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A Mouse Model of Retinal Ischemia-Reperfusion Injury Through Elevation of Intraocular Pressure
Published on: July 14, 2016
A lncRNA-encoded mitochondrial micropeptide exacerbates microglia-mediated neuroinflammation in retinal
Xintong Zheng1, Mingwei Wang1, Shuting Liu1
1State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China.
Abstract:
As a common pathology of many ocular disorders such as diabetic retinopathy and glaucoma, retinal ischemia/reperfusion (IR) triggers inflammation and microglia activation that lead to irreversible retinal damage. The detailed molecular mechanism underlying retinal IR injury, however, remains poorly understood at present. Here we report the bioinformatic identification of a lncRNA 1810058I24Rik (181-Rik) that was shown to encode a mitochondrion-located micropeptide Stmp1. Its deficiency in mice protected retinal ganglion cells from retinal IR injury by attenuating the activation of microglia and the Nlrp3 inflammasome pathway. Moreover, its genetic knockout in mice or knockdown in primary microglia promoted mitochondrial fusion, impaired mitochondrial membrane potential, and reactive oxygen species (ROS) production, diminished aerobic glycolysis, and ameliorated inflammation. It appears that 181-Rik may trigger the Nlrp3 inflammasome activation by controlling mitochondrial functions through inhibiting expression of the metabolic sensor uncoupling protein 2 (Ucp2) and activating expression of the Ca2+ sensors S100a8/a9. Together, our findings shed new light on the molecular pathogenesis of retinal IR injury and may provide a fresh therapeutic target for IR-associated neurodegenerative diseases.
Insights
Researchers identified a novel long noncoding RNA (181-Rik) and its micropeptide (Stmp1) involved in retinal ischemia/reperfusion injury. Targeting this pathway may offer new treatments for neurodegenerative eye diseases.
Area of Science:
- Ophthalmology
- Neuroscience
- Molecular Biology
Background:
- Retinal ischemia/reperfusion (IR) injury, common in diabetic retinopathy and glaucoma, causes inflammation and microglia activation, leading to irreversible vision loss.
- The precise molecular mechanisms driving retinal IR injury remain largely unknown.
- Microglia activation and inflammasome pathways are implicated in the pathogenesis of retinal IR.
Purpose of the Study:
- To elucidate the molecular mechanisms of retinal IR injury.
- To identify novel molecular targets for therapeutic intervention in IR-associated ocular disorders.
Main Methods:
- Bioinformatic identification of long noncoding RNAs (lncRNAs) and micropeptides.
- Genetic knockout and knockdown studies in mice and primary microglia.
- Assessment of mitochondrial function, including fusion, membrane potential, and reactive oxygen species (ROS) production.
- Analysis of inflammatory markers and inflammasome pathway activation (Nlrp3 inflammasome).
- Evaluation of metabolic changes, specifically aerobic glycolysis.
Main Results:
- A lncRNA, 1810058I24Rik (181-Rik), was identified, encoding a mitochondrion-located micropeptide, Stmp1.
- Mice deficient in 181-Rik showed protection of retinal ganglion cells from IR injury, with reduced microglia activation and Nlrp3 inflammasome activity.
- Genetic knockout of 181-Rik or its knockdown in microglia improved mitochondrial function, reduced ROS production and inflammation, and diminished aerobic glycolysis.
- 181-Rik appears to activate Nlrp3 inflammasome by modulating mitochondrial function, inhibiting uncoupling protein 2 (Ucp2), and activating S100a8/a9 expression.
Conclusions:
- 181-Rik and its micropeptide Stmp1 play a critical role in the molecular pathogenesis of retinal IR injury.
- The 181-Rik/Stmp1 axis influences mitochondrial function and inflammatory responses, contributing to retinal damage.
- Targeting the 181-Rik pathway presents a potential therapeutic strategy for neurodegenerative diseases associated with retinal IR.
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