New Mitochondrial Response Pathway May Advance Treatments for Inflammatory Diseases

In a study published on Immunity, University of California San Diego researchers described the biochemical pathway that results in the generation of oxidized mtDNA, how mitochondria expel it and cause the powerful and catastrophic inflammatory response observed in autoimmune conditions like lupus and rheumatoid arthritis.

Each mitochondrion contains copies of mitochondrial DNA (mtDNA). In response to cell damage or stress, mtDNA is expelled from the mitochondrion, oxidized, cleaved, and then triggers immune and inflammatory responses. mtDNA release into the cytosol or bloodstream can occur as a response to sepsis, traumatic injury, or cytotoxicity. While the concentration of circulating oxidized mtDNA in the bloodstream corresponds with the severity of autoimmune conditions, scientists are still unsure if mtDNA is simply a biomarker or if it plays a significant role in disease pathology.

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Critical Role of FEN1 in Fueling the “Auto-Inflammatory Fire”

The researchers discovered that when macrophages come in contact with metabolic stress/danger signals, the mitochondria reacted to take up calcium ions from the cytosol, resulting in the generation and release of oxidized mtDNA (Ox-mtDNA) through the opening of mitochondrial permeability transition pores.

However, oxidized mitochondrial DNA is large, making it unlikely to escape via the pores on the mitochondrial membrane. The team identified that endonuclease FEN1 is responsible for cleaving large mtDNA into smaller segments, allowing escape and leading to further inflammatory activations. These smaller mtDNA fragments then go on to activate NLRP3 and cGAS, NLRP3 is part of a multi-protein complex called the inflammasome that activates inflammatory responses, while cGAS is an enzyme that generates a small molecule that acts as a chemical messenger to encourage the production of other cytokines. Overexcitation of both NLRP3 and cGAS is characteristic in patients with autoimmune diseases, where the immune system attacks normal body tissues.

These new findings shed light on how mitochondria affect the immune system with the pathway, FEN1’s role in triggering the immune cascade, and how possible therapeutic interventions may be developed for autoimmune diseases such as lupus and arthritis.

Author

Fujie Tham