Extracellular Mitochondria and Mitochondrial Components Act as Damage-Associated Molecular Pattern Molecules in the Mouse Brain

Mitochondria and mitochondrial debris are found in the brain’s extracellular space, and extracellular mitochondrial components can act as damage associated molecular pattern (DAMP) molecules. To characterize the effects of potential mitochondrial DAMP molecules on neuroinflammation, we injected eith...

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Bibliographic Details
Published in:Journal of neuroimmune pharmacology 2016-12, Vol.11 (4), p.622-628
Main Authors: Wilkins, Heather M., Koppel, Scott J., Weidling, Ian W., Roy, Nairita, Ryan, Lauren N., Stanford, John A., Swerdlow, Russell H.
Format: Article
Language:English
Subjects:
Alarmins - metabolism
Animals
Biomedical and Life Sciences
Biomedicine
Brain
Brain - metabolism
Brain - pathology
Brief Report
Cell Biology
DNA, Mitochondrial - administration & dosage
DNA, Mitochondrial - metabolism
DNA, Mitochondrial - toxicity
Extracellular Fluid - metabolism
Immunology
Inflammation - chemically induced
Inflammation - metabolism
Inflammation - pathology
Inflammation Mediators - metabolism
Male
Mice
Mice, Inbred C57BL
Mitochondria
Mitochondria - metabolism
Mitochondrial DNA
Neurosciences
Pharmacology/Toxicology
Phosphorylation
Proteins
Rodents
Virology
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Summary:Mitochondria and mitochondrial debris are found in the brain’s extracellular space, and extracellular mitochondrial components can act as damage associated molecular pattern (DAMP) molecules. To characterize the effects of potential mitochondrial DAMP molecules on neuroinflammation, we injected either isolated mitochondria or mitochondrial DNA (mtDNA) into hippocampi of C57BL/6 mice and seven days later measured markers of inflammation. Brains injected with whole mitochondria showed increased Tnfα and decreased Trem2 mRNA, increased GFAP protein, and increased NFκB phosphorylation. Some of these effects were also observed in brains injected with mtDNA (decreased Trem2 mRNA, increased GFAP protein, and increased NFκB phosphorylation), and mtDNA injection also caused several unique changes including increased CSF1R protein and AKT phosphorylation. To further establish the potential relevance of this response to Alzheimer’s disease (AD), a brain disorder characterized by neurodegeneration, mitochondrial dysfunction, and neuroinflammation we also measured App mRNA, APP protein, and Aβ 1–42 levels. We found mitochondria (but not mtDNA) injections increased these parameters. Our data show that in the mouse brain extracellular mitochondria and its components can induce neuroinflammation, extracellular mtDNA or mtDNA-associated proteins can contribute to this effect, and mitochondria derived-DAMP molecules can influence AD-associated biomarkers.
ISSN:1557-1890
1557-1904
DOI:10.1007/s11481-016-9704-7