Emmerzaal, Tim L.Preston, GraemeGeenen, BramVerweij, VivienneWiesmann, MaximilianVasileiou, ElisavetGrüter, Femkede Groot, CornéSchoorl, Jeroende Veer, RenskeRoelofs, MonicaArts, MartijnHendriksen, YaraKlimars, EvaDonti, Taraka R.Graham, Brett H.Morava, EvaRodenburg, Richard J.Kozicz, Tamas2020-10-302020-10-302020-06-01Emmerzaal, T. L., Preston, G., Geenen, B., Verweij, V., Wiesmann, M., Vasileiou, E., Grüter, F., de Groot, C., Schoorl, J., de Veer, R., Roelofs, M., Arts, M., Hendriksen, Y., Klimars, E., Donti, T. R., Graham, B. H., Morava, E., Rodenburg, R. J., & Kozicz, T. (2020). Impaired mitochondrial complex I function as a candidate driver in the biological stress response and a concomitant stress-induced brain metabolic reprogramming in male mice. Translational Psychiatry, 10(1), 1–13. https://doi.org/10.1038/s41398-020-0858-y2158-3188https://hdl.handle.net/1805/24204Mitochondria play a critical role in bioenergetics, enabling stress adaptation, and therefore, are central in biological stress responses and stress-related complex psychopathologies. To investigate the effect of mitochondrial dysfunction on the stress response and the impact on various biological domains linked to the pathobiology of depression, a novel mouse model was created. These mice harbor a gene trap in the first intron of the Ndufs4 gene (Ndufs4GT/GT mice), encoding the NDUFS4 protein, a structural component of complex I (CI), the first enzyme of the mitochondrial electron transport chain. We performed a comprehensive behavioral screening with a broad range of behavioral, physiological, and endocrine markers, high-resolution ex vivo brain imaging, brain immunohistochemistry, and multi-platform targeted mass spectrometry-based metabolomics. Ndufs4GT/GT mice presented with a 25% reduction of CI activity in the hippocampus, resulting in a relatively mild phenotype of reduced body weight, increased physical activity, decreased neurogenesis and neuroinflammation compared to WT littermates. Brain metabolite profiling revealed characteristic biosignatures discriminating Ndufs4GT/GT from WT mice. Specifically, we observed a reversed TCA cycle flux and rewiring of amino acid metabolism in the prefrontal cortex. Next, exposing mice to chronic variable stress (a model for depression-like behavior), we found that Ndufs4GT/GT mice showed altered stress response and coping strategies with a robust stress-associated reprogramming of amino acid metabolism. Our data suggest that impaired mitochondrial CI function is a candidate driver for altered stress reactivity and stress-induced brain metabolic reprogramming. These changes result in unique phenomic and metabolomic signatures distinguishing groups based on their mitochondrial genotype.en-USAttribution 4.0 InternationalPhysiologyMolecular neuroscienceImpaired mitochondrial complex IArticle