Loss of Prohibitin Membrane Scaffolds Impairs Mitochondrial Architecture and Leads to Tau Hyperphosphorylation and Neurodegeneration

Fusion and fission of mitochondria maintain the functional integrity of mitochondria and protect against neurodegeneration, but how mitochondrial dysfunctions trigger neuronal loss remains ill-defined. Prohibitins form large ring complexes in the inner membrane that are composed of PHB1 and PHB2 subunits and are thought to function as membrane scaffolds. In Caenorhabditis elegans, prohibitin genes affect aging by moderating fat metabolism and energy production. Knockdown experiments in mammalian cells link the function of prohibitins to membrane fusion, as they were found to stabilize the dynamin-like GTPase OPA1 (optic atrophy 1), which mediates mitochondrial inner membrane fusion and cristae morphogenesis. Mutations in OPA1 are associated with dominant optic atrophy characterized by the progressive loss of retinal ganglion cells, highlighting the importance of OPA1 function in neurons. Here, we show that neuron-specific inactivation of Phb2 in the mouse forebrain causes extensive neurodegeneration associated with behavioral impairments and cognitive deficiencies. We observe early onset tau hyperphosphorylation and filament formation in the hippocampus, demonstrating a direct link between mitochondrial defects and tau pathology. Loss of PHB2 impairs the stability of OPA1, affects mitochondrial ultrastructure, and induces the perinuclear clustering of mitochondria in hippocampal neurons. A destabilization of the mitochondrial genome and respiratory deficiencies manifest in aged neurons only, while the appearance of mitochondrial morphology defects correlates with tau hyperphosphorylation in the absence of PHB2. These results establish an essential role of prohibitin complexes for neuronal survival in vivo and demonstrate that OPA1 stability, mitochondrial fusion, and the maintenance of the mitochondrial genome in neurons depend on these scaffolding proteins. Moreover, our findings establish prohibitin-deficient mice as a novel genetic model for tau pathologies caused by a dysfunction of mitochondria and raise the possibility that tau pathologies are associated with other neurodegenerative disorders caused by deficiencies in mitochondrial dynamics

Ablation of TrkB signalling in CCK neurons results in hypercortisolism and obesity

Dysregulation of hypothalamic-pituitary-adrenal (HPA) axis activity leads to debilitating neuroendocrine or metabolic disorders such as Cushing's syndrome (CS). Glucocorticoids control HPA axis activity through negative feedback to the pituitary gland and the central nervous system (CNS). However, the cellular mechanisms involved are poorly understood, particularly in the CNS. Here we show that, in mice, selective loss of TrkB signalling in cholecystokinin (CCK)-GABAergic neurons induces glucocorticoid resistance, resulting in increased corticotrophin-releasing hormone expression, chronic hypercortisolism, adrenocortical hyperplasia, glucose intolerance and mature-onset obesity, reminiscent of the human CS phenotype. Interestingly, obesity is not due to hyperphagia or decreased energy expenditure, but is associated with increased de novo lipogenesis in the liver. Our study therefore identifies CCK neurons as a novel and critical cellular component of the HPA axis, and demonstrates the requirement of TrkB for the transmission of glucocorticoid signalling

K-ATP-Channel-Dependent Regulation of Catecholaminergic Neurons Controls BAT Sympathetic Nerve Activity and Energy Homeostasis

Brown adipose tissue (BAT) is a critical regulator of glucose, lipid, and energy homeostasis, and its activity is tightly controlled by the sympathetic nervous system. However, the mechanisms underlying CNS-dependent control of BAT sympathetic nerve activity (SNA) are only partly understood. Here, we demonstrate that catecholaminergic neurons in the locus coeruleus (LC) adapt their firing frequency to extracellular glucose concentrations in a K-ATP-channel-dependent manner. Inhibiting K-ATP-channel-dependent control of neuronal activity via the expression of a variant K-ATP channel in tyrosine-hydroxylase-expressing neurons and in neurons of the LC enhances diet-induced obesity in mice. Obesity results from decreased energy expenditure, lower steady-state BAT SNA, and an attenuated ability of centrally applied glucose to activate BAT SNA. This impairs the thermogenic transcriptional program of BAT. Collectively, our data reveal a role of K-ATP-channel-dependent neuronal excitability in catecholaminergic neurons in maintaining thermogenic BAT sympathetic tone and energy homeostasis

The Fat Mass and Obesity-Associated Protein (FTO) Regulates Locomotor Responses to Novelty via D2R Medium Spiny Neurons

Variations in the human FTO gene have been linked to obesity and altered connectivity of the dopaminergic neurocircuitry. Here, we report that fat mass and obesity-associated protein (FTO) in dopamine D2 receptor-expressing medium spiny neurons (D2 MSNs) of mice regulate the excitability of these cells and control their striatopallidal globus pallidus external (GPe) projections. Lack of FTO in D2 MSNs translates into increased locomotor activity to novelty, associated with altered timing behavior, without impairing the ability to control actions or affecting reward-driven and conditioned behavior. Pharmacological manipulations of dopamine D1 receptor (D1R)- or D2R-dependent pathways in these animals reveal altered responses to D1- and D2-MSN-mediated control of motor output. These findings reveal a critical role for FTO to control D2 MSN excitability, their projections to the GPe, and behavioral responses to novelty

Obesity-Induced CerS6-Dependent C-16:0 Ceramide Production Promotes Weight Gain and Glucose Intolerance

Ceramides increase during obesity and promote insulin resistance. Ceramides vary in acyl-chain lengths from C-14:0 to C-30:0 and are synthesized by six ceramide synthase enzymes (CerS1-6). It remains unresolved whether obesity-associated alterations of specific CerSs and their defined acyl-chain length ceramides contribute to the manifestation of metabolic diseases. Here we reveal that CERS6 mRNA expression and C-16:0 ceramides are elevated in adipose tissue of obese humans, and increased CERS6 expression correlates with insulin resistance. Conversely, CerS6-deficient (CerS6 D/D) mice exhibit reduced C-16:0 ceramides and are protected from high-fat-diet-induced obesity and glucose intolerance. CerS6 deletion increases energy expenditure and improves glucose tolerance, not only in CerS6 D/D mice, but also in brown adipose tissue-(CerS6 DBAT) and liver-specific (CerS6 DLIVER) CerS6 knockout mice. CerS6 deficiency increases lipid utilization in BAT and liver. These experiments highlight CerS6 inhibition as a specific approach for the treatment of obesity and type 2 diabetes mellitus, circumventing the side effects of global ceramide synthesis inhibition

Application of tobacco hairy roots for the removal of malachite green from aqueous solutions: Experimental design, kinetic, equilibrium, and thermodynamic studies

Tobacco hairy roots (THR) were used to evaluate its potential for the biosorption and removal of malachite green (MG) from aqueous solutions. A 32 full factorial design was applied to study the effects of pH and THR concentration on the biosorption capacity. Under the optimal conditions (pH of 7.0 and THR concentration of 1 g L−1), dye removal efficiency was around 92%. Experimental data obtained from kinetic studies demonstrated good concordance with the pseudo-second-order model. Equilibrium studies were developed and the data were evaluated by Langmuir, Freundlich, and Sips models, being the Sips model the most adequate (maximum biosorption capacity of 277.2 mg g−1). Thermodynamically, the biosorption of MG on THR proved to be endothermic, spontaneous, and favorable. Desorption was feasible under acidic conditions and the biosorbent could be reused three times. THR was tested in simulated effluent and the removal percentage was 87%, demonstrating that this material is a promising biosorbent which can be used to treat colored wastewaters.Fil: Escudero, Leticia Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales. Laboratorio de Química Analítica para Investigación y Desarrollo; ArgentinaFil: Agostini, Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; ArgentinaFil: Dotto, Guilherme L.. Universidade Federal de Santa Maria; Brasi