The mitochondria: the proverbial powerhouse of the cell. Of course, mitochondria are so much more than that single phrase we learn in high school biology class. Mitochondria also have their own DNA (mtDNA) which is wholly separate from the rest of the body’s nuclear DNA. In a groundbreaking discovery, researchers have uncovered a delicate balance between mitochondrial integrity and cellular health. When mtDNA doesn’t go where it’s supposed to, it can cause an inflammatory response that negatively impacts a person’s health.  

Researchers from the Salk Institute and UC San Diego have found a novel mechanism responsible for banishing dysfunctional mtDNA from the mitochondria. Once expelled, this aberrant mtDNA is labeled as “foreign” by the rest of the body’s immune system. This causes a cascade of events, activating cellular pathways typically associated with inflammation to combat foreign invaders such as viruses.

Published in Nature Cell Biology, the findings unveil potential therapeutic targets aimed at disrupting this inflammatory pathway, offering promise for alleviating inflammation associated with aging and diseases like lupus or rheumatoid arthritis.

“We knew that mtDNA was escaping mitochondria, but how was still unclear,” says Professor Gerald Shadel, senior and co-corresponding author and director of the San Diego-Nathan Shock Center of Excellence in the Basic Biology of Aging at Salk. “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.”

The innate immune system, our body's frontline defense against pathogens, also responds to molecules resembling pathogens, including displaced mtDNA. This response, while crucial for combating infections, can inadvertently lead to chronic inflammation and exacerbate various diseases.

Driven by the need to understand how mtDNA escapes mitochondria and triggers immune responses, the researchers employed sophisticated imaging techniques to unravel the mysteries within mitochondria.

"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,” says Laura Newman, lead author and assistant professor at the University of Virginia. “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.”

The study describes a process initiated by malfunctions in mtDNA replication, leading to the accumulation of nucleoids within mitochondria. Subsequently, the cell expels these nucleoids to endosomes for permanent removal. However, an overload of nucleoids causes endosomes to leak, releasing mtDNA into the cell and prompting an immune response.

“Using our cutting-edge imaging tools for probing mitochondria dynamics and mtDNA release, we have discovered an entirely novel release mechanism for mtDNA,” says co-corresponding author Uri Manor, 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.”

Looking ahead, the researchers aim to elucidate the intricacies of this mtDNA-disposal and immune-activation pathway, exploring its role in various biological contexts and its potential for therapeutic interventions. This discovery opens avenues for innovative approaches to alleviate inflammation and combat age-related diseases.

‍