MitoQ administration exerts anxiolytic effects in vivo

One third of patients suffering from anxiety disorders do not respond to current anxiolytic treatments. It is therefore critical to identify novel drug targets for improved response rates. We developed a proteomics and metabolomics platform to identify molecular differences in mice selectively bred for high vs. low anxiety. Our multi -omics approach revealed altered brain mitochondrial pathways in high anxiety mice. We then pharmacologically manipulated the identified mitochondrial alterations in vivo with MitoQ, an antioxidant selectively targeting mitochondria, in order to assess whether selective pharmacological targeting exerts anxiolytic-like effects. MitoQ administration reduced anxiety-related behavior in treated compared to untreated high anxiety mice. This anxiolytic effect was specific for high anxiety as MitoQ treatment did not affect anxiety-related phenotypes of C57BL/6N and DBA/2J mice. MitoQ treatment alters the brain metabolome and that MitoQ treatment response is characterized by distinct molecular signatures in brain and plasma. This is the first time that a mechanism-based approach is used to manipulate a behavioral phenotype. Our work indicates that selective mitochondrial targeting has the potential to attenuate the high anxiety phenotype in vivo. Given that long-term MitoQ administration is well-tolerated with no reported side effects in humans, these data pave the way for translational applications in patient cohorts.

This study was supported by DFG.