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
Open Access
- 1 June 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Translational Psychiatry
- Vol. 10 (1), 1-13
- https://doi.org/10.1038/s41398-020-0858-y
Abstract
Mitochondria 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.Keywords
This publication has 89 references indexed in Scilit:
- Endocrine disorders in mitochondrial diseaseMolecular and Cellular Endocrinology, 2013
- Natural disease course and genotype‐phenotype correlations in Complex I deficiency caused by nuclear gene defects: what we learned from 130 casesJournal of Inherited Metabolic Disease, 2012
- Two patients with hepatic mtDNA depletion syndromes and marked elevations of S-adenosylmethionine and methionineMolecular Genetics and Metabolism, 2012
- Study of plasma metabolic profiling and biomarkers of chronic unpredictable mild stress rats based on gas chromatography/mass spectrometryRapid Communications in Mass Spectrometry, 2010
- Stress generation in depression: A systematic review of the empirical literature and recommendations for future studyClinical Psychology Review, 2010
- A Meta-Analysis of Cytokines in Major DepressionBiological Psychiatry, 2010
- The neuro-symphony of stressNature Reviews Neuroscience, 2009
- Dissecting the effects of mtDNA variations on complex traits using mouse conplastic strainsGenome Research, 2008
- Mice with Mitochondrial Complex I Deficiency Develop a Fatal EncephalomyopathyCell Metabolism, 2008
- A public gene trap resource for mouse functional genomicsNature Genetics, 2004