes more mitochondria function properly.

Mitochondrial diseases caused by Polg mutations vary in severity. In young children, these diseases can quickly lead to brain damage and life-threatening liver problems, while others experience muscle weakness, epilepsy and organ failure later in childhood. POLG mutations recently came to media attention when Prince Frederik of Nassau, Luxembourg, died in March 2025 at just 22 years old.

The Polg gene regulates the production of DNA polymerase gamma, an enzyme that copies mitochondrial DNA. Without them, the mitochondria cannot function normally and therefore cannot supply the cell with energy.

A breakthrough

Maria Falkenberg and Claes Gustafsson, professors at the Sahlgrlenska Academy at the University of Gothenburg, led the work behind the study, which has now been published in the journalNature.

We show that the molecule PZL-A can restore the function of mutant DNA polymerase gamma and improve the synthesis of mitochondrial DNA in cells from patients. This improves the mitochondria's ability to provide energy to the cell. “

Maria Falkenberg, Professor of Biomedical Laboratory Science

"This is a breakthrough because we can demonstrate for the first time that a small molecule can help improve the function of the defective DNA polymerase. Our results pave the way for a completely new treatment strategy," says Claes Gustafsson, Professor of Medicinal Chemistry.

From laboratory to medication

More than twenty years of basic research led to the discovery of PZL-A. The molecule was identified after analyzing hundreds of chemical compounds in collaboration with Pretzel Therapeutics, with another one of the study's lead authors, Vice President of Chemistry Simon Giroux, leading the chemical development of the molecule. So far, the molecule has been studied in cells from patients as well as in animal models.

Sebastian Valenzuela, a doctoral student at Sahlgrenska Academy, analyzed the structure of the molecule, including cryo-electron microscopy.

"We show exactly where the molecule binds between two separate chains of the enzyme. The binding site is extremely specific, which helps us understand how the enzyme works and how we can influence it," says Sebastian Valenzuela, first author of the study.

The Brezel therapeutic will soon begin Phase I trials with a refined version of the molecule to test its safety in healthy volunteers. Since mitochondrial DNA deficiency is also observed in other mitochondrial, age-related and neurodegenerative diseases, substances similar to PZL-A may gain broader therapeutic use. Pretzel Therapeutics is part of the Gothenburg Region Life Sciences Cluster, with its Swedish operations conducted at Goco Health Innovation City and its headquarters in Waltham, Massachusetts, outside Boston.

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