Neonatal Rotenone Administration Induces Psychiatric Disorder-Like Behavior and Changes in Mitochondrial Biogenesis and Synaptic Proteins in Adulthood.

Since psychiatric disorders are associated with changes in the development of the nervous system, an energy-dependent mechanism, we investigated whether mitochondrial inhibition during the critical neurodevelopment window in rodents would be able to induce metabolic alterations culminating in psychiatric-like behavior. We treated male Wistar rat puppies (P) with rotenone (Rot), an inhibitor of mitochondrial complex I, from postnatal days 5 to 11 (P5-P11). We demonstrated that at P60 and P120, Rot-treated animals showed hyperlocomotion and deficits in social interaction and aversive contextual memory, features observed in animal models of schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder. During adulthood, Rot-treated rodents also presented modifications in CBP and CREB levels in addition to a decrease in mitochondrial biogenesis and Nrf1 expression. Additionally, NFE2L2-activation was not altered in Rot-treated P60 and P120 animals; an upregulation of pNFE2L2/ NFE2L2 was only observed in P12 cortices. Curiously, ATP/ADP levels did not change in all ages evaluated. Rot administration in newborn rodents also promoted modification in Rest and Mecp2 expression, and in synaptic protein levels, named PSD-95, Synaptotagmin-1, and Synaptophysin in the adult rats. Altogether, our data indicate that behavioral abnormalities and changes in synaptic proteins in adulthood induced by neonatal Rot administration might be a result of adjustments in CREB pathways and alterations in mitochondrial biogenesis and Nrf1 expression, rather than a direct deficiency of energy supply, as previously speculated. Consequently, Rot-induced psychiatric-like behavior would be an outcome of alterations in neuronal paths due to mitochondrial deregulation.

Oxygen Consumption Evaluation: An Important Indicator of Metabolic State, Cellular Function, and Cell Fate Along Neural Deregulation.

Depletion of oxygen (O2) levels and reduction in the ATP synthesis (or even its complete blockage) are important characteristics of mitochondrial dysfunction; features that are often correlated with neurodegeneration. The measurement of oxygen consumption rate (OCR) is thus essential to evaluate cellular metabolism, survival, and neuroprotective strategies. In the present chapter, we describe the oxygen consumption assay using a Clark-type oxygen electrode in different types of samples named cells suspension (from primary and established cell culture), brain slices (ex vivo), and fresh brain tissues. In addition, we demonstrate herein how the program Oxygraph can be used in order to analyze the data and different approaches to normalize it.

Decreased Mitochondrial Function, Biogenesis, and Degradation in Peripheral Blood Mononuclear Cells from Amyotrophic Lateral Sclerosis Patients as a Potential Tool for Biomarker Research.

Amyotrophic lateral sclerosis (ALS) is a multifactorial and progressive neurodegenerative disease of unknown etiology. Due to ALS's unpredictable onset and progression rate, the search for biomarkers that allow the detection and tracking of its development and therapeutic efficacy would be of significant medical value. Considering that alterations of energy supply are one of ALS's main hallmarks and that a correlation has been established between gene expression in human brain tissue and peripheral blood mononuclear cells (PBMCs), the present work investigates whether changes in mitochondrial function could be used to monitor ALS. To achieve this goal, PBMCs from ALS patients and control subjects were used; blood sampling is a quite non-invasive method and is cost-effective. Different parameters were evaluated, namely cytosolic calcium levels, mitochondrial membrane potential, oxidative stress, and metabolic compounds levels, as well as mitochondrial dynamics and degradation. Altogether, we observed lower mitochondrial calcium uptake/retention, mitochondria depolarization, and redox homeostasis deregulation, in addition to a decrease in critical metabolic genes, a diminishment in mitochondrial biogenesis, and an augmentation in mitochondrial fission and autophagy-related gene expression. All of these changes can contribute to the decreased ATP and pyruvate levels observed in ALS PBMCs. Our data indicate that PBMCs from ALS patients show a significant mitochondrial dysfunction, resembling several findings from ALS' neural cells/models, which could be exploited as a powerful tool in ALS research. Our findings can also guide future studies on new pharmacological interventions for ALS since assessments of brain samples are challenging and represent a relevant limited strategy. Graphical abstract.

Mitochondrial Dysfunction and Changes in High-Energy Compounds in Different Cellular Models Associated to Hypoxia: Implication to Schizophrenia.

Schizophrenia (SZ) is a multifactorial mental disorder, which has been associated with a number of environmental factors, such as hypoxia. Considering that numerous neural mechanisms depends on energetic supply (ATP synthesis), the maintenance of mitochondrial metabolism is essential to keep cellular balance and survival. Therefore, in the present work, we evaluated functional parameters related to mitochondrial function, namely calcium levels, mitochondrial membrane potential, redox homeostasis, high-energy compounds levels and oxygen consumption, in astrocytes from control (Wistar) and Spontaneously Hypertensive Rats (SHR) animals exposed both to chemical and gaseous hypoxia. We show that astrocytes after hypoxia presented depolarized mitochondria, disturbances in Ca2+ handling, destabilization in redox system and alterations in ATP, ADP, Pyruvate and Lactate levels, in addition to modification in NAD+/NADH ratio, and Nfe2l2 and Nrf1 expression. Interestingly, intrauterine hypoxia also induced augmentation in mitochondrial biogenesis and content. Altogether, our data suggest that hypoxia can induce mitochondrial deregulation and a decrease in energy metabolism in the most prevalent cell type in the brain, astrocytes. Since SHR are also considered an animal model of SZ, our results can likewise be related to their phenotypic alterations and, therefore, our work also allow an increase in the knowledge of this burdensome disorder.

Metabolic Alteration and Amyotrophic Lateral Sclerosis Outcome: A Systematic Review.

Background: The development of strategies that could not only efficiently detect the onset of Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disorder with no cure but also predict its development and evaluate therapeutic intervention would be of great value. In this respect, the metabolic status of ALS patients has called attention. Hence, this study aimed to investigate the potential correlation between changes in ALS's metabolic parameters with the disease outcome in a systematic review. Methods: The manuscripts were manually searched within different databases (PubMed, Web of Science and Cochrane). The inclusion criteria were original articles and reviews about individuals with ALS and its survival, disease prognosis and metabolism (weight, cholesterol, hypertension, BMI, and glycaemia). The authors also established three different exclusion criteria: studies including ALS and other degenerative disorders, works including animal models and published before the year 2000. Results: In total, 29 papers were selected. From all manuscripts, only 82.8% ensured the participation of sALS patients. Also, 27.6% of selected studies described the presence of a genetic mutation. Regarding ALS prognosis, patient's age, the age of ALS onset, ALS duration and survival, <50% of the papers addressed these issues. Specifically, regarding metabolism, 65.5% of articles mentioned BMI, 20.7% mentioned any data concerning hypertension, 6.89% cardiovascular risk, 10.3% obesity, 13.78% diabetes and 10.3% glycaemia. Concerning lipid metabolism, more results were gathered, but still, they did not suffice to establish a correlation with ALS development. Conclusions: Altogether, the authors concluded that available information is not enough to establish a link between ALS and metabolism. In reality, less than half of the manuscripts evaluated show an association between both factors. Nonetheless, it is worth mentioning that metabolism does influence ALS, but not in a unique manner. There is a debate about patients' hypo- and hypermetabolism. Thus, to provide a reliable record, a public policy in which all research and clinical centers might assess the parameters discussed herein is suggested. Accordingly, this systematic review attempts to provide a comprehensible database to facilitate multicentered collaboration, validation, and clinical translation.