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Item does not contain fulltext 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 Ndufs4(GT/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.

Phosphoglucomutase 1 (PGM1) encodes the metabolic enzyme that interconverts glucose-6-P and glucose-1-P. Mutations in PGM1 cause impairment in glycogen metabolism and glycosylation, the latter manifesting as a congenital disorder of glycosylation (CDG). This unique metabolic defect leads to abnormal N-glycan synthesis in the endoplasmic reticulum (ER) and the Golgi apparatus (GA). On the basis of the decreased galactosylation in glycan chains, galactose was administered to individuals with PGM1-CDG and was shown to markedly reverse most disease-related laboratory abnormalities. The disease and treatment mechanisms, however, have remained largely elusive. Here, we confirm the clinical benefit of galactose supplementation in PGM1-CDG-affected individuals and obtain significant insights into the functional and biochemical regulation of glycosylation. We report here that, by using tracer-based metabolomics, we found that galactose treatment of PGM1-CDG fibroblasts metabolically re-wires their sugar metabolism, and as such replenishes the depleted levels of galactose-1-P, as well as the levels of UDP-glucose and UDP-galactose, the nucleotide sugars that are required for ER- and GA-linked glycosylation, respectively. To this end, we further show that the galactose in UDP-galactose is incorporated into mature, de novo glycans. Our results also allude to the potential of monosaccharide therapy for several other CDG. ispartof: American Journal of Human Genetics vol:104 issue:5 pages:835-846 ispartof: location:United States status: Published online

Contains fulltext : 235749.pdf (Publisher’s version ) (Open Access) Exposure to antibiotic treatment has been associated with increased vulnerability to various psychiatric disorders. However, a research gap exists in understanding how adolescent antibiotic therapy affects behavior and cognition. Many antibiotics that target bacterial translation may also affect mitochondrial translation resulting in impaired mitochondrial function. The brain is one of the most metabolically active organs, and hence is the most vulnerable to impaired mitochondrial function. We hypothesized that exposure to antibiotics during early adolescence would directly affect brain mitochondrial function, and result in altered behavior and cognition. We administered amoxicillin, chloramphenicol, or gentamicin in the drinking water to young adolescent male wild-type mice. Next, we assayed mitochondrial oxidative phosphorylation complex activities in the cerebral cortex, performed behavioral screening and targeted mass spectrometry-based acylcarnitine profiling in the cerebral cortex. We found that mice exposed to chloramphenicol showed increased repetitive and compulsive-like behavior in the marble burying test, an accurate and sensitive assay of anxiety, concomitant with decreased mitochondrial complex IV activity. Our results suggest that only adolescent chloramphenicol exposure leads to impaired brain mitochondrial complex IV function, and could therefore be a candidate driver event for increased anxiety-like and repetitive, compulsive-like behaviors.

Contains fulltext : 235754.pdf (Publisher’s version ) (Closed access) Individuals with mitochondrial disease often present with psychopathological comorbidity, and mitochondrial dysfunction has been proposed as the underlying pathobiology in various psychiatric disorders. Several studies have suggested that medications used to treat neuropsychiatric disorders could directly influence mitochondrial function. This review provides a comprehensive overview of the effect of these medications on mitochondrial function. We collected preclinical information on six major groups of antidepressants and other neuropsychiatric medications and found that the majority of these medications either positively influenced mitochondrial function or showed mixed effects. Only amitriptyline, escitalopram, and haloperidol were identified as having exclusively adverse effects on mitochondrial function. In the absence of formal clinical trials, and until such trials are completed, the data from preclinical studies reported and discussed here could inform medication prescribing practices for individuals with psychopathology and impaired mitochondrial function in the underlying pathology.

Mitochondrial metabolism is increasingly implicated in psychopathologies and mood disorders, including post-traumatic stress disorder (PTSD). We recently reported that mice exposed to a novel paradigm for the induction of PTSD-like behavior displayed reduced mitochondrial electron transport chain (mtETC) complex activity as well as decreased multi-system fatty acid oxidation (FAO) flux. Based on these results, we hypothesized that stressed and PTSD-like animals would display evidence of metabolic reprogramming in both cerebellum and plasma consistent with increased energetic demand, mitochondrial metabolic reprogramming, and increased oxidative stress. We performed targeted metabolomics in both cerebellar tissue and plasma, as well as untargeted nuclear magnetic resonance (NMR) spectroscopy in the cerebellum of 6 PTSD-like and 7 resilient male mice as well as 7 trauma-naïve controls. We identified numerous differences in amino acids and tricarboxylic acid (TCA) cycle metabolite concentrations in the cerebellum and plasma consistent with altered mitochondrial energy metabolism in trauma exposed and PTSD-like animals. Pathway analysis identified metabolic pathways with significant metabolic pathway shifts associated with trauma exposure, including the tricarboxylic acid cycle, pyruvate, and branched-chain amino acid metabolism in both cerebellar tissue and plasma. Altered glutamine and glutamate metabolism, and arginine biosynthesis was evident uniquely in cerebellar tissue, while ketone body levels were modified in plasma. Importantly, we also identified several cerebellar metabolites (e.g. choline, adenosine diphosphate, beta-alanine, taurine, and myo-inositol) that were sufficient to discriminate PTSD-like from resilient animals. This multilevel analysis provides a comprehensive understanding of local and systemic metabolite fingerprints associated with PTSD-like behavior, and subsequently altered brain bioenergetics. Notably, several transformed metabolic pathways observed in the cerebellum were also reflected in plasma, connecting central and peripheral biosignatures of PTSD-like behavior. These preliminary findings could direct further mechanistic studies and offer insights into potential metabolic interventions, either pharmacological or dietary, to improve PTSD resilience., Graphical abstract Image 1, Highlights • Trauma-exposed mice display cerebellar and multi-system metabolic reprogramming. • Stressed mice display altered multisystem mitochondrial bioenergetics. • Cerebellar metabolites are sufficient discriminate PTSD-like and resilient mice. • Plasma metabolomics identifies potential dietary promotors of trauma resilience. • Cerebellar metabolic reprogramming is reflected in plasma biosignature.

Viruses spread between hosts through particles, but within hosts, viral genomes can spread from cell to cell through fusion, evading antiviral defenses and obviating costly infectious virion production1-3. Billions of electromechanically coupled cardiomyocytes (CMs) make myocardium inherently vulnerable to pathological electromechanical short circuits caused by intercellular viral spread 4-6. Beyond respiratory illness, COVID-19 affects the heart7 and cardiac injury and arrhythmias are serious public health concerns8-12. By studying myocardium of a young woman who died suddenly, diagnosed postmortem with COVID-19, we discovered highly focal myocardial SARS-CoV-2 infection spreading from one CM to another through intercellular junctions identified by highly concentrated sarcolemmal t-tubule viral spike glycoprotein. SARS-CoV-2 permissively infected beating human induced pluripotent stem cell (hiPSC)-CMs building multinucleated cardiomyotubes (CMTs) through cell type-specific fusion driven by proteolytically-activated spike glycoprotein. Recombinant spike glycoprotein, co-localizing to sarcolemma and sarcoplasmic reticulum, produced multinucleated CMTs with pathological structure, electrophysiology and Ca2+ excitation-contraction coupling. Blocking cleavage, a peptide-based protease inhibitor neutralized SARS-CoV-2 spike glycoprotein pathogenicity. We conclude that SARS-CoV-2 spike glycoprotein, efficiently primed, activated and strategically poised during biosynthesis, can exploit the CM’s inherent membranous connectivities to drive heart damage directly, uncoupling clinically common myocardial injury from lymphocytic myocarditis, often suspected but rarely confirmed in COVID-19.

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.

The impact of trauma on mental health is complex with poorly understood underlying mechanisms. Mitochondrial dysfunction is increasingly implicated in psychopathologies and mood disorders, including post-traumatic stress disorder (PTSD). We hypothesized that defects in mitochondrial energy metabolism in the cerebellum, an emerging region of interest in the pathobiology of mood disorders, would be associated with PTSD-like symptomatology, and that PTSD-like symptomatology would correlate with the activities of the mitochondrial electron transport chain (mtETC) and fatty acid oxidation (FAO) pathways. We assayed mitochondrial energy metabolism and fatty acid profiling using targeted metabolomics in mice exposed to a recently developed paradigm for PTSD-induction. 48 wild type male FVB.129P2 mice were exposed to a trauma, and PTSD-like and resilient animals were identified using behavioral profiling. Mice displaying PTSD-like symptomatology displayed reduced mtETC complex activities in the cerebellum, and cerebellar mtETC complex activity negatively correlated with PTSD-like symptomatology. PTSD-like animals also displayed fatty acid profiles consistent with FAO dysfunction in both cerebellum and plasma. Machine learning analysis of all biochemical measures in this cohort of animals also identified plasma acetylcarnitine, along with reduced activity of cerebellar complex I and IV as well as succinate:cytochrome c oxidoreductase as state predictive discriminators of PTSD-symptomatology. Our data also suggest that trauma-induced impaired mtETC function in the cerebellum and concomitant impaired multi-system fatty acid oxidation are candidate drivers of PTSD-like behavior in mice. These bioenergetic and metabolic changes may offer an informative window into the underlying biology and highlight novel potential targets for diagnostics and therapeutic interventions in PTSD., Highlights • Cerebellar mitochondrial dysfunction directly correlates with PTSD symptomatology. • Cerebellar mitochondrial dysfunction is a candidate driver event for trauma susceptibility. • Circulating fatty acids are biomarkers for trauma susceptibility. • A multidimensional cerebellar and body metabolic reprogramming predicts susceptibility to trauma.

Contains fulltext : 181642.pdf (Publisher’s version ) (Closed access) PurposePhosphoglucomutase-1 deficiency is a subtype of congenital disorders of glycosylation (PGM1-CDG). Previous casereports in PGM1-CDG patients receiving oral D-galactose (D-gal) showed clinical improvement. So far no systematic in vitro and clinical studies have assessed safety and benefits of D-gal supplementation. In a prospective pilot study, we evaluated the effects of oral D-gal in nine patients.MethodsD-gal supplementation was increased to 1.5 g/kg/day (maximum 50 g/day) in three increments over 18 weeks. Laboratory studies were performed before and during treatment to monitor safety and effect on serum transferrin-glycosylation, coagulation, and liver and endocrine function. Additionally, the effect of D-gal on cellular glycosylation was characterized in vitro.ResultsEight patients were compliant with D-gal supplementation. No adverse effects were reported. Abnormal baseline results (alanine transaminase, aspartate transaminase, activated partial thromboplastin time) improved or normalized already using 1 g/kg/day D-gal. Antithrombin-III levels and transferrin-glycosylation showed significant improvement, and increase in galactosylation and whole glycan content. In vitro studies before treatment showed N-glycan hyposialylation, altered O-linked glycans, abnormal lipid-linked oligosaccharide profile, and abnormal nucleotide sugars in patient fibroblasts. Most cellular abnormalities improved or normalized following D-gal treatment. D-gal increased both UDP-Glc and UDP-Gal levels and improved lipid-linked oligosaccharide fractions in concert with improved glycosylation in PGM1-CDG.ConclusionOral D-gal supplementation is a safe and effective treatment for PGM1-CDG in this pilot study. Transferrin glycosylation and ATIII levels were useful trial end points. Larger, longer-duration trials are ongoing.

Alzheimer's disease (AD) is a severe neurodegenerative disorder for which the exact etiology is largely unknown. An increasingly recognized and investigated notion is the pathogenic role of mitochondrial dysfunction in AD. We assessed mitochondrial oxidative-phosphorylation (OXPHOS) enzyme activities in the APPswe/PS1ΔE9 mouse model from 4.5 to 14 months of age. We show an age-dependent decrease in mitochondrial complex-II activity starting at 9 months in APP/PS1 mice. Other enzymes of the OXPHOS do not show any alterations. Since amyloid-β (Aβ) plaques are already present from 4 months of age, mitochondrial dysfunction likely occurs downstream of Aβ pathology in this mouse model.

Item does not contain fulltext Nesfatin-1, derived from an 82-amino-acid peptide precursor protein nucleobindin-2 (NUCB2), is a highly conserved peptide across mammalian species. Initial functional and neuroanatomical studies on NUCB2/nesfatin-1 in the central nervous system have supported a role for NUCB2/nesfatin-1 as a novel satiety molecule. In recent years, however, it has become apparent that this neuropeptide is involved in various other processes, one of which is the stress response. Stress-associated activation of NUCB2/nesfatin-1 neurons, together with nesfatin-1's central actions in the brain, is indicative of its significance in the stress adaptation response. Interestingly, increasing body of evidence implicates also NUCB2/nesfatin-1 in various forms of stress-associated psychopathologies, such as anxiety and depression. In this review, we will outline evidence that has significantly broadened our understanding of the biological significance of NUCB2/nesfatin-1 far beyond to be only a hypothalamic peptide with potent anorexigenic actions. NUCB2/nesfatin-1 neurons in the brain seem to emerge as novel, integral regulators of the stress adaptation response.

Contains fulltext : 155371.pdf (Publisher’s version ) (Closed access) Ghrelin is a stomach hormone normally associated with feeding behavior and energy homeostasis. Recent studies highlight that ghrelin targets the brain to regulate a diverse number of functions, including learning, memory, motivation, stress responses, anxiety, and mood. In this review, we discuss recent animal and human studies showing that ghrelin regulates the hypothalamic-pituitary-adrenal axis and affects anxiety and mood disorders, such as depression and fear. We address the neural sites of action through which ghrelin regulates the hypothalamic-pituitary-adrenal axis and associated stress-induced behaviors, including the centrally projecting Edinger-Westphal nucleus, the hippocampus, amygdala, locus coeruleus, and the ventral tegmental area. Stressors modulate many behaviors associated with motivation, fear, anxiety, depression, and appetite; therefore, we assess the potential role for ghrelin as a stress feedback signal that regulates these associated behaviors. Finally, we briefly discuss important areas for future research that will help us move closer to potential ghrelin-based therapies to treat stress responses and related disorders.

Item does not contain fulltext The occurrence of obesity, commonly estimated using body mass index (BMI), and the most common late-onset dementia, Alzheimer's disease (AD), are increasing globally. The year 2013 marked a decade of epidemiologic observational reports on the association between BMI and late-onset dementias. In this review, we highlight epidemiological studies that measured both mid- and late-life BMI in association with dementia. Studies investigating the association between midlife BMI and risk for dementia demonstrated generally an increased risk among overweight and obese adults. When measured in late-life, elevated BMI has been associated with lower risk. In addition, being underweight and/or having a decrease in BMI in late-life are associated with higher dementia risk compared to BMI in the normal range or stable BMI. In this review, a decade (2003-2013) of epidemiologic observational studies on associations between BMI and AD is highlighted. These observations provide a strong base for addressing biological mechanisms underlying this complex association.

Contains fulltext : 136060.pdf (Publisher’s version ) (Open Access) It is well established that the cholesterol-transporter apolipoprotein epsilon (APOE) genotype is associated with the risk of developing neurodegenerative diseases. Recently, brain functional connectivity (FC) in apoE-epsilon4 carriers has been investigated by means of resting-state fMRI, showing a marked differentiation in several functional networks at different ages compared with carriers of other apoE isoforms. The causes of such hampered FC are not understood. We hypothesize that vascular function and synaptic repair processes, which are both impaired in carriers of epsilon4, are the major contributors to the loss of FC during aging. To test this hypothesis, we integrated several different MRI techniques with immunohistochemistry and investigated FC changes in relation with perfusion, diffusion, and synaptic density in apoE4 and apoE-knock-out (KO) mice at 12 (adult) and 18 months of age. Compared with wild-type mice, we detected FC deficits in both adult and old apoE4 and apoE-KO mice. In apoE4 mice, these changes occurred concomitant with increased mean diffusivity in the hippocampus, whereas perfusion deficits appear only later in life, together with reduced postsynaptic density levels. Instead, in apoE-KO mice FC deficits were mirrored by strongly reduced brain perfusion since adulthood. In conclusion, we provide new evidence for a relation between apoE and brain connectivity, possibly mediated by vascular risk factors and by the efficiency of APOE as synaptic modulator in the brain. Our results show that multimodal MR neuroimaging is an excellent tool to assess brain function and to investigate early neuropathology and aging effects in translational research. 13 p.

Contains fulltext : 125271.pdf (Publisher’s version ) (Closed access) Orexin is a neuropeptide that has been implicated in several processes, such as induction of appetite, arousal and alertness and sleep/wake regulation. Multiple lines of evidence also suggest that orexin is involved in the stress response. When orexin is administered intracerebroventricular it activates the hypothalamic pituitary adrenal (HPA)-axis, which is the main regulator of the stress response. The HPA-axis is not the only player in the stress response evidence suggests that urocortin 1 (Ucn1), a member of the corticotropin releasing factor (CRF) neuropeptide family, also plays an important role in the stress response adaptation. Ucn1 is primarily synthetized in the centrally projecting Edinger-Westphal nucleus (EWcp), which also receives dense innervation by orexin terminals. In this study we tested the hypothesis that orexin would directly shape the response of EWcp-Ucn1 neurons to acute cold stress. To test this hypothesis, we first assessed whether orexinergic axon terminals would innervate EWcp-Ucn1/CART neurons, and next we exposed orexin deficient (orexin-KO) male mice and their male wild-type (WT) littermates to acute cold stress for 2h. We also assessed stress-associated changes in plasma corticosterone (CORT), as well as the activation of Ucn1/CART neurons in the EWcp nucleus. We found that orexin immunoreactive axon terminals were juxtaposed to EWcp-Ucn1/CART neurons, which also expressed orexin receptor 1 mRNA. Furthermore, acute stress strongly activated the EWcp-Ucn1/CART neurons and increased plasma CORT in both WT littermates and orexin-KO mice, however no genotype effect was found on these indices. Taken together our data show that orexin in general is not involved in the animal's acute stress response (plasma CORT) and it does not play a direct role in shaping the response of EWcp-Ucn1 neurons to acute stress either. 01 december 2013