Carnation Italian Ringspot Virus p36 Expression Induces Mitochondrial Fission and Respiratory Chain Complex Impairment in Yeast.

Positive-strand RNA virus replication invariably occurs in association with host cell membranes, which are induced to proliferate and rearrange to form vesicular structures where the virus replication complex is assembled. In particular, carnation Italian ringspot virus (CIRV) replication takes place on the mitochondrial outer membrane in plant and yeast cells. In this work, the model host was used to investigate the effects of CIRV p36 expression on the mitochondrial structure and function through the determination of mitochondrial morphology, mitochondrial respiratory parameters, and respiratory chain complex activities in p36-expressing cells.

Targeting mitochondrial impairment for the treatment of cardiovascular diseases: From hypertension to ischemia-reperfusion injury, searching for new pharmacological targets.

Mitochondria and mitochondrial proteins represent a group of promising pharmacological target candidates in the search of new molecular targets and drugs to counteract the onset of hypertension and more in general cardiovascular diseases (CVDs). Indeed, several mitochondrial pathways result impaired in CVDs, showing ATP depletion and ROS production as common traits of cardiac tissue degeneration. Thus, targeting mitochondrial dysfunction in cardiomyocytes can represent a successful strategy to prevent heart failure.

Personalized Medicine in Mitochondrial Health and Disease: Molecular Basis of Therapeutic Approaches Based on Nutritional Supplements and Their Analogs.

Mitochondrial diseases (MDs) may result from mutations affecting nuclear or mitochondrial genes, encoding mitochondrial proteins, or non-protein-coding mitochondrial RNA. Despite the great variability of affected genes, in the most severe cases, a neuromuscular and neurodegenerative phenotype is observed, and no specific therapy exists for a complete recovery from the disease. The most used treatments are symptomatic and based on the administration of antioxidant cocktails combined with antiepileptic/antipsychotic drugs and supportive therapy for multiorgan involvement.

Mitochondrial Membranes of Human SH-SY5Y Neuroblastoma Cells Express Serotonin 5-HT Receptor.

Mitochondria in neurons contribute to energy supply, the regulation of synaptic transmission, Ca homeostasis, neuronal excitability, and stress adaptation. In recent years, several studies have highlighted that the neurotransmitter serotonin (5-HT) plays an important role in mitochondrial biogenesis in cortical neurons, and regulates mitochondrial activity and cellular function in cardiomyocytes. 5-HT exerts its diverse actions by binding to cell surface receptors that are classified into seven distinct families (5-HT1 to 5-HT7).

Acid Stress Triggers Resistance to Acetic Acid-Induced Regulated Cell Death through Activation Which Requires in Yeast.

Acid stress causes resistance to acetic acid-induced regulated cell death (AA-RCD) in budding yeast, resulting in catalase activation. In order to explore the molecular determinants of evasion of AA-RCD triggered by acid stress adaptation, we studied the involvement and the possible interplay of the master regulator of transcription high-osmolarity glycerol 1 () and , a positive regulator of the -dependent mitochondrial retrograde signaling. Viability, DNA fragmentation, and ROS accumulation have been analyzed in wild-type and mutant cells lacking and/or .

Inhibition of Drp1-mediated mitochondrial fission improves mitochondrial dynamics and bioenergetics stimulating neurogenesis in hippocampal progenitor cells from a Down syndrome mouse model.

Functional and structural damages to mitochondria have been critically associated with the pathogenesis of Down syndrome (DS), a human multifactorial disease caused by trisomy of chromosome 21 and associated with neurodevelopmental delay, intellectual disability and early neurodegeneration. Recently, we demonstrated in neural progenitor cells (NPCs) isolated from the hippocampus of Ts65Dn mice -a widely used model of DS - a severe impairment of mitochondrial bioenergetics and biogenesis and reduced NPC proliferation. Here we further investigated the origin of mitochondrial dysfunction in DS and explored a possible mechanistic link among alteration of mitochondrial dynamics, mitochondrial dysfunctions and defective neurogenesis in DS.

The transcription factors or are required for RTG pathway activation and evasion from yeast acetic acid-induced programmed cell death in raffinose.

Yeast grown on glucose undergoes programmed cell death (PCD) induced by acetic acid (AA-PCD), but evades PCD when grown in raffinose. This is due to concomitant relief of carbon catabolite repression (CCR) and activation of mitochondrial retrograde signaling, a mitochondria-to-nucleus communication pathway causing up-regulation of various nuclear target genes, such as , encoding peroxisomal citrate synthase, dependent on the positive regulator in response to mitochondrial dysfunction. CCR down-regulates genes mainly involved in mitochondrial respiratory metabolism.

Synthesis and Biological Evaluation of a Valinomycin Analog Bearing a Pentafluorophenyl Active Ester Moiety.

A valuable analog of the K(+)-ionophore valinomycin (1), bearing a pentafluorophenyl ester moiety, has been obtained by selective reaction between the tertiary hydroxyl moiety of analog 2 (available from valinomycin hydroxylation) and the isocyanate group of pentafluorophenyl N-carbonyl glycinate (3) catalyzed by bis(N,N-dimethylformamide)dichlorodioxomolybdenum(VI). LC-HRMS studies show that analog 4 undergoes easy derivatization under mild conditions by reaction with OH- and NH2-containing compounds. Mitochondrial depolarization assays suggest that 4 acts as a K(+)-ionophore, provided that the glycine carboxyl group is appropriately masked.

Yeast growth in raffinose results in resistance to acetic-acid induced programmed cell death mostly due to the activation of the mitochondrial retrograde pathway.

In order to investigate whether and how a modification of mitochondrial metabolism can affect yeast sensitivity to programmed cell death (PCD) induced by acetic acid (AA-PCD), yeast cells were grown on raffinose, as a sole carbon source, which, differently from glucose, favours mitochondrial respiration. We found that, differently from glucose-grown cells, raffinose-grown cells were mostly resistant to AA-PCD and that this was due to the activation of mitochondrial retrograde (RTG) response, which increased with time, as revealed by the up-regulation of the peroxisomal isoform of citrate synthase and isocitrate dehydrogenase isoform 1, RTG pathway target genes. Accordingly, the deletion of RTG2 and RTG3, a positive regulator and a transcription factor of the RTG pathway, resulted in AA-PCD, as shown by TUNEL assay.

MED1101: a new dialdehydic compound regulating P2×7 receptor cell surface expression in U937 cells.

Background Information: P2×7R is a member of the ionotropic family of purinergic receptors activated by millimolar concentrations of extracellular ATP such as induced by inflammatory stimuli. The receptor is widely expressed in cells of haematopoietic origin such as monocytes, macrophages and microglia. There is growing interest in anta-gonist compounds of the P2×7R since it has been demonstrated to be a viable therapeutic target for inflammatory diseases.

CFTR regulation in human airway epithelial cells requires integrity of the actin cytoskeleton and compartmentalized cAMP and PKA activity.

The cystic fibrosis transmembrane conductance regulator (CFTR) mutation ΔF508CFTR still causes regulatory defects when rescued to the apical membrane, suggesting that the intracellular milieu might affect its ability to respond to cAMP regulation. We recently reported that overexpression of the Na(+)/H(+) exchanger regulatory factor NHERF1 in the cystic fibrosis (CF) airway cell line CFBE41o-rescues the functional expression of ΔF508CFTR by promoting F-actin organization and formation of the NHERF1-ezrin-actin complex. Here, using real-time FRET reporters of both PKA activity and cAMP levels, we find that lack of an organized subcortical cytoskeleton in CFBE41o-cells causes both defective accumulation of cAMP in the subcortical compartment and excessive cytosolic accumulation of cAMP.

Valinomycin induced energy-dependent mitochondrial swelling, cytochrome c release, cytosolic NADH/cytochrome c oxidation and apoptosis.

In valinomycin induced stimulation of mitochondrial energy dependent reversible swelling, supported by succinate oxidation, cytochrome c (cyto-c) and sulfite oxidase (Sox) [both present in the mitochondrial intermembrane space (MIS)] are released outside. This effect can be observed at a valinomycin concentration as low as 1 nM. The rate of cytosolic NADH/cyto-c electron transport pathway is also greatly stimulated.

Ceramide-induced activation of cytosolic NADH/cytochrome c electron transport pathway: An additional source of energy for apoptosis.

We have investigated whether increase in the oxidation rate of exogenous cytochrome c (cyto-c), induced by long-chain ceramides, might be due to an increased rate of cytosolic NADH/cyto-c electron transport pathway. This process was identified in isolated liver mitochondria and has been studied in our laboratory for many years. Data from highly specific test of sulfite oxidase prove that exogenous cyto-c both in the absence and presence of ceramide cannot permeate through the mitochondrial outer membrane.

Interaction of nitric oxide with the activity of cytosolic NADH/cytochrome c electron transport system.

Nitric oxide ((.)NO) generated by the dissociation of S-nitrosoglutathione or added as gaseous solution, inhibits the oxidation of exogenous NADH supported by the activity of the cytosolic NADH/cyto-c electron transport pathway. The inhibition is immediate, very strong, higher at lower oxygen concentration, independent on the (.

Effect of magnesium ions on the activity of the cytosolic NADH/cytochrome c electron transport system.

Cytochrome c (cyto-c), added to isolated mitochondria, activates the oxidation of extramitochondrial NADH and the generation of a membrane potential, both linked to the activity of the cytosolic NADH/cyto-c electron transport pathway. The data presented in this article show that the protective effect of magnesium ions on the permeability of the mitochondrial outer membrane, supported by previously published data, correlates with the finding that, in hypotonic but not isotonic medium, magnesium promotes a differential effect on both the additional release of endogenous cyto-c and on the increased rate of NADH oxidation, depending on whether it is added before or after the mitochondria. At the same time, magnesium prevents or almost completely removes the binding of exogenously added cyto-c.

Protective effect of magnesium and potassium ions on the permeability of the external mitochondrial membrane.

The data reported are fully consistent with the well-known observation that exogenous cytochrome c (cyto-c) molecules do not permeate through the outer membrane of mitochondria (MOM) incubated in isotonic medium (250 mM sucrose). Cyto-c is unable to accept electrons from the sulfite/cyto-c oxido-reductase (Sox) present in the intermembrane space, unless mitochondria are solubilized. Mitochondria incubated in a very high hypotonic medium (25 mM sucrose), in contrast to any expectation, continue to be not permeable to added cyto-c even if Sox and adenylate kinase are released into the medium.

Porin and cytochrome oxidase containing contact sites involved in the oxidation of cytosolic NADH.

Cytochrome c (cyto-c) added to isolated mitochondria promotes the oxidation of extra-mitochondrial NADH and the reduction of molecular oxygen associated to the generation of an electrochemical membrane potential available for ATP synthesis. The electron transport pathway activated by exogenous cyto-c molecules is completely distinct from the one catalyzed by the respiratory chain. Dextran sulfate (500 kDa), known to interact with porin (the voltage-dependent anion channel), other than to inhibit the release of ATP synthesized inside the mitochondria, greatly decreases the activity of exogenous NADH/cyto-c system of intact mitochondria but has no effect on the reconstituted system made of mitoplasts and external membrane preparations.

Cytochrome c-induced cytosolic nicotinamide adenine dinucleotide oxidation, mitochondrial permeability transition, and apoptosis.

A catalytic amount of cytochrome c (cyto-c) added to the incubation medium of isolated mitochondria promotes the transfer of reducing equivalents from extramitochondrial nicotinamide adenine dinucleotide in its reduced state (NADH) to molecular oxygen inside the mitochondria, a process coupled to the generation of a membrane potential. This mimics in many aspects the early stages of those apoptotic pathways characterized by the persistence of mitochondrial membrane potential but with cyto-c already exported into the cytosol. In cyclosporin-sensitive and calcium-induced mitochondrial permeability transition (MPT) a release of cyto-c can also be observed.