Patients with rare mitochondrial diseases already face a host of serious health issues, from muscle weakness to neurological problems and heart conditions. But one of their most life-threatening challenges has remained a mystery—why are they so vulnerable to severe infections?
Now, scientists at The Jackson Laboratory (JAX) may have finally pinpointed why. Their new study, published in Nature Communications , shows that damaged mitochondria put the immune system in a constant state of alert, leading to dangerous overreactions when patients encounter bacteria. This excessive immune response can cause widespread inflammation and tissue damage, making infections far more deadly than they would be for a healthy person.
"Our work sheds new light on why infections hit some patients with mitochondrial disease so hard," said JAX Associate Professor Phillip West , the study's senior author. "And even more exciting, we've identified specific molecules that could be targeted with new treatments to protect this vulnerable population."
The study focused on a rare and progressive mitochondrial disorder called polymerase gamma disease, or PolG. West's team used a powerful approach—studying mice with the same genetic mutation found in human patients. The research was done in collaboration with The PolG Foundation , founded by the family of Prince Frederik de Nassau from Luxembourg, who passed away this year due to complications from PolG.
A better mouse model, a big impact
Most people know mitochondria as the cell's energy factories, but West has spent years uncovering their unexpected role in immunity. His previous research showed that mitochondria don't just generate power; they also act as key regulators of the immune system.
Clinicians had long known that patients with mitochondrial diseases get sick more often than other people — and often develop more severe, sometimes deadly, infections from viruses and bacteria. But researchers had never been able to pinpoint the molecular mechanisms underlying this vulnerability.
To get closer to the answer, West's team, including Professor Steve Murray of the JAX Rare Disease Translational Center, developed a new mouse model carrying a PolG mutation seen in human patients. Then, they introduced Pseudomonas aeruginosa, a bacterium notorious for causing lung and skin infections in hospitalized and immunocompromised patients.
"In patients with mitochondrial disease, this bacterium can be highly problematic," said West. "It's ubiquitous in the environment, and it quickly becomes antibiotic-resistant. Pseudomonas infections can easily spiral out of control and may reoccur, even after treatment."
The immune system's overreaction
After infection, immune cells of the PolG mice launched an attack, unleashing a storm of inflammatory molecules that did more harm than good. Instead of fighting the infection, the immune system's overreaction caused massive tissue damage, especially in the lungs.
"The over-active inflammatory response mirrors that seen in severe COVID-19 cases—immune cells going haywire and attacking the body's own tissues," West explained. "Instead of helping, the response actually makes things worse."
Digging deeper, the researchers discovered the root of the problem: dysfunctional mitochondria were basally activating the immune system. Even without bacteria present, the PolG cells kept producing high levels of an inflammatory molecule called type I interferon. This, in turn, activated a bacterial sensor called caspase-11, priming the immune system for an extreme response.
Under normal circumstances, caspase-11 helps the body detect bacteria. But in PolG mutant mice, too much caspase-11 means even mild bacterial exposure triggers a massive immune explosion.
"Immune cells from PolG mice self-destruct more frequently, releasing harmful molecules that amplify the inflammation," said West.
In a separate study , West and co-author Peter McGuire of the National Human Genome Research Institute, found that white blood cells from patients with other mitochondrial diseases exhibited a similar pattern—suggesting this issue extends beyond just PolG.
A new path to treatments
The discovery opens the door to innovative treatments. Instead of suppressing the entire immune system, which would leave patients vulnerable to infections, West's team is exploring ways to block the caspase-11 pathway. This targeted approach could prevent the harmful overreaction while still allowing the body to fight infections normally.
"If we can dial down this hyperactive response without shutting down the immune system entirely, it could be a game-changer," said Jordyn Van Portfliet, lead author on the study.
Beyond mitochondrial disease, these findings could have broader implications. Mitochondrial damage is also linked to conditions like neurodegenerative diseases and severe COVID-19. Understanding the connection between mitochondria and inflammation could lead to better treatments across multiple diseases.
