Theranostics 2022; 12(7):3196-3216. doi:10.7150/thno.71029 This issue

Research Paper

Neuronal STAT3/HIF-1α/PTRF axis-mediated bioenergetic disturbance exacerbates cerebral ischemia-reperfusion injury via PLA2G4A

Weili Jin1,2*, Jixing Zhao1,2*, Eryan Yang1,2*, Yunfei Wang1,2, Qixue Wang1,2, Ye Wu1,2, Fei Tong1,2, Yanli Tan3, Junhu Zhou1,2, Chunsheng Kang1,2✉

1. Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China.
2. Tianjin Neurological Institute, Key Laboratory of Post-neurotrauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin City, Tianjin 300052, China.
3. Department of Pathology, Affiliated Hospital of Hebei University, Baoding 071000, China.
*These authors contributed equally to this work.

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Citation:
Jin W, Zhao J, Yang E, Wang Y, Wang Q, Wu Y, Tong F, Tan Y, Zhou J, Kang C. Neuronal STAT3/HIF-1α/PTRF axis-mediated bioenergetic disturbance exacerbates cerebral ischemia-reperfusion injury via PLA2G4A. Theranostics 2022; 12(7):3196-3216. doi:10.7150/thno.71029. Available from https://www.thno.org/v12p3196.htm

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Abstract

Graphic abstract

Ischemic stroke is an acute and severe neurological disease with high mortality and disability rates worldwide. Polymerase I and transcript release factor (PTRF) plays a pivotal role in regulating cellular senescence, glucose intolerance, lipid metabolism, and mitochondrial bioenergetics, but its mechanism, characteristics, and functions in neuronal cells following the cerebral ischemia-reperfusion (I/R) injury remain to be determined.

Methods: Transcription factor motif analysis, chromatin immunoprecipitation (ChIP), luciferase and co-Immunoprecipitation (co-IP) assays were performed to investigate the mechanisms of PTRF in neuronal cells after I/R injury. Lentiviral-sgRNA against PTRF gene was introduced to HT22 cells, and adeno-associated virus (AAV) encoding a human synapsin (hSyn) promoter-driven construct was transduced a short hairpin RNA (shRNA) against PTRF mRNA in primary neuronal cells and the cortex of the cerebral I/R mice for investigating the role of PTRF in neuronal damage and PLA2G4A change induced by the cerebral I/R injury.

Results: Here, we reported that neuronal PTRF was remarkably increased in the cerebral penumbra after I/R injury, and HIF-1α and STAT3 regulated the I/R-dependent expression of PTRF via binding to its promoter in neuronal cells. Moreover, overexpression of neuronal PTRF enhanced the activity and stability of PLA2G4A by decreasing its proteasome-mediated degradation pathway. Subsequently, PTRF promoted reprogramming of lipid metabolism and altered mitochondrial bioenergetics, which could lead to oxidative damage, involving autophagy, lipid peroxidation, and ferroptosis via PLA2G4A in neuronal cells. Furthermore, inhibition of neuronal PTRF/PLA2G4A-axis markedly reduced the neurological deficits, cerebral infarct volumes, and mortality rates in the mice following cerebral I/R injury.

Conclusion: Our results thus identify that the STAT3/HIF-1α/PTRF-axis in neurons, aggravating cerebral I/R injury by regulating the activity and stability of PLA2G4A, might be a novel therapeutic target for ischemic stroke.

Keywords: polymerase I and transcript release factor (PTRF), cerebral ischemia-reperfusion (I/R) injury, lipid metabolism, mitochondrial bioenergetics, oxidative damage