Astrocytic IGF-1 and IGF-1R Orchestrate Mitophagy in Traumatic Brain Injury

Background: Defective brain hormonal signaling and autophagy have been associated with neurodegeneration after brain insults, characterized by neuronal loss and cognitive dysfunction. However, less studies have link them in the context of brain injury. Insulin like growth factor-1 (IGF-1) is an important hormone that contributes to growth, cell proliferation and autophagy, also expressed in the brain. Methods We applied proteomics to investigate the role of astrocytic IGF-1 in TBI and related neuroprotective mechanisms. Results We found reduced plasma IGF-1 is correlated with cognition in TBI patients. Overexpression of astrocytic IGF-1 improves cognitive dysfunction in TBI mice and cocultured astrocytes prevent neuronal excitotoxicity with IGF-1 pathway dependent. At the molecular level, proteomics data show IGF-1 related NF-kB pathway transcriptionally regulates decapping mRNA2 (Dcp2) and miR-let-7, together with IGF-1R to orchestrate mitophagy in TBI. Finally, we demonstrate that TBI induces impaired mitophagy at the chronic stage and IGF-1 treatment could facilitate the mitophagy marker. Conclusion By showing that IGF-1 is an important mediator of the beneficial effect of neural-endocrine network in TBI models, our findings place IGF-1/IGF-1R as a potential target capable of non-coding RNAs and opposing mitophagy failure and cognition impairment in TBI.