Proteins requiring post-translational modifications such as N-linked glycosylation are processed in the endoplasmic reticulum (ER). A diverse array of cellular stresses can lead to dysfunction of the ER and ultimately to an imbalance between protein-folding capacity and protein-folding load. Cells monitor protein folding by an inbuilt quality control system involving both the ER and the Golgi apparatus. Unfolded or misfolded proteins are tagged for degradation via ER associated degradation (ERAD) or sent back through the folding cycle. Continued accumulation of incorrectly folded proteins can also trigger the Unfolded Protein Response (UPR). In mammalian cells, UPR is a complex signaling program mediated by three ER transmembrane receptors: activating transcription factor 6 (ATF6), inositol requiring kinase 1 (IRE1) and double-stranded RNA-activated protein kinase (PKR)-like endoplasmic reticulum kinase (PERK). UPR performs three functions, adaptation, alarm and apoptosis. During adaptation, the UPR tries to reestablish folding homeostasis by inducing the expression of chaperones that enhance protein folding. Simultaneously, global translation is attenuated to reduce the ER folding load while the degradation rate of unfolded proteins is increased. If these steps fail, the UPR induces a cellular alarm and mitochondrial mediated apoptosis program. UPR malfunctions have been associated with a wide range of disease states including tumor progression, diabetes, as well as immune and inflammatory disorders. This review describes recent advances in understanding the molecular structure of UPR in mammalian cells, its functional role in cellular stress, and its pathophysiology.
The menstrual cycle is an essential life rhythm governed by interacting levels of progesterone, estradiol, follicular stimulating, and luteinizing hormones. To study metabolic changes, biofluids were collected at four timepoints in the menstrual cycle from 34 healthy, premenopausal women. Serum hormones, urinary luteinizing hormone and self-reported menstrual cycle timing were used for a 5-phase cycle classification. Plasma and urine were analyzed using LC-MS and GC-MS for metabolomics and lipidomics; serum for clinical chemistries; and plasma for B vitamins using HPLC-FLD. Of 397 metabolites and micronutrients tested, 208 were significantly (p < 0.05) changed and 71 reached the FDR 0.20 threshold showing rhythmicity in neurotransmitter precursors, glutathione metabolism, the urea cycle, 4-pyridoxic acid, and 25-OH vitamin D. In total, 39 amino acids and derivatives and 18 lipid species decreased (FDR < 0.20) in the luteal phase, possibly indicative of an anabolic state during the progesterone peak and recovery during menstruation and the follicular phase. The reduced metabolite levels observed may represent a time of vulnerability to hormone related health issues such as PMS and PMDD, in the setting of a healthy, rhythmic state. These results provide a foundation for further research on cyclic differences in nutrient-related metabolites and may form the basis of novel nutrition strategies for women.
Mathematical modeling is an essential tool for a comprehensive understanding of cell metabolism and its interactions with the environmental and process conditions. Recent developments in the construction and analysis of stoichiometric models made it possible to define limits on steady-state metabolic behavior using flux balance analysis. However, detailed information about enzyme kinetics and enzyme regulation is needed to formulate kinetic models that can accurately capture the dynamic metabolic responses.The use of mechanistic enzyme kinetics is a difficult task due to uncertainty in the kinetic properties of enzymes. Therefore, the majority of recent works consider only the mass action kinetics for the reactions in the metabolic networks. In this work, we applied the ORACLE framework and constructed a large-scale, mechanistic kinetic model of optimally grown E. coli. We investigated the complex interplay between stoichiometry, thermodynamics, and kinetics in determining the flexibility and capabilities of metabolism. Our results indicate that enzyme saturation is a necessary consideration in modeling metabolic networks and it extends the feasible ranges of the metabolic fluxes and metabolite concentrations. Our results further suggest that the enzymes in metabolic networks have evolved to function at different saturation states to ensure greater flexibility and robustness of the cellular metabolism.
The microbiome has been demonstrated to play an integral role in the maintenance of many aspects of health that are also associated with aging. In order to identify areas of potential exploration and intervention, we simultaneously characterized age-related alterations in gut microbiome, muscle physiology and serum proteomic and lipidomic profiles in aged rats to define an integrated signature of the aging phenotype. We demonstrate that aging skews the composition of the gut microbiome, in particular by altering the Sutterella to Barneseilla ratio, and alters the metabolic potential of intestinal bacteria. Age-related changes of the gut microbiome were associated with the physiological decline of musculoskeletal function, and with molecular markers of nutrient processing/availability, and inflammatory/immune status in aged versus adult rats. Altogether, our study highlights that aging leads to a complex interplay between the microbiome and host physiology, and provides candidate microbial species to target physical and metabolic decline during aging by modulating gut microbial ecology.
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