Mitochondria are structures within cells that convert energy from food into a form that the cell can use. Most DNA is packaged in chromosomes within the nucleus, but mitochondria also have small amounts of their own DNA. Mitochondrial DNA (mtDNA) contains 37 genes, all of which are essential for normal mitochondrial function. When mtDNA stays where it’s supposed to be (inside the mitochondria), both mitochondria and cells remain healthy. However, if it invades other than its natural location, it can mount an immune response that promotes inflammation.
Now, Salk scientists and colleagues at the University of California, San Diego (UCSD) have discovered a new mechanism used to remove improperly functioning mtDNA from inside mitochondria to the outside. When this happens, mtDNA is flagged as foreign DNA and activates cellular pathways used to promote inflammation to remove pathogens from cells.
Their discovery is natural cell biology In an article titled “Mitochondrial DNA replication stress establishes an endosomal pathway for nucleoid processing prone to trigger activation of the innate immune system”
“The relationship between aberrant mitochondria and nucleoid dynamics, mtDNA release, and cGAS-STING activation remains unclear,” the researchers said in their study. Here we show that enlarged nucleoids that remain bound to TFAM exit mitochondria under various mtDNA replication stress conditions and during herpes simplex virus-1 infection. ”
“We knew that mtDNA was escaping from the mitochondria, but we still didn’t know how it was escaping from the mitochondria,” said the study’s senior and co-corresponding author and professor of medicine. , explains Dr. Gerald Schedel, director of the San Diego Nathan Schock Center of Excellence for Basic Biology. Senior citizen and holder of the Audrey Geisel Chair in Biomedical Sciences at Salk University. “Using imaging and cell biology approaches, we can track the steps in the pathway that moves mtDNA out of mitochondria, and we can target it with therapeutic interventions to prevent the resulting inflammation. Now.”
Scientists have been working to determine how mtDNA leaves mitochondria and triggers the innate immune response, but the previously characterized pathway was the one the Salk team was investigating. This was not the case for unique mtDNA stress conditions.
“We made a huge breakthrough when we determined that mtDNA resides in a mysterious membrane structure after it leaves the mitochondria. After assembling all the puzzle pieces, we realized that the structure was an endosome. ,” said lead author and former postdoctoral fellow Dr. Laura Newman. She was a researcher in Schaedel’s lab and is currently an assistant professor at the University of Virginia. “This discovery ultimately led to the realization that her mtDNA was being discarded and some of it was being leaked in the process.”
The researchers discovered a process that begins with a malfunction in mtDNA replication, causing mtDNA-containing protein clumps called nucleoids to accumulate inside mitochondria. The cell then begins to remove the non-replicating nucleoids by transporting them to endosomes. Endosomes become overloaded with these nucleoids, resulting in leakage and mtDNA suddenly becoming free within the cell. The cell flags the mtDNA as foreign DNA and initiates the DNA-sensing cGAS-STING pathway, causing inflammation.
“By using state-of-the-art imaging tools to examine mitochondrial dynamics and mtDNA release, we discovered an entirely new release mechanism for mtDNA,” said co-corresponding author and director of Waite Advanced Biotechnology at Salk University. added Dr. Uri Manar, former director and current head of the Photonics Core. Assistant Professor at UCSD. “How other interactions between organelles control innate immune pathways, how different cell types release mtDNA, and how this new pathway can be used to reduce inflammation during disease and aging. There are a lot of follow-up questions that we can’t wait to ask, including whether they can be targeted like this.”
The researchers are currently investigating mtDNA disposal and research, including what biological environment is required to initiate this pathway and what downstream effects may occur on human health. We would like to elucidate the immune activation pathway in more detail. The findings provide new targets for therapeutics to disrupt inflammatory pathways and reduce inflammation during aging and diseases such as lupus and rheumatoid arthritis.
