ScienceDaily: How mitochondrial injury ignites the ‘autoinflammatory fire’


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Mitochondria (which are self-contained organelles with their own mini-chromosomes, DNA) are embedded within cells. They are responsible for generating the chemical energy necessary to fuel essential functions of life and well being.

When mitochondria are damaged, stressed, or dysfunctional, they expel their DNA (“mtDNA”), which is oxidized, cleaved and released into the cell’s cytosol (the fluid in a cell in the organelles float) and then into the bloodstream to trigger inflammation. The severity of disease, flare-ups, and the ability to respond to treatments are all affected by autoimmune conditions such as Lupus or rheumatoid.

Unanswered questions in this field include whether oxidized mitochondrial DNA is a biomarker of disease or an indicator.

A new study has been published in the July 13, 20,22 issue of the journal. Immunity,Researchers at University of California San Diego School of Medicine have shared their biochemical pathway, which results in the creation of oxidized mitochondrial DNA. They also describe how mitochondria expel it and how this triggers the complex and destructive inflammation response.

“In addition to charting a new pathway responsible for the generation of inflammation-provoking fragments of oxidized mtDNA, this work opens the door to the development of new anti-inflammatory agents,” said senior study author Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology at UC San Diego School of Medicine.

Macrophages, a white blood cell type that detects infection and tissue damage and marshals immune system cells to react, are quick to take up calcium ions from cytosol. This causes the formation of reactive oxygen substances that leads to oxidized mitochondrial DNA and opens pores in mitochondrial membranes that allow for oxidized mitochondrial DNA escape.

“However, this oxidized mtDNA can be difficult to pass through mitochondrial pores so it must be broken down into smaller pieces,” Hongxu Xian PhD, first author of the study and a postdoctoral fellow in Karin’s lab. FEN1 is the enzyme that does this job.

FEN1 cuts mtDNA fragments into small pieces. These fragments are then oxidized and enter the cytosol, where they can bind to NLRP3 or cGAS. NLRP3 forms part of a multiprotein complex called the Inflammasome. It activates inflammatory response. cGAS, an enzyme that produces a small molecule that acts like a chemical messenger in order to encourage the production of other Cytokines — proteins that stimulate or recruit immune cells.

Together, NLRP3 & cGAS trigger inflammation. In autoimmune diseases, this has typically run amok. This causes the immune system’s attack on healthy cells and tissues.

Xian said that the new findings highlight FEN1’s critical role in promoting “auto-inflammatory fire.” Xian and his colleagues have shown that FEN1 inhibitors can block NLRP3 signaling and cGAS signaling, preventing the onset and progression of inflammation.

“This work is significant not only because it explains the origin and pathogenesis of common rheumatic disorders, but also because it could lead to the development of novel biomarkers or treatments for lupus,” Monica Guma MD PhD, an associate Professor in the UC San Diego School of Medicine. She was not involved with the study.

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MaterialsProvided by University of California, San Diego. Original by Scott LaFee Notice: Content can be edited to improve style and length.


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