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Inflammation Research
Erschienen in:

27.02.2024 | Original Research Paper

SS-31 inhibits mtDNA–cGAS–STING signaling to improve POCD by activating mitophagy in aged mice

verfasst von: Yelong Ji, Yuanyuan Ma, Yimei Ma, Ying Wang, Xining Zhao, Danfeng Jin, Li Xu, Shengjin Ge

Erschienen in: Inflammation Research | Ausgabe 4/2024

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Abstract

Background

Neuroinflammation is crucial in the development of postoperative cognitive dysfunction (POCD), and microglial activation is an active participant in this process. SS-31, a mitochondrion-targeted antioxidant, is widely regarded as a potential drug for neurodegenerative diseases and inflammatory diseases. In this study, we sought to explore whether SS-31 plays a neuroprotective role and the underlying mechanism.

Methods

Internal fixation of tibial fracture was performed in 18-month-old mice to induce surgery-associated neurocognitive dysfunction. LPS was administrated to BV2 cells to induce neuroinflammation. Neurobehavioral deficits, hippocampal injury, protein expression, mitophagy level and cell state were evaluated after treatment with SS-31, PHB2 siRNA and an STING agonist.

Results

Our study revealed that SS-31 interacted with PHB2 to activate mitophagy and improve neural damage in surgically aged mice, which was attributed to the reduced cGAS–STING pathway and M1 microglial polarization by decreased release of mitochondrial DNA (mtDNA) but not nuclear DNA (nDNA). In vitro, knockdown of PHB2 and an STING agonist abolished the protective effect of SS-31.

Conclusions

SS-31 conferred neuroprotection against POCD by promoting PHB2-mediated mitophagy activation to inhibit mtDNA release, which in turn suppressed the cGAS–STING pathway and M1 microglial polarization.
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Metadaten
Titel
SS-31 inhibits mtDNA–cGAS–STING signaling to improve POCD by activating mitophagy in aged mice
verfasst von
Yelong Ji
Yuanyuan Ma
Yimei Ma
Ying Wang
Xining Zhao
Danfeng Jin
Li Xu
Shengjin Ge
Publikationsdatum
27.02.2024
Verlag
Springer International Publishing
Erschienen in
Inflammation Research / Ausgabe 4/2024
Print ISSN: 1023-3830
Elektronische ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-024-01860-1

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