Melatonin transport into mitochondria

Melatonin is a well-known, nighttime-produced indole found in bacteria, eukaryotic unicellulars, animals or vascular plants. In vertebrates, melatonin is the major product of the pineal gland, which accounts for its increase in serum during the dark phase, but it is also produced by many other organs and cell types. Such a wide distribution is consistent with its multiple and well-described functions which include from the circadian regulation and adaptation to seasonal variations to immunomodulatory and oncostatic actions in different types of tumors. The discovery of its antioxidant properties in the early 1990s opened a new field of potential protective functions in multiple tissues. A special mention should be made regarding the nervous system, where the indole is considered a major neuroprotector. Furthermore, mitochondria appear as one of the most important targets for the indole’s protective actions. Melatonin’s mechanisms of action vary from the direct molecular interaction with free radicals (free radical scavenger) to the binding to membrane (MLT1A and MLT1B) or nuclear receptors (RZR/RORα). Receptor binding has been associated with some, but not all of the indole functions reported to date. Recently, two new mechanisms of cellular uptake involving the facilitative glucose transporters GLUT/SLC2A and the proton-driven oligopeptide transporter PEPT1/2 have been reported. Here we discuss the potential importance that these newly discovered transport systems could have in determining the actions of melatonin, particularly in the mitochondria. We also argue the relative importance of passive diffusion vs active transport in different parts of the cell.     

Regulation of the H<Superscript>+</Superscript>-ATP synthase by IF1: a role in mitohormesis

The mitochondrial H⁺-ATP synthase is a primary hub of cellular homeostasis by providing the energy required to sustain cellular activity and regulating the production of signaling molecules that reprogram nuclear activity needed for adaption to changing cues. Herein, we summarize findings regarding the regulation of the activity of the H⁺-ATP synthase by its physiological inhibitor, the ATPase inhibitory factor 1 (IF1) and their functional role in cellular homeostasis. First, we outline the structure and the main molecular mechanisms that regulate the activity of the enzyme. Next, we describe the molecular biology of IF1 and summarize the regulation of IF1 expression and activity as an inhibitor of the H⁺-ATP synthase emphasizing the role of IF1 as a main driver of energy rewiring and cellular signaling in cancer. Findings in transgenic mice in vivo indicate that the overexpression of IF1 is sufficient to reprogram energy metabolism to an enhanced glycolysis and activate reactive oxygen species (ROS)-dependent signaling pathways that promote cell survival. These findings are placed in the context of mitohormesis, a program in which a mild mitochondrial stress triggers adaptive cytoprotective mechanisms that improve lifespan. In this regard, we emphasize the role played by the H⁺-ATP synthase in modulating signaling pathways that activate the mitohormetic response, namely ATP, ROS and target of rapamycin (TOR). Overall, we aim to highlight the relevant role of the H⁺-ATP synthase and of IF1 in cellular physiology and the need of additional studies to decipher their contributions to aging and age-related diseases.     

Electroneutral absorption of NaCl by the aldosterone-sensitive distal nephron: implication for normal electrolytes homeostasis and blood pressure regulation

Sodium absorption by the distal part of the nephron, i.e., the distal convoluted tubule, the connecting tubule, and the collecting duct, plays a major role in the control of homeostasis by the kidney. In this part of the nephron, sodium transport can either be electroneutral or electrogenic. The study of electrogenic Na⁺ absorption, which is mediated by the epithelial sodium channel (ENaC), has been the focus of considerable interest because of its implication in sodium, potassium, and acid–base homeostasis. However, recent studies have highlighted the crucial role played by electroneutral NaCl absorption in the regulation of the body content of sodium chloride, which in turn controls extracellular fluid volume and blood pressure. Here, we review the identification and characterization of the NaCl cotransporter (NCC), the molecule accounting for the main part of electroneutral NaCl absorption in the distal nephron, and its regulators. We also discuss recent work describing the identification of a novel “NCC-like” transport system mediated by pendrin and the sodium-driven chloride/bicarbonate exchanger (NDCBE) in the β-intercalated cells of the collecting system.     

Developmental regulation of p70 S6 kinase by a G protein-coupled receptor dynamically modelized in primary cells

The mechanisms whereby G protein-coupled receptors (GPCR) activate signalling pathways involved in mRNA translation are ill-defined, in contrast to tyrosine kinase receptors (TKR). We compared a GPCR and a TKR, both endogenously expressed, for their ability to mediate phosphorylation of 70-kDa ribosomal S6 kinase p70S6K in primary rat Sertoli cells at two developmental stages. In proliferating cells stimulated with follicle-stimulating hormone (FSH), active p70S6K was phosphorylated on T389 and T421/S424, through cAMP-dependent kinase (PKA) and phosphatidyl-inositide-3 kinase (PI3K) antagonizing actions. In FSH-stimulated differentiating cells, active p70S6K was phosphorylated solely on T389, PKA and PI3K independently enhancing its activity. At both developmental stages, insulin-induced p70S6K regulation was consistent with reported data. Therefore, TKR and GPCR trigger distinct p70S6K active conformations. p70S6K developmental regulation was formalized in a dynamic mathematical model fitting the data, which led to experimentally inaccessible predictions on p70S6K phosphorylation rate.     

Un curare d'une Erythrine africaine

Summary An alcaloid C₁₆H₁₉NO₃ has been isolated fromErythrina tholloniana; the iodohydrate of this erythroidine has a melting point of 225°C and 239°C for its chlorhydrate. It has a powerful curare-like action on the frog or on its isolated sciatic-sartorius preparation; at a concentration of less than 1/1,000,000, a complete neuromuscular block is produced: the electrical stimulation of the motor nerve does not produce any contraction, but the muscle reacts by an end-plate potential having the same characteristics (shape, duration, possibility of summation) as the electrical waves produced in the same preparation curarized by ordinary curare or by quaternary ammonium derivatives. Decurarization by veratrine 1/200,000 is accompanied by the same electrical reactions as those which have been described in preparations treated by curare.On mammals, the alcaloid has little curariform activity; on the isolated phrenic-diaphragm preparation of the rat, incomplete block was produced at a concentration of 1/5000.