Unlocking the Healing Power of Mitochondria: A New Frontier in Treating Inflammatory Diseases

Researchers in the lab of Navdeep Chandel, PhD, the David W. Cugell, MD, Professor of Medicine in the Division of Pulmonary and Critical Care, have identified the mechanism by which mitochondria affect the immune response of the body through the modulation of particular cell signaling pathways, according to a recent study released in Science Advances.  

The results emphasize the opportunity to target mitochondrial functionality particularly in immune cells to combat a variety of inflammation-related disorders.  

“Treatments focused on enhancing mitochondrial performance could aid inflammatory conditions such as inflammatory bowel disease, sepsis, and prolonged infections by bolstering the immune system’s capability to handle inflammation,” remarked Chandel, who also serves as a professor of Biochemistry and Molecular Genetics and is a member of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.  

Mitochondria harbor the mitochondrial electron transport chain (ETC), a series of protein complexes through which electrons traverse, generating ATP, or cellular energy. Functionality of the mitochondrial ETC also regulates macrophages, specialized immune cells vital in combating infections and managing inflammation within the organism.  

Macrophages are responsible for releasing an anti-inflammatory protein known as IL-10, which mitigates inflammation and curtails excessive immune reactions that may cause harm to the body. Nonetheless, the precise mechanisms that permit mitochondrial ETC to govern macrophage immune reactions have largely remained elusive.  

Utilizing bulk-RNA sequencing to investigate mice lacking mitochondrial ETC complex III in their macrophages, researchers found that a specific type of reactive oxygen species (ROS)—unstable molecules containing oxygen that readily react with other cellular molecules—produced by mitochondrial complex III, referred to as superoxide, is crucial for macrophages to secrete IL-10. 

Additionally, the researchers identified that mice with flawed mitochondrial complexes faced difficulties in recovering from infections and inflammation as their cells released diminished levels of IL-10. Nevertheless, activating a specific ROS-dependent signaling pathway within the cells reinstated IL-10 secretion, as noted in the study. 

“This discovery underscores an unrecognized link between mitochondrial function, the regulation of inflammation, and the signaling pathways that modulate it,” highlighted Chandel. 

In summary, the results accentuate the critical role of mitochondria extending beyond mere energy synthesis and indicate that mitochondria could serve as a beneficial therapeutic focus for addressing various inflammatory disorders and enhancing current treatments, as per Chandel. 

“Increasing IL-10 levels via mitochondrial pathways holds potential for the management of autoimmune diseases such as rheumatoid arthritis and lupus, wherein the immune system erroneously attacks the body. Enhancing the function of mitochondrial complex III, or mirroring its influences, may also accelerate recovery from severe infections. Moreover, inhibiting mitochondrial complex III could reduce IL-10 mediated inflammation suppression and complement existing immunotherapeutic approaches,” stated Chandel. 

Joshua Stoolman, PhD, a research associate in the Chandel laboratory, served as the 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 research received backing from 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 collaboration with the Rhodes Trust.