Researchers in the US have discovered how ‘leaky’ human mitochondria – the cells’ energy factories – can lead to inflammation in autoimmune diseases such as lupus and rheumatoid arthritis.
The new finding published in the journal “Nature Cell Biology” may lead to the development of better treatments for these diseases, to an improvement in the human body’s ability to fight viruses and to a slowing of aging.
Destructive immune response
The new discovery reveals how genetic material can ‘escape’ from our cellular ‘batteries’ known as mitochondria and trigger a devastating immune response.
By developing treatments that target this process in the future, experts may one day be able to put a “brake” on harmful inflammation, thus preventing the heavy costs it entails for the human body.
Causing autoimmune and chronic diseases
“When mitochondria don’t copy their genetic material properly, they try to … get rid of it by leaking it into the cell.
However, if this happens too often and the cell cannot remove all of this material, inflammation is caused – in turn, high levels of inflammation can lead to diseases including autoimmune and chronic diseases,” said researcher Dr Laura Newman from the Department of Cytology of Biology at the University of Virginia School of Medicine and added: “Now that we are beginning to understand how this inflammation starts, we may be able to prevent this process with the ultimate goal of reducing inflammation and treating disease.”
The mystery of mitochondrial DNA leakage
Mitochondria have their own genetic material that is separate from that which acts as the… instruction sheet for our cells. Scientists knew that this mitochondrial DNA could leak into cells and cause inflammation. However, what exactly causes this leak has been a mystery until today.
Towards new therapeutic interventions
“We knew that mitochondrial DNA was leaking from the mitochondria, but how this was happening remained unclear,” noted Dr. Gerald Sandel, director of the Salk Institute’s San Diego-Nathan Shock Center of Excellence in the Basic Biology of Aging. The researcher added that “using imaging and cell biology approaches, we were able to follow the mitochondrial DNA transport pathway out of the mitochondria step by step. So we can now try to target this pathway with therapeutic interventions to prevent the inflammation that is the result of mitochondrial DNA ‘leakage'”
Dysfunction in mitochondrial DNA replication
Dr. Sandel and Dr. Newman (who was a postdoctoral researcher in Dr. Sandel’s lab when the study was conducted) and their colleagues used sophisticated imaging techniques to determine what is happening in the “leaky” mitochondria. They discovered that the leak is triggered by a malfunction in the replication of mitochondrial DNA resulting in the accumulation of protein masses called nucleoids.
THE…. overflowed cellular dustbin
To try to solve this problem, the cells containing the defective mitochondria begin to export the extra nucleoids to the cellular “waste basket” they have. However, these “garbage cans” called endosomes can … overflow from the large volume of garbage, scientists have seen. And when they… overflow they start releasing mitochondrial DNA into the cell. The cell reacts to this “garbage attack” by marking the nucleoids as foreign DNA (commonly as an invader such as a virus) and unleashes an immune response that leads to harmful inflammation.
The goal is to reduce inflammation in diseases and aging
“Using our advanced imaging tools we have discovered a completely new mechanism of mitochondrial DNA release,” said Uri Manor, assistant professor at the University of California, San Diego, one of the authors of the study, and added: “There are so many questions that are now being raised as how other interactions between organelles control innate immunity pathways, how different cell types secrete mitochondrial DNA, and how we can target the new pathway we discovered to reduce inflammation in both disease and aging.”
Viral invasion, the mitochondrial pathway and chronic diseases
Dr. Newman will look for these answers next time to shed light on different diseases. As he said, for example, “many viruses attack mitochondria during infection, so we will examine whether mitochondria use this pathway to signal viral invasion and whether overactivation of this pathway can later lead to chronic diseases”.
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