Tag: mitochondrial disease

Categories : Diseases, Syndromes and Conditions PaediatricsTags : Leave a comment

Weaker Immune Response to Viruses in Children with Mitochondrial Disorders

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Credit: NIH

In a new study, National Institutes of Health (NIH) researchers found that altered B cell function in children with mitochondrial disorders led to a weaker and less diverse antibody response to viral infections. The study, published in Frontiers in Immunology, was led by researchers at the National Human Genome Research Institute (NHGRI), who analysed the gene activities of immune cells in children with mitochondrial disorders and found that B cells, which produce antibodies to fight viral infections, are less able to survive cellular stress.

“Our work is one of the first examples to study how B cells are affected in mitochondrial disease by looking at human patients,” said Eliza Gordon-Lipkin, MD, assistant research physician in NHGRI’s Metabolism, Infection and Immunity Section and co-first author of the paper.

Mitochondria are important components of nearly every cell in the body because they convert food and oxygen into energy. Genomic variants in more than 350 genes have been linked to mitochondrial disorders with varied symptoms depending on which cells are affected.

“For children with mitochondrial disorders, infections can be life threatening or they can worsen the progression of their disorder,” said Peter McGuire, MBBCh, NHGRI investigator, head of the Metabolism, Infection and Immunity Section and senior author of the study. “We wanted to understand how immune cells differ in these patients and how that influences their response to infections.”

Around 1 in 5000 people worldwide have a mitochondrial disorder. Examples of mitochondrial disorders are Leigh’s syndrome, which primarily affects the nervous system, and Kearns-Sayre syndrome, which primarily affects the eyes and heart.

While mitochondrial disorders are known to affect organs such as the heart, liver, and brain, less is known how they affect the immune system.

Using a genomic technique called single-cell RNA sequencing, which analyzes gene activity in different cell types, researchers studied immune cells found in blood. These cells include different types of white blood cells that help the body fight infections. During stressful conditions, these cells produce a microRNA called mir4485. MicroRNAs are small strings of RNA that help control when and where genes are turned on and off. mir4485 controls cellular pathways that help cells survive.

“We think that B cells in these patients undergo cellular stress when they turn into plasma cells and produce antibodies, and these B cells then try to survive by producing the microRNA to cope,” said Dr. McGuire. “But the B cells are too fragile due to their limited energy, so they are unable to survive the stressful conditions.”

Researchers used a technique called VirScan to look at all past viral infections, assess how well the immune system fought those infections and see the effects of B cells and plasma cells on antibody production. With a weaker antibody response, the immune systems in children with mitochondrial disorders are less able to recognize and neutralize invading viruses and clear infections.

Researchers aim to use the results of this study to guide future treatment of patients with mitochondrial disorders, noting that more translational studies are needed in this research area.

Source: National Institutes of Health

Categories : New Compounds and TreatmentsTags :

Treatment for Mitochondrial Diseases Within Reach

On By ModernMedia
Credit: NIH

A medical breakthrough could result in 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 helps more mitochondria function properly.

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

The POLG gene regulates the production of DNA polymerase gamma, an enzyme that copies mitochondrial DNA. Without it, the mitochondria cannot function normally and, as a result, fail to provide the cell with energy.

A breakthrough

Maria Falkenberg and Claes Gustafsson, professors at Sahlgrenska Academy at the University of Gothenburg, have led the work behind the study now being published in the journal Nature.

“We demonstrate that the molecule PZL-A can restore the function of mutated DNA polymerase gamma and improve the synthesis of mitochondrial DNA in cells from patients. This improves the ability of the mitochondria to provide the cell with energy,” says Maria Falkenberg.

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

From lab to medication

More than twenty years of basic research led to the discovery of PZL-A. The molecule was identified following the analysis of hundreds of chemical compounds in collaboration with Pretzel Therapeutics, where another one of the lead authors of the study, Simon Giroux, has led 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, has analysed the molecule’s structure, including by means of cryo-electron microscopy.

“We demonstrate 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.

Pretzel Therapeutics has just embarked on phase I studies with a refined version of the molecule in order to test its safety on healthy volunteers. Since a lack of mitochondrial DNA is also seen in other mitochondrial, age-related, and neurodegenerative diseases, substances similar to PZL-A may gain broader therapeutic use.

Source: University of Gothenburg