Chronic fluoxetine or ketamine treatment differentially affects brain energy homeostasis which is not exacerbated in mice with trait suboptimal mitochondrial function

• Published in: The European journal of neuroscience 2021-05, Vol.53 (9), p.2986-3001
• Main Authors: Emmerzaal, Tim L., Jacobs, Leah, Geenen, Bram, Verweij, Vivienne, Morava, Eva, Rodenburg, Richard J., Kozicz, Tamas
• Format: Article
• Language: English
• Subjects: Animal models; Antidepressants; antidepressive agents; Bioenergetics; Electron transport chain; electron transport chain complex proteins; Energy balance; Fluoxetine; Genotypes; Homeostasis; Ketamine; Mental disorders; Metabolomics; mice; Mitochondria; NADH-ubiquinone oxidoreductase; Phenotypes; Psychopathology; stress
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.14901

Antidepressants have been shown to influence mitochondrial function directly, and suboptimal mitochondrial function (SMF) has been implicated in complex psychiatric disorders. In the current study, we used a mouse model for trait SMF to test the hypothesis that chronic fluoxetine treatment in mice subjected to chronic stress would negatively impact brain bioenergetics, a response that would be more pronounced in mice with trait SMF. In contrast, we hypothesized that chronic ketamine treatment would positively impact mitochondrial function in both WT and mice with SMF. We used an animal model for trait SMF, the Ndufs4GT/GT mice, which exhibit 25% lower mitochondrial complex I activity. In addition to antidepressant treatment, mice were subjected to chronic unpredictable stress (CUS). This paradigm is widely used to model complex behaviours expressed in various psychiatric disorders. We assayed several physiological indices as proxies for the impact of chronic stress and antidepressant treatment. Furthermore, we measured brain mitochondrial complex activities using clinically validated assays as well as established metabolic signatures using targeted metabolomics. As hypothesized, we found evidence that chronic fluoxetine treatment negatively impacted brain bioenergetics. This phenotype was, however, not further exacerbated in mice with trait SMF. Ketamine did not have a significant influence on brain mitochondrial function in either genotype. Here we report that trait SMF could be a moderator for an individual's response to antidepressant treatment. Based on these results, we propose that in individuals with SMF and comorbid psychopathology, fluoxetine should be avoided, whereas ketamine could be a safer choice of treatment. The impact of antidepressants on mitochondrial function is complex and poorly understood. Here, we studied brain bioenergetics and used targeted metabolomics analysis to show that chronic fluoxetine, but not ketamine, treatment resulted in decreased mitochondrial CIII and CIV activity concomitant with brain metabolic rewiring in the frontal cortex in wild‐type mice. These changes were not exacerbated in a mouse model with suboptimal mitochondrial function presenting with 25% decreased CI activity.