title: Selective Mitochondrial Targeting Exerts Anxiolytic Effects In Vivo.
abstract: Current treatment strategies for anxiety disorders are predominantly symptom-based. However, a third of anxiety patients remain unresponsive to anxiolytics highlighting the need for more effective, mechanism-based therapeutic approaches. We have previously compared high vs low anxiety mice and identified changes in mitochondrial pathways, including oxidative phosphorylation and oxidative stress. In this work, we show that selective pharmacological targeting of these mitochondrial pathways exerts anxiolytic effects in vivo. We treated high anxiety-related behavior (HAB) mice with MitoQ, an antioxidant that selectively targets mitochondria. MitoQ administration resulted in decreased anxiety-related behavior in HAB mice. This anxiolytic effect was specific for high anxiety as MitoQ treatment did not affect the anxiety phenotype of C57BL/6N and DBA/2J mouse strains. We furthermore investigated the molecular underpinnings of the MitoQ-driven anxiolytic effect and found that MitoQ treatment alters the brain metabolome and that the response to MitoQ treatment is characterized by distinct molecular signatures. These results indicate that a mechanism-driven approach based on selective mitochondrial targeting has the potential to attenuate the high anxiety phenotype in vivo, thus paving the way for translational implementation as long-term MitoQ administration is well-tolerated with no reported side effects in mice and humans.
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Nussbaumer
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Larysa
authors.initials: L
authors.lastname: Teplytska
authors.affiliation: MRC-Mitochondrial Biology Unit, Cambridge, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: MRC-Mitochondrial Biology Unit, Cambridge, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Logan
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Turck
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Michaela D
authors.initials: MD
authors.lastname: Filiou
mesh_terms: D000221:Adaptation, Ocular / Q000187:drug effects; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001007:Anxiety / Q000188:drug therapy* / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D019417:Hindlimb Suspension; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D046228:Microarray Analysis; D008928:Mitochondria / Q000187:drug effects*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D014151:Anti-Anxiety Agents; D009943:Organophosphorus Compounds; D014451:Ubiquinone; C429014:mitoquinone; D002374:Catalase