‘Leaky’ Mitochondria Can Make Us Sick And Age

"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 researcher Laura E. Newman, PhD, of the University of Virginia School of Medicine. "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 called mtDNA that is separate from DNA that serves as the operating instructions for our cells, and when the mtDNA escapes into our cells it causes inflammation. However, until now what exactly causes this has been a mystery. Using sophisticated imaging techniques, the researchers found that the leak was triggered by a malfunction in mtDNA replication, causing the accumulation of masses of nucleoid proteins. 

According to the researchers, to try and fix this the cell containing the faulty mitochondria begins to export the excess nucleoids to its cellular trash bins (endosomes), but they can become overwhelmed by the volume of debris and respond by releasing mtDNA into the cell. Then the cell responds to the trash overflow of hazardous waste by flagging the nucleoids as foreign DNA, as it would for a virus, and launches an immune response that results in harmful inflammation. 

"We knew that mtDNA was escaping mitochondria, but how was still unclear," said Gerald Shadel, PhD, director of the San Diego-Nathan Shock Center of Excellence in the Basic Biology of Aging at the Salk Institute. "Using imaging and cell biology approaches, we're able to trace the steps of the pathway for moving mtDNA out of the mitochondria, which we can now try to target with therapeutic interventions to hopefully prevent the resulting inflammation."

"We had a huge breakthrough when we saw that mtDNA was inside of a mysterious membrane structure once it left mitochondria. After assembling all of the puzzle pieces, we realized that structure was an endosome," Newman said. "That discovery eventually led us to the realization that the mtDNA was being disposed of and, in the process, some of it was leaking out."

"Using our cutting-edge imaging tools for probing mitochondria dynamics and mtDNA release, we have discovered an entirely novel release mechanism for mtDNA," said researcher Uri Manor, PhD, former director of the Waitt Advanced Biophotonics Core at Salk and current assistant professor at UC San Diego. "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."

"We want to understand the physiological and disease contexts where this process can become activated," said Newman. "For example, many viruses attack mitochondria during infection, so we will be testing whether mitochondria purposely use this pathway to sound the alarm against invading viruses, and whether over-reliance on this pathway to fight off infection can later trigger chronic diseases.”