title: Extracellular Mitochondria and Mitochondrial Components Act as Damage-Associated Molecular Pattern Molecules in the Mouse Brain.
abstract: 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 Aβ1-42levels. 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.
authors: Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA.|University of Kansas Alzheimer's Disease Center, Kansas City, KS, USA.
authors: Heather M
authors: HM
authors: Wilkins
authors: Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA.|University of Kansas Alzheimer's Disease Center, Kansas City, KS, USA.
authors: Scott J
authors: SJ
authors: Koppel
authors: University of Kansas Alzheimer's Disease Center, Kansas City, KS, USA.|Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
authors: Ian W
authors: IW
authors: Weidling
authors: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
authors: Nairita
authors: N
authors: Roy
authors: University of Kansas Alzheimer's Disease Center, Kansas City, KS, USA.
authors: Lauren N
authors: LN
authors: Ryan
authors: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
authors: John A
authors: JA
authors: Stanford
authors: Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA. rswerdlow@kumc.edu.|University of Kansas Alzheimer's Disease Center, Kansas City, KS, USA. rswerdlow@kumc.edu.|Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA. rswerdlow@kumc.edu.|Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA. rswerdlow@kumc.edu.|University of Kansas School of Medicine, MS 2012, Landon Center on Aging, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA. rswerdlow@kumc.edu.
authors: Russell H
authors: RH
authors: Swerdlow
mesh_terms: D000067531:Alarmins / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004272:DNA, Mitochondrial / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D045604:Extracellular Fluid / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*
chemical_list: D000067531:Alarmins; D004272:DNA, Mitochondrial; D018836:Inflammation Mediators
keywords: Alzheimer’s disease (AD); Amyloid precursor protein (APP); Damage associated molecular pattern (DAMP); Mitochondria; Mitochondrial DNA (mtDNA); Neuroinflammation