In a groundbreaking study published in Science Advances, scientists in the laboratory of Navdeep Chandel, Ph.D., the David W. Cugell, MD, Professor of Medicine in the Division of Pulmonary and Critical Care, have made a pivotal discovery that could open new avenues for treating a variety of inflammation-related diseases. Their findings highlight how mitochondria—the powerhouse of cells—affect the body’s immune responses, particularly through the regulation of certain cell signaling pathways. The research lays the groundwork for potential therapeutic interventions aimed at improving mitochondrial function, which could have far-reaching implications for diseases such as inflammatory bowel disease, sepsis, and chronic infections.
Mitochondria, traditionally known for their role in energy production, are far more involved in cellular activities than previously understood. Beyond generating ATP through the mitochondrial electron transport chain (ETC), recent research suggests that these organelles also have a significant impact on immune cell function, specifically in modulating inflammation. This new discovery challenges and expands our understanding of mitochondrial dynamics and their influence on immune health.
Mitochondrial Activity and Immune Cell Regulation
At the core of this study is the relationship between mitochondria and macrophages, a type of white blood cell essential for immune defense. Macrophages play a crucial role not only in fighting infections but also in regulating inflammation. They are responsible for clearing pathogens and debris from tissues, and they control inflammatory responses to ensure that the immune system does not overreact and harm healthy tissues.
One of the important immune-regulatory proteins released by macrophages is IL-10, which works to dampen excessive inflammation and prevent tissue damage caused by an overactive immune system. However, the mechanisms that allow mitochondria to influence the release of IL-10 from macrophages have remained unclear—until now.
The Role of Reactive Oxygen Species (ROS)
Using bulk-RNA sequencing, the research team investigated the cellular processes involved in macrophage function in mice with impaired mitochondrial ETC complex III, an integral part of the mitochondrial machinery. This complex, vital to the electron transport chain, enables cells to produce ATP by transferring electrons. The scientists identified a critical molecule—superoxide, a type of reactive oxygen species (ROS), which is a byproduct of the mitochondrial ETC.
Superoxide plays an essential role in macrophages’ ability to release IL-10. ROS, including superoxide, are often associated with oxidative stress, a condition where the body produces an excessive amount of free radicals, potentially causing harm to cells. However, this study demonstrated that superoxide, in controlled amounts, actually promotes healthy immune function by stimulating macrophages to release IL-10. This finding was particularly significant because, for the first time, it clarified how mitochondrial activity could regulate inflammation by modulating immune signaling pathways.
Impact of Mitochondrial Dysfunction in Macrophages
In the study, mice with defective mitochondrial complex III struggled to recover from infections and inflammation. This impairment was associated with reduced IL-10 production, leaving these animals with insufficient mechanisms to control inflammation. The researchers went on to activate a specific ROS-dependent signaling pathway to restore IL-10 production in these cells, demonstrating that a targeted approach could reverse the negative effects of mitochondrial dysfunction.
This discovery is crucial because it identifies mitochondria as more than just the cellular powerhouses; they are key players in regulating the immune system’s response to inflammation and infection. With this newfound knowledge, researchers can now explore ways to manipulate mitochondrial function as a therapeutic strategy for diseases characterized by uncontrolled inflammation, such as inflammatory bowel disease (IBD), rheumatoid arthritis, and sepsis.
Potential Implications for Treating Inflammatory Diseases
The ability to modulate mitochondrial function to regulate IL-10 levels has immense therapeutic potential. Dr. Chandel, who is also a professor of Biochemistry and Molecular Genetics and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, believes that boosting mitochondrial activity could help manage a variety of autoimmune and inflammatory diseases.
Rheumatoid arthritis, lupus, and other autoimmune disorders—conditions in which the immune system mistakenly attacks the body’s own tissues—could benefit from therapies aimed at enhancing mitochondrial function. Increasing IL-10 production may prevent the immune system from attacking healthy cells, potentially improving the effectiveness of existing treatments for autoimmune diseases.
Moreover, mitochondrial dysfunction is often linked to impaired recovery from infections. By targeting mitochondrial pathways to enhance IL-10 production, patients recovering from severe infections could experience a faster and more efficient immune response. On the flip side, inhibiting mitochondrial complex III to decrease IL-10 activity could have value in combination with immunotherapies that aim to strengthen the immune response in cancer patients.
Advancing Inflammation-Based Therapeutics
Chandel’s study also has broader implications for the field of immunotherapy. By targeting mitochondrial activity directly within immune cells like macrophages, it may be possible to fine-tune inflammation levels in the body, allowing for the suppression of harmful overactive immune responses and the promotion of beneficial immune regulation. This insight offers a novel approach to treating inflammatory diseases and could lead to the development of therapies that are more personalized, efficient, and effective than current methods.
The findings from this study have prompted researchers to consider mitochondrial function not just in the context of energy metabolism but also as a modifiable target for therapeutic intervention. Developing mitochondrial-targeted treatments could represent a promising next step in the evolving landscape of precision medicine, which tailors treatment to an individual’s unique cellular characteristics.
Conclusion: A New Frontier in Immunology
In summary, the research led by Navdeep Chandel and his team represents a significant advancement in our understanding of how mitochondria influence immune responses. Through their impact on macrophage behavior and IL-10 regulation, mitochondria play an integral role in controlling inflammation, a factor in many diseases ranging from chronic infections to autoimmune conditions.
By harnessing mitochondrial pathways to regulate immune responses, scientists now have a promising strategy for developing new treatments for a variety of inflammation-driven diseases. Whether it’s enhancing IL-10 to reduce autoimmune flare-ups or modulating mitochondrial complex III to optimize recovery from infections, the potential to address long-standing challenges in immunology has never been more real.
With these findings, Dr. Chandel and his colleagues have unlocked a previously unexplored area of cellular function, broadening our understanding of both mitochondrial health and immune regulation. Their research highlights the indispensable role of mitochondria beyond mere energy production, suggesting a future where mitochondrial-targeted therapies could become an essential part of managing inflammation and immune-related diseases.
Reference: Joshua S. Stoolman et al, Mitochondria complex III–generated superoxide is essential for IL-10 secretion in macrophages, Science Advances (2025). DOI: 10.1126/sciadv.adu4369