New JAX Study Reveals Why Patients with Mitochondrial Disease Are More Vulnerable to Infections

Patients suffering from rare mitochondrial diseases confront a myriad of severe health challenges, including muscle weakness, neurological impairments, and cardiac complications. Yet among these difficulties, a particularly puzzling and life-threatening issue has remained elusive: their heightened vulnerability to severe bacterial infections. Recent groundbreaking research from The Jackson Laboratory (JAX) is shedding light on this critical question, revealing the intricate molecular crosstalk between damaged mitochondria and the immune system’s overzealous response to invading pathogens. This work promises not only to deepen our understanding of mitochondrial pathology but also to open new therapeutic avenues.

Mitochondria, traditionally known as the cell’s “powerhouses,” have long been recognized for their role in generating adenosine triphosphate (ATP), the cellular energy currency. However, emerging research over the past decade has revolutionized this view, highlighting mitochondria’s pivotal roles in immunity and inflammation. The recent study led by JAX Associate Professor Phillip West, published in Nature Communications, reveals how the malfunction of mitochondria at the cellular level hyperactivates the innate immune response through a cascade involving the inflammatory protease caspase-11. This hyperactivation leads to excessive inflammation and consequent tissue injury, particularly during bacterial infections.

At the heart of the investigation is polymerase gamma (PolG) disease, a rare inherited mitochondrial disorder characterized by progressive defects in mitochondrial DNA replication and repair. Using a novel mouse model harboring the same PolG mutations found in affected human patients, the team simulated conditions that closely mirror the human disease state. These genetically engineered mice provided an unprecedented window into the cellular and molecular defects driving immune dysregulation in mitochondrial disease – a subject that has long confounded clinicians and researchers alike.

When these PolG mutant mice were exposed to Pseudomonas aeruginosa, a ubiquitous and opportunistic pathogen notorious for causing severe lung and skin infections especially among hospitalized and immunocompromised individuals, the researchers observed devastating immune responses. Instead of mounting a protective defense, the mutant mice exhibited an overwhelming inflammatory reaction marked by extensive lung tissue damage. This intense inflammation was disproportionate to the bacterial load, signaling that the immune response itself contributed substantially to pathology rather than the pathogen alone.

Delving into the molecular underpinnings of this phenomenon, the scientists identified a continuous baseline activation of type I interferons, a class of cytokines critical for antiviral and antibacterial defense. The chronically elevated interferon signaling in PolG immune cells acted as a primer for the activation of caspase-11, a protease that ordinarily functions as a cytosolic sensor for bacterial lipopolysaccharide (LPS) – a key component of Gram-negative bacterial cell walls. In healthy conditions, caspase-11’s role is to detect invading bacteria and initiate pyroptosis, a form of programmed cell death that limits infection spread. However, in the PolG mice, caspase-11 was excessively active even in the absence of bacterial challenge, setting the stage for runaway inflammation.

This pathological state triggers immune cells, particularly macrophages, to undergo pyroptosis more frequently than normal. The lytic death of these cells releases potent inflammatory mediators that further amplify tissue damage and immune system dysregulation. The researchers vividly describe this phenomenon as the immune cells effectively “self-destructing” and fueling a vicious cycle of inflammation. Importantly, this immune hyperactivation bears striking resemblance to the dysregulated immune responses observed in critical illness contexts such as severe COVID-19, where excessive cytokine storms cause collateral organ injury.

Extending their findings beyond animal models, West and colleagues collaborated with the National Human Genome Research Institute to analyze white blood cells from human patients with various mitochondrial diseases. These cells exhibited a comparable inflammatory signature featuring elevated caspase-11 activity and type I interferon production, suggesting a common underlying mechanism that may exacerbate infection susceptibility across different mitochondrial pathologies. This convergence of murine and human data adds robust translational weight to the study’s conclusions.

The implications of these findings are profound, offering a potential paradigm shift in how mitochondrial disease-related infections might be treated. Traditional approaches that broadly suppress immune function risk leaving patients defenseless against infections. By contrast, selectively targeting the caspase-11 signaling axis could modulate the immune response to mitigate harmful inflammation without compromising host defenses. This nuanced, targeted approach offers hope for developing disease-modifying therapies that address the root cause of immune dysfunction in mitochondrial diseases.

Jordyn Van Portfliet, the study’s lead author, emphasizes the transformative potential of these discoveries: “If we can dial down this hyperactive immune response without shutting down the immune system entirely, it could be a game-changer for patients with mitochondrial disorders.” Such therapeutics, if realized, might not only reduce infection severity but also prevent the often fatal inflammatory cascades that follow bacterial insult in this vulnerable population.

Beyond the immediate clinical relevance for mitochondrial disorder patients, the study highlights broader biological insights. The link between mitochondrial integrity and immune regulation may also illuminate pathways relevant to a spectrum of inflammatory diseases, including neurodegenerative conditions and acute viral syndromes like COVID-19. This intersection of mitochondrial biology and immunology is rapidly emerging as a fertile ground for novel interventions across multiple disciplines of medicine.

The journey to this discovery was bolstered by collaborations with the PolG Foundation, an organization supporting research and patients affected by polymerase gamma disease. Founded by the family of Prince Frederik de Nassau of Luxembourg, who succumbed to complications of PolG disease, the foundation’s support underscores the human significance of this research. It is a poignant reminder of how bench science, patient experience, and advocacy can synergize toward breakthroughs with tangible clinical impact.

In conclusion, this study by West and colleagues marks a significant leap forward in decoding the complex immune dysfunction afflicting patients with mitochondrial diseases. By unveiling caspase-11-driven macrophage hyperinflammation as a key player in PolG-associated pathology, their work opens promising vistas for targeted therapeutics. As the field further explores mitochondrial-immunity dynamics, hopes are high that these insights will translate into life-saving treatments for mitochondrial disease patients and others suffering from inflammatory disorders linked to mitochondrial damage.

Subject of Research: Animals
Article Title: Caspase-11 drives macrophage hyperinflammation in PolG-related mitochondrial disease
News Publication Date: 20-May-2025
Web References:

https://www.nature.com/articles/s41467-025-59907-8
http://dx.doi.org/10.1038/s41467-025-59907-8
References: Included within article citations in text
Image Credits: The Jackson Laboratory
Keywords: Diseases and disorders, Genetics, Immunology, Molecular biology

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