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 longterm MitoQ administration is well-tolerated with no reported side effects in mice and humans.

Exposure‐induced changes of plasma metabolome and gene expression in patients with panic disorder

“…A previous study reported an association between oxidative stress and certain anxiety disorders (obsessive‐compulsive disorder and PD), implicating that oxidative metabolism may affect anxiety (Kuloglu et al, ). Furthermore, reduced ascorbic acid levels in the hippocampus of mice with high anxiety‐related behavior has been associated with anxiolytic effects of MitoQ treatment (Nussbaumer et al, ). Thus, ascorbic acid levels may reflect anxiety‐related changes in the periphery and the brain.…”

Stable isotope metabolic labeling suggests differential turnover of the DPYSL protein family

“…In vivo metabolic labeling with a 15 N‐labeled diet introduces the stable nitrogen isotope 15 N into amino acids of live organisms. We have previously used in vivo 15 N metabolic labeling to identify protein expression changes in mouse models of neuropsychiatric phenotypes and investigated the effects of pharmacologically manipulating these changes . Here, we show that in addition to protein expression, 15 N metabolic labeling can simultaneously yield protein turnover data, information that cannot be gained by immunochemical methods.…”

“…of pharmacologically manipulating these changes [10]. Here, we show that in addition to protein expression, 15 N metabolic labeling can simultaneously yield protein turnover data, information that cannot be gained by immunochemical methods.…”

Die Kraftwerke der Zellen- über die Behandlung von psychiatrischen Symptomen bei Patienten mit Mitochondriopathien

“…In Tierstudien und in-vitro werden bereits Substanzen zur Behandlung von psychiatrischen Erkrankungen durch pharmakologische Beeinflussung der Atmungskette erprobt [25][26][27]. Im Mausmodell konnten anxiolytische Effekte nach Gabe eines mitochondrienspezifischen Antioxidans erzielt werden [28].…”

“…Es gibt einige Hinweise aus randomisiert-kontrollierten Studien auf Basis derer der Einsatz von antioxidativen Substanzen sowie Creatin und Coenzym Q10 empfohlen werden kann [38,39]. Weitere mitochondrienspezifische Antioxidantien werden erst im Tiermodell erprobt [28,40].…”