Endosomes (magenta) collect around mitochondria (blue) after infection with virus HSV-1, which attacks mtDNA (green) and causes its release. Credit: Salk Institute
One of the ways our cells respond to damage and infection is with what’s known as the innate immune system. While the innate immune response is the first line of defense against viruses, it can also respond to molecules the body makes that simply resemble pathogens—including misplaced mtDNA. This response can lead to chronic inflammation and contribute to human diseases and aging.
Scientists have been working to uncover how mtDNA leaves mitochondria and triggers the innate immune response, but the previously characterized pathways did not apply to the unique mtDNA stress conditions the research team was investigating. So, they turned to sophisticated imaging techniques to gather clues as to where and when things were going awry in those 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 first author Laura Newman, former postdoctoral researcher in Shadel’s lab and current 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 team discovered a process beginning with a malfunction in mtDNA replication that caused mtDNA-containing protein masses called nucleoids to pile up inside of mitochondria. Noticing this malfunction, the cell then begins to remove the replication-halting nucleoids by transporting them to endosomes, a collection of organelles that sort and send cellular material for permanent removal. The endosome gets overloaded with these nucleoids, springs a leak and mtDNA is suddenly loose in the cell. The cell flags that mtDNA as foreign DNA—the same way it flags a virus’ DNA—and initiates the DNA-sensing cGAS-STING pathway to cause inflammation.
The researchers hope to map out more of this complicated mtDNA-disposal and immune-activation pathway, including what biological circumstances—like mtDNA replication dysfunction and viral infection—are required to initiate the pathway and what downstream effects there may be on human health. They also see an opportunity for therapeutic innovation using this pathway, which represents a new cellular target to reduce inflammation.
Other authors include Sammy Weiser Novak, Gladys Rojas, Nimesha Tadepalle, Christina Towers, Matthew Donnelly, Sagnika Ghosh, Sienna Rocha, and Ricardo Rodriguez-Enriquez of Salk; Danielle Grotjahn and Michaela Medina of The Scripps Research Institute; Marie-Ève Tremblay of the University of Victoria in Canada; Cara Schiavon and Joshua Chevez of UC San Diego; and Ian Lemersal of the La Jolla Institute for Immunology.
The work was supported by the National Institutes of Health (R01 AR069876, P30AG068635, 1K99GM141482, 1F32GM137580, T32GM007198, 5R00CA245187, and 5R00CA245187-04S1), an Allen-AHA Initiative in Brain Health and Cognitive Impairment award (19PABH134610000H), a National Science Foundation NeuroNex Award (2014862), Chan-Zuckerberg Initiative Imaging Scientist Award, the LIFE Foundation, a George E. Hewitt Foundation for Medical Research Postdoctoral Fellowship, Paul F. Glenn Foundation for Medical Research Postdoctoral Fellowship, Salk Pioneer Fund Postdoctoral Scholar Award, the Waitt Foundation, Yale University School of Medicine Center for Cellular and Molecular Imaging, a Canada Research Chair (Tier 2) in Neurobiology of Aging and Cognition, and a Canada Foundation for Innovation John R. Evans Leaders Fund (grant 39965).
— Adapted from a Salk Institute release
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