Anxiety and Brain Mitochondria: A Bidirectional Crosstalk

Filiou, Michaela D.; Sandi, Carmen

doi:10.1016/j.tins.2019.07.002

Cited by 106 publications

(90 citation statements)

References 152 publications

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“…These findings suggest that GABA may play a crucial role in multiple pathways leading to mPFC structural deficits in depression 54,78 . In addition, our finding of increased emotional reactivity of Ndufs4 GT/GT mice is in line with a recent review suggesting that mitochondria could contribute to anxiety through alterations in the GABA/glutamate ratio 79 .…”

Section: Discussionsupporting

confidence: 92%

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

et al. 2020

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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 (Ndufs4 GT/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 multiplatform targeted mass spectrometry-based metabolomics. Ndufs4 GT/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 Ndufs4 GT/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 Ndufs4 GT/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.

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Section: Discussionsupporting

confidence: 92%

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

et al. 2020

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“…In particular, low mitochondrial function, expressed as reduced mitochondrial respiratory capacity, decreased ATP levels, and increased oxidative stress in the nucleus accumbens shell has been reported in rats showing anxiety-like behavior [ 39 , 48 , 49 , 50 ]. Moreover, reduced CCO activity in the prefrontal cortex, the hippocampus, and the mesolimbic dopaminergic system (including the nucleus accumbens shell) have been reported after chronic social defeat in rodents and in congenitally-helpless rats showing depression-like behavior [ 43 , 47 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

Sex-Specific Effects of Early Life Stress on Brain Mitochondrial Function, Monoamine Levels and Neuroinflammation

et al. 2020

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Sex differences have been reported in the susceptibility to early life stress and its neurobiological correlates in humans and experimental animals. However, most of the current research with animal models of early stress has been performed mainly in males. In the present study, prolonged maternal separation (MS) paradigm was applied as an animal model to resemble the effects of adverse early experiences in male and female rats. Regional brain mitochondrial function, monoaminergic activity, and neuroinflammation were evaluated as adults. Mitochondrial energy metabolism was greatly decreased in MS females as compared with MS males in the prefrontal cortex, dorsal hippocampus, and the nucleus accumbens shell. In addition, MS males had lower serotonin levels and increased serotonin turnover in the prefrontal cortex and the hippocampus. However, MS females showed increased dopamine turnover in the prefrontal cortex and increased norepinephrine turnover in the striatum, but decreased dopamine turnover in the hippocampus. Sex differences were also found for pro-inflammatory cytokine levels, with increased levels of TNF-α and IL-6 in the prefrontal cortex and hippocampus of MS males, and increased IL-6 levels in the striatum of MS females. These results evidence the complex sex- and brain region-specific long-term consequences of early life stress.

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“…In parallel, mitochondria, inflammation, and oxidative stress are also important links in the pathogenesis of psychiatric disorders, especially mood disorders [65][66][67][68]. Current theories propose a model based on neuroinflammation and dysregulation of brain energy generation, involving dysfunction in stress-response mechanisms [69].…”

Section: Mitochondria Inflammation and Oxidative Stressmentioning

confidence: 99%

Non-alcoholic fatty liver disease (NAFLD) as a neglected metabolic companion of psychiatric disorders: common pathways and future approaches

Soto-Angona

Anmella

Valdés-Florido

et al. 2020

BMC Med

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Background Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in over 5% of the parenchyma in the absence of excessive alcohol consumption. It is more prevalent in patients with diverse mental disorders, being part of the comorbidity driving loss of life expectancy and quality of life, yet remains a neglected entity. NAFLD can progress to non-alcoholic steatohepatitis (NASH) and increases the risk for cirrhosis and hepatic carcinoma. Both NAFLD and mental disorders share pathophysiological pathways, and also present a complex, bidirectional relationship with the metabolic syndrome (MetS) and related cardiometabolic diseases. Main text This review compares the demographic data on NAFLD and NASH among the global population and the psychiatric population, finding differences that suggest a higher incidence of this disease among the latter. It also analyzes the link between NAFLD and psychiatric disorders, looking into common pathophysiological pathways, such as metabolic, genetic, and lifestyle factors. Finally, possible treatments, tailored approaches, and future research directions are suggested. Conclusion NAFLD is part of a complex system of mental and non-communicable somatic disorders with a common pathogenesis, based on shared lifestyle and environmental risks, mediated by dysregulation of inflammation, oxidative stress pathways, and mitochondrial function. The recognition of the prevalent comorbidity between NAFLD and mental disorders is required to inform clinical practice and develop novel interventions to prevent and treat these complex and interacting disorders.

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Anxiety and Brain Mitochondria: A Bidirectional Crosstalk

Cited by 106 publications

References 152 publications

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

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

Sex-Specific Effects of Early Life Stress on Brain Mitochondrial Function, Monoamine Levels and Neuroinflammation

Non-alcoholic fatty liver disease (NAFLD) as a neglected metabolic companion of psychiatric disorders: common pathways and future approaches

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