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SS-31 inhibits mtDNA-cGAS-STING signaling to improve POCD by activating mitophagy in aged mice
Yelong Ji1, Yuanyuan Ma1, Yimei Ma1
1Department of Anesthesia, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai, 200032, China.
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.
Insights
SS-31, a mitochondrion-targeted antioxidant, protects against postoperative cognitive dysfunction (POCD) by activating mitophagy and reducing neuroinflammation. It inhibits the cGAS-STING pathway and M1 microglial polarization, offering neuroprotection.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Neuroinflammation and microglial activation are key in postoperative cognitive dysfunction (POCD).
- SS-31, a mitochondrion-targeted antioxidant, is investigated for neurodegenerative and inflammatory diseases.
- The study explores SS-31's neuroprotective role and mechanism in POCD.
Purpose of the Study:
- To investigate the neuroprotective effects of SS-31 against surgery-induced neurocognitive dysfunction.
- To elucidate the underlying mechanism involving mitophagy, mitochondrial DNA (mtDNA) release, and the cGAS-STING pathway.
- To determine SS-31's impact on microglial polarization in the context of POCD.
Main Methods:
- Tibial fracture surgery in aged mice to induce POCD.
- In vitro induction of neuroinflammation in BV2 cells using LPS.
- Evaluation of neurobehavior, hippocampal injury, protein expression, mitophagy, and cell states following SS-31, PHB2 siRNA, or STING agonist treatment.
Main Results:
- SS-31 treatment improved neural damage in surgically aged mice by activating mitophagy via PHB2 interaction.
- Reduced cGAS-STING pathway activation and M1 microglial polarization were observed, linked to decreased mtDNA release.
- Knockdown of PHB2 or STING agonist administration negated SS-31's protective effects in vitro.
Conclusions:
- SS-31 confers neuroprotection against POCD.
- This protection is mediated by PHB2-activated mitophagy, inhibiting mtDNA release.
- SS-31 suppresses the cGAS-STING pathway and M1 microglial polarization, mitigating neuroinflammation.
