Study Explains How "Leaky" Mitochondria Drive Inflammation and Disease

A new study from University of Virginia School of Medicine researchers explains how dysfunctional mitochondria can result in inflammation linked to conditions like lupus and rheumatoid arthritis. This newfound understanding opens avenues for developing improved treatments for these diseases, enhancing antiviral defenses, and potentially slowing down aging processes. 

“When mitochondria don’t correctly replicate their genetic material, they try to eliminate it. However, if this is happening too often and the cell can’t dispose of all of it, it can cause inflammation, and too much inflammation can lead to disease, including autoimmune and chronic diseases,” said Laura E. Newman, first author of the paper published in Nature Cell Biology. “Now that we are beginning to understand how this inflammation starts, we might be able to prevent this process, with the ultimate goal of limiting inflammation and treating disease.”

Mitochondria have their own set of genetic material, separate from the DNA that serves as the operating instructions for our cells. Scientists have known that this mitochondrial DNA, known as mtDNA, can escape into our cells and cause inflammation. But exactly what caused this has been a mystery until now.

The team used sophisticated imaging techniques to determine what was happening inside the leaky mitochondria. They found that the leak was triggered by a malfunction in mtDNA replication. This caused the accumulation of protein masses caused nucleoids. To try to fix this problem, the cell containing the faulty mitochondrion begins to export the excess nucleoids to its cellular trash bins. But the trash bins, called endosomes, can become overwhelmed by the volume of debris, the scientists found. These overburdened endosomes respond by releasing mtDNA into the cell—in short, the trash can overflows.

“Using our cutting-edge imaging tools for probing mitochondria dynamics and mtDNA release, we have discovered an entirely novel release mechanism for mtDNA,” explained author Uri Manor. “There are so many follow-up questions we cannot wait to ask, like how other interactions between organelles control innate immune pathways, how different cell types release mtDNA, and how we can target this new pathway to reduce inflammation during disease and aging.”