Understanding Why Patients with Mitochondrial Disease Are More Prone to Infections

Patients diagnosed with mitochondrial diseases face a range of serious health challenges, including muscle weakness, neurological issues, and heart problems. Despite these known complications, one of the most dangerous aspects has remained elusive—why do these individuals seem remarkably more vulnerable to severe infections?

Recent research conducted by scientists at The Jackson Laboratory (JAX) has shed light on this question. Their latest study, published in Nature Communications, reveals that damaged mitochondria cause a constant state of immune system alertness. This persistent activation results in exaggerated immune responses when patients encounter bacteria, which can lead to extensive inflammation and tissue injury. Consequently, infections tend to be more severe and often more deadly in patients with mitochondrial disorders.

According to Phillip West, Associate Professor at JAX and senior author of the study, "Our research provides new insights into why infections disproportionately affect those with mitochondrial disease. Importantly, we've identified specific molecules that may be targeted for future therapies to protect this vulnerable group."

The focus was on a rare and progressive mitochondrial disorder known as polymerase gamma disease (PolG). To investigate, West's team utilized a mouse model carrying a mutation similar to that found in human patients. This study was conducted in collaboration with The PolG Foundation, established by the family of Prince Frederik de Nassau from Luxembourg, who succumbed to complications of PolG.

Mitochondria are primarily known as the energy-producing structures within cells, but West’s previous research has shown they also play a crucial role in regulating immune responses. Patients with mitochondrial diseases are known to have heightened susceptibility to infections and often experience more severe forms of viral and bacterial illnesses, yet the molecular mechanisms behind this vulnerability remained unclear.

Using the newly developed mouse model, researchers introduced Pseudomonas aeruginosa, a bacterium notorious for causing difficult-to-treat infections in immunocompromised and hospital patients. The results were striking: in mitochondrial disease models, immune cells overreacted, unleashing a storm of inflammatory molecules that caused more harm than the infection itself, especially in the lungs.

Further analysis revealed that dysfunctional mitochondria activate the immune system abnormally. Even in the absence of bacteria, cells with mitochondrial damage produced high levels of type I interferon, which in turn activated a bacterial sensor called caspase-11. Normally, caspase-11 helps detect bacteria and trigger immune responses, but in PolG models, its overactivation led to extreme inflammation. This hyperresponsive state caused immune cells to self-destruct and release harmful inflammatory molecules, aggravating tissue damage.

These findings indicate that in mitochondrial diseases, the immune system’s exaggerated response, rather than the infection itself, is often responsible for severe illness. Interestingly, similar patterns of immune overreaction were observed in white blood cells from patients with other mitochondrial conditions, suggesting a common underlying mechanism.

This discovery opens new possibilities for targeted treatments. Instead of broadly suppressing the immune system—which could leave patients vulnerable to infections—the aim is now to develop interventions that specifically block the hyperactive pathways, such as caspase-11. Such precision therapies could prevent dangerous inflammatory responses while preserving the immune system’s ability to fight infections.

JAX researchers are optimistic that this approach could revolutionize treatment strategies for mitochondrial disorders and potentially other diseases linked to mitochondrial damage, including neurodegenerative conditions and severe COVID-19 cases. By understanding the link between mitochondrial health and immune regulation, scientists hope to improve outcomes for many vulnerable patients.

For more detailed information, the study titled "Caspace-11 drives macrophage hyperinflammation in Polg-related mitochondrial disease" can be accessed via the DOI: 10.1038/s41467-025-59907-8.