In a groundbreaking study, researchers from the Salk Institute and the University of California San Diego have identified a new pathway used by cells to remove dysfunctional mitochondrial DNA (mtDNA) from within mitochondria. The discovery sheds light on how misplaced mtDNA triggers an immune response that promotes inflammation, opening up possibilities for therapeutic interventions to mitigate inflammation associated with aging and diseases like lupus and rheumatoid arthritis. The findings were published in Nature Cell Biology.
Mitochondria, the powerhouses of cells, possess their own unique set of genetic instructions known as mtDNA, distinct from the nuclear DNA of the cell. While properly confined within mitochondria, mtDNA supports the overall health of both mitochondria and cells. However, when mtDNA escapes its designated location, it can initiate an immune response that triggers inflammation.
Led by senior and co-corresponding author Professor Gerald Shadel, the researchers set out to unravel the mystery of how mtDNA leaves mitochondria and activates the innate immune response. Previous pathways identified did not account for the specific stress conditions affecting mtDNA under examination. Employing advanced imaging techniques, the team observed that mtDNA was contained within a membrane structure resembling an endosome once it departed from mitochondria.
Further investigations revealed a cascade of events: an error in mtDNA replication caused protein clusters called nucleoids, containing mtDNA, to accumulate within mitochondria. The cell recognized this malfunction and initiated the removal of nucleoids by transporting them to endosomes, which serve as organelles responsible for sorting and eliminating cellular material. As the endosome became overwhelmed with nucleoids, it developed a leak, allowing mtDNA to escape into the cell.
Interestingly, the cell identified the released mtDNA as foreign DNA, triggering the same response employed against viral DNA. This activated the DNA-sensing cGAS-STING pathway, leading to inflammation. The study’s first author, Laura Newman, highlighted the significance of this discovery, emphasizing the crucial role played by endosomes in facilitating mtDNA disposal.
Building on their cutting-edge imaging tools for investigating mitochondria dynamics and mtDNA release, the researchers not only uncovered the novel mechanism of mtDNA release but also outlined numerous follow-up questions. They aim to explore how organelle interactions influence innate immune pathways, understand the different mtDNA release processes in various cell types, and develop strategies to target this newfound pathway to reduce inflammation in the context of diseases and aging.
The team envisions mapping out the intricate details of the mtDNA-disposal and immune activation pathway, including identifying the biological triggers that initiate the pathway and exploring potential downstream effects on human health. Additionally, they foresee the opportunity for therapeutic advancements by targeting this pathway, presenting a new cellular approach to combat inflammation.
The findings of this study provide valuable insights into the fundamental mechanisms underlying mtDNA release and inflammation initiation. As further research unfolds, the potential for targeted therapeutics to disrupt this pathway holds promise for alleviating inflammation associated with aging and various diseases.
For more information, refer to the study titled “Mitochondrial DNA replication stress enacts an endosomal pathway of nucleoid disposal prone to innate immune system activation” published in Nature Cell Biology (2024). DOI: 10.1038/s41556-023-01343-1.
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