Melatonin Reduces Mito-Inflammation in Ischaemic Hippocampal HT22 Cells and Modulates the cGAS–STING Cytosolic DNA Sensing Pathway and FGF21 Release

: Mitochondrial dysfunction is a key event in many pathological conditions, including neurodegenerative processes. When mitochondria are damaged, they release damage-associated molecular patterns (DAMPs) that activate mito-inflammation. The present study assessed mito-inflammation after in vitro oxygen-glucose deprivation as a representation of ischaemia, followed by reoxygenation (OGD/R) of HT22 cells and modulation of the inflammatory response by melatonin. We observed that melatonin prevented mitochondrial structural damage and dysfunction caused by OGD/R. Melatonin reduced oxidative damage and preserved the enzymatic activity for complexes I, III and IV, encoded by mitochondrial DNA, which were reduced by OGD/R. No effect was observed on complex II activity encoded by nuclear DNA. The release of mtDNA into the cytosol was also prevented with a consequent reduction of the cGAS-STING pathway and IFNβ and IL-6 production. Interestingly, melatonin also increased the early release of the fibroblast growth factor-21 (FGF-21), a mitokine secreted in response to mitochondrial stress. These data indicate that melatonin reduces mito-inflammation and modulates FGF-21 release, further highlighting the key role of this molecule in preserving mitochondrial integrity in OGD/R deprivation-type ischaemic brain injury.