Mitochondria, often seen as cellular powerhouses, play a surprising role in immune regulation.
Researchers found that mitochondrial complex III generates reactive oxygen species (ROS), which help immune cells release IL-10, an anti-inflammatory protein. Without proper mitochondrial function, immune responses become dysregulated, leading to prolonged inflammation and slow recovery from infections.
Mitochondria’s Role in Immune Response
Scientists in Dr. Navdeep Chandel’s laboratory at Northwestern University have uncovered how mitochondria help regulate the immune system by influencing key cell signaling pathways. Their study, published on January 22 in Science Advances, suggests that targeting mitochondrial function in immune cells could lead to new treatments for inflammation-related diseases.
“Therapies aimed at improving mitochondrial activity could benefit inflammatory diseases such as inflammatory bowel disease, sepsis, and chronic infections by enhancing the immune system’s ability to regulate inflammation,” said Chandel, also a professor of Biochemistry and Molecular Genetics and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
How Mitochondria Influence Macrophages
Mitochondria, best known as the cell’s energy producers, contain the electron transport chain (ETC), a network of protein complexes that generate ATP. Beyond energy production, the ETC also plays a crucial role in controlling macrophages—specialized immune cells that fight infections and regulate inflammation.
Macrophages also release an anti-inflammatory protein called IL-10, which reduces inflammation and prevents excess immune responses that can harm the body. The underlying mechanisms that allow mitochondrial ETC to control macrophage immune responses, however, have remained poorly understood.
Reactive Oxygen Species and Inflammation Control
Using bulk-RNA sequencing to study mice with macrophages deficient in mitochondria ETC complex III, the scientists discovered that a type of reactive oxygen species (ROS), or unstable molecules that contain oxygen and easily react with other molecules in a cell, that is produced by mitochondrial complex III, called superoxide, is critical for macrophages to release IL-10.
The scientists also discovered those mice with the defective mitochondrial complex also struggled to recover from infection and inflammation because their cells released less IL-10. However, activating a specific ROS dependent signaling pathway in the cells restored IL-10 release, according to the study.
A Paradigm Shift in Mitochondrial Research
“This finding highlights a previously unknown connection between mitochondrial activity, inflammation control and the signaling pathways that regulate it,” Chandel said.
Overall, the findings underscore mitochondria’s essential role beyond energy production and suggest that mitochondria may be a promising therapeutic target for treating a range of inflammatory diseases and enhancing current therapies, according to Chandel.
“Boosting IL-10 levels through mitochondrial pathways offers promise for managing autoimmune disorders like rheumatoid arthritis and lupus, where the immune system mistakenly attacks the body. Enhancing the function of mitochondrial complex III, or mimicking its effects, may also improve recovery from severe infections. Additionally, inhibiting mitochondrial complex III would decrease IL-10 suppression of inflammation, and could cooperate with existing immunotherapies,” Chandel said.
Reference: “Mitochondria complex III–generated superoxide is essential for IL-10 secretion in macrophages” by Joshua S. Stoolman, Rogan A. Grant, Leah K. Billingham, Taylor A. Poor, Samuel E. Weinberg, Madeline C. Harding, Ziyan Lu, Jason Miska, Marten Szibor, GR Scott Budinger and Navdeep S. Chandel, 22 January 2025, Science Advances.
DOI: 10.1126/sciadv.adu4369
Joshua Stoolman, PhD, a research associate in the Chandel laboratory, was lead author of the study.
Co-authors include Rogan Grant, PhD, a Schmidt Science Fellow at Northwestern, Samuel Weinberg, ‘19 MD, ‘19 PhD, assistant professor of Pathology in the Division of Experimental Pathology, Jason Miska, PhD, assistant professor of Neurological Surgery, and Scott Budinger, MD, the Ernest S. Bazley Professor of Airway Diseases and chief of Pulmonary and Critical Care in the Department of Medicine.
This work was supported by the National Institutes of Health grants 2P01AG049665-06, 5P01HL154998, NI2T32AI083216-11, 1S10OD011996-01, 5P01HL154998 and 5T32HL076139-18; National Cancer Institute grants CCSG P30 CA060553, CCSG P30 CA060553 and 1S10OD011996-01; and Schmidt Science Fellows, in partnership with the Rhodes Trust.
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