Aging is amongst the strongest risk factors for neurodegenerative disease and elevated Type I interferon (IFN) signaling has been associated with both normal aging and central nervous system (CNS) diseases. Type I IFN is normally produced by nucleated cells in response to the detection of viral pathogen associated molecular patterns (PAMPs) by pathogen recognition receptors (PRRs). More recently it has been appreciated that Type I IFNs are also produced in response to endogenous stimuli, in the absence of viral pathogens. While Type I IFN signaling has been shown to be elevated in human and murine brains during normal aging, the underlying cause was unknown. Here we demonstrate by flow cytometry that aging results in increased size and numbers of mitochondria in the murine brain. Despite identifying increased mitochondrial number and mitochondrial DNA content, we found no change to mitochondrially-encoded transcripts, suggesting either deficits in mitophagy or augmented biogenesis due to insufficient oxidative phosphorylation. Interestingly, mitochondrial numbers correlated with elevated Type I IFN signaling in aging, linking mitochondria to the age-dependent innate immune response in the CNS. Using genetically engineered mice, we excluded roles for two critical innate immune pathways, STING and IRAK4, in the age-dependent increase in Type I IFN signaling in the brain. Notably, we subsequently identified a mitochondrially restricted innate immune protein, mitochondrial antiviral signaling (MAVS) as an essential molecular mediator of the age-dependent Type I IFN response; MAVS deficiency in aged mice restored Type I IFN signaling in the CNS to the levels observed in adult wildtype mice. Further, using intracerebroventricular (icv) administration of antisense oligonucleotides (ASO) as an orthogonal approach, we reduced MAVS transcript and protein expression within the CNS and thereby reduced Type I IFN signaling. Our data demonstrate a specific and selective role of MAVS expression in the CNS in Type I IFN signaling in aging. To investigate the relationship between mitochondrial aging and MAVS activation, we isolated cytoplasmic and mitochondrial RNA from young and aged animals as MAVS is most studied for its response to RNA ligands. Upon transfection into reporter cells, we found that mitochondrial RNA, but not cytoplasmic RNA, from both young and aged mice was sufficient to induce Type I IFN reporter activity in a MAVS-dependent manner. Furthermore, we attempted to mimic the increase of mitochondria observed in the aging CNS by transferring mitochondria from young and aged animals to recipient cells. Mitochondrial transfer also induced MAVS-dependent Type I IFN signaling in wildtype, but not MAVS null, mouse embryonic fibroblasts (MEFs). Collectively, our findings suggest that the accumulation of mitochondria in aging serves as a robust source of MAVS pathway ligands and implicate a novel link between mitochondrial aging and MAVS-mediated innate immune signaling in the CNS.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/45502 |
| Date | 23 January 2023 |
| Creators | Henry, Kate L. |
| Contributors | Wolozin, Benjamin |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | Attribution 4.0 International, http://creativecommons.org/licenses/by/4.0/ |
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