Scientists have discovered a new way in which misplaced mitochondrial DNA (mtDNA) can be a cause of inflammation, which may equip clinicians with the tools to use these diseases as therapeutic interventions against inflammation associated with aging and other diseases. Credit: SciTechDaily.com.
Salk scientists show a pathway for mouse cell inflammation – the pathway from mitochondrial stress through to leaking endosomes to the start of the immune system – which shows new potential targets for reducing inflammation in aging and disease.
Power-generating mitochondria in the human body contain different mtDNA motifs, distinct from nuclear DNA, that assist mitochondria in creating life-giving energy. If the mtDNA stays in place (inside mitochondria), it helps maintain mitochondrial and cellular health, but if it exits the system, it can trigger an immune response that promotes inflammation.
A new technique has been identified by scientists from UC San Diego and Salk, which allows the removal of incorrectly functioning mitochondrial mtDNA. This process detects the mtDNA as foreign DNA and triggers a cellular pathway that is typically used to eliminate pathogens such as viruses.
Today (February 8, 2024) the study published in the journal Nature Cell Biology found that many new targets for drugs that could target target the inflammatory pathway to reduce inflammation as people age and with diseases such as lupus or rheumatoid arthritis can be identified.
During HSV-1 infection, mtDNA is attacked and released, resulting in the formation of endosomes (magenta) that encircle mitochondria (green).
According to Professor Gerald Shadel, the senior and co-corresponding author of the study, the mechanism by which mtDNA is expelled from mitochondria had not been fully understood.
Sonnenweiss cells are activated by the innate immune system, which is responsible for protecting our cells from damage and infection. However, this response can also be affected by misplaced mtDNA and other molecules that mimic pathogens in the form of chronic inflammation.
Uri Manor, Laura Newman, Gerald Shadel, and others are featured from left to right. The Salk Institute is the source of the credit for this image.
The Salk team was working on analyzing the peculiar mtDNA stress conditions to understand the processes by which mtDNA leaves mitochondria and activates the innate immune response. Consequently, they utilized advanced imaging techniques to discover the locations of abnormalities in these mitochondria and identify underlying mechanisms.
Laura Newman, a former postdoctoral researcher in Shadel’s lab and current assistant professor at the University of Virginia, conducted a study that was a significant breakthrough. They discovered that the mtDNA was contained within an unfamiliar membrane structure after exiting the mitochondria, and they identified it as an endosome.
The research team observed that mtDNA replication was hindered, leading to the accumulation of nucleoids within mitochondria. The cell then removes these proteins by transporting them to endosomes. When this process is detected, it triggers the loss of mtDNA and signals the initiation of inflammation through the cGAS-STING pathway.
We have utilized our state-of-the-art imaging techniques to investigate mitochondria dynamics and mtDNA release, leading to the identification of an innovative mechanism for mtDNA release.
The researchers aspire to characterize more of the intricate mtDNA-disposal and immune-activation pathway, analyzing the underlying biological factors that initiate this pathway, such as mtDNA replication dysfunction and viral infection, and the potential therapeutic innovation stemming from this pathway.
The innate immune system’s potential activation is linked to mitochondrial DNA replication stress, as reported in Nature Cell Biology. DOI 10.1038/s41556-023-01343-1. 8 February 2024.
Sammy Weiser Novak, Gladys Rojas, Nimesha Tadepalle, Cara Schiavon, Christina Towers, Matthew Donnelly, Sagnika Ghosh, Sienna Rocha, and Ricardo Rodriguez-Enriquez of Salk are among the other authors.
This work was supported by grants from the National Institutes of Health, such as the Neurology and Aging Brain Impairment Research Awards, the NeuroNexus Award, the LAS Award, the UCLA School of Medicine, and the Woodruff Cancer Research Fund.
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