Non-canonical STAT3 pathway induces alterations of mitochondrial dynamic proteins in the hippocampus of an LPS-induced murine neuroinflammation model.

Abstract

The activation of STAT3 is a crossroads of cellular regulation, induced in its canonical pathway by phosphorylation on a critical tyrosine residue (Y705). The existence of a STAT3 non-canonical signaling mechanisms, induced by phosphorylation at serine 727 (S727), has been recently identified in vitro. After cytoplasmic activation, non-canonical STAT3 could move to the level of mitochondria-endoplasmic reticulum contacts (MERCs). We have previously shown that LPS injections in mouse model induce STAT3 canonical pathway, leading to its nuclear translocation and to neuroinflammation. However, the effects of LPS on activation of the non-canonical pathway and its consequences on protein complexes of MERCs remain to be determined. In an in vivo LPS mouse model, we found that systemic inflammation induces in hippocampus the non-canonical STAT3 pathway. LPS-induced STAT3 affects specifically MERC protein BAP31, and that of a mitochondrial membrane protein known to interact with it, TOM40. These findings shed light on the role of STAT3 on mitochondrial - endoplasmic reticulum interaction under inflammatory conditions, offering new perspectives for targeting mitochondrial function and STAT3 activation in disease contexts.