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

AbstractMitochondria 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 increasedTnf α and decreasedTrem2 mRNA, increased GFAP protein, and increased NF κB phosphorylation. Some of these effects were also observed in brains injected with mtDNA (decreasedTrem2 mRNA, increased GFAP protein, and increased NF κB 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 dysf unction, and neuroinflammation we also measuredApp mRNA, APP protein, and A β1 –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.
Source: Journal of NeuroImmune Pharmacology - Category: Drugs & Pharmacology Source Type: research