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Trends in Biochemical Sciences Nov 2023Biomembranes are complex materials composed of lipids and proteins that compartmentalize biochemistry. They are actively remodeled in response to physical and metabolic... (Review)
Review
Biomembranes are complex materials composed of lipids and proteins that compartmentalize biochemistry. They are actively remodeled in response to physical and metabolic cues, as well as during cell differentiation and stress. The concept of homeoviscous adaptation has become a textbook example of membrane responsiveness. Here, we discuss limitations and common misconceptions revolving around it. By highlighting key moments in the life cycle of a transmembrane protein, we illustrate that membrane thickness and a finely regulated membrane compressibility are crucial to facilitate proper membrane protein insertion, function, sorting, and inheritance. We propose that the unfolded protein response (UPR) provides a mechanism for endoplasmic reticulum (ER) membrane homeostasis by sensing aberrant transverse membrane stiffening and triggering adaptive responses that re-establish membrane compressibility.
Topics: Endoplasmic Reticulum Stress; Unfolded Protein Response; Homeostasis; Endoplasmic Reticulum; Membrane Proteins
PubMed: 37652754
DOI: 10.1016/j.tibs.2023.08.004 -
The American Journal of Physiology Mar 1987Metabolism of aldosterone during the latent period prior to the action of the hormone may be of physiological importance. In the rat, liver metabolizes aldosterone in a... (Review)
Review
Metabolism of aldosterone during the latent period prior to the action of the hormone may be of physiological importance. In the rat, liver metabolizes aldosterone in a sex-dependent manner; larger quantities of neutral polar and reduced aldosterone derivatives are found in male rat kidney; correlating with the larger physiological responses of male rats to aldosterone. The target tissues, mammalian kidney and toad urinary bladder, are also capable of metabolizing aldosterone in situ to neutral polar, 5 alpha- and 5 beta-reduced, and monosulfate derivatives. The 5 alpha-reduced metabolites possess significant antinatriuretic activity and are preferentially synthesized by rat kidney nuclei. The metabolic pathways leading to the synthesis of 5 alpha-reduced metabolites and their subsequent neutral polar derivatives appear to be regulated by dietary sodium and can be inhibited by antimineralocorticoids. At concentrations somewhat higher than aldosterone, these 5 alpha-reduced metabolites also can recreate the development of hypertension and suppress plasma renin activity in young adrenalectomized spontaneously hypertensive rats. Thus, several of the metabolically transformed aldosterone derivatives can be correlated with physiological regulation and/or expression of the actions of the hormone.
Topics: Aldosterone; Animals; Female; Kidney; Liver; Male; Mineralocorticoids; Models, Biological; Sex Factors; Urinary Bladder
PubMed: 3548434
DOI: 10.1152/ajprenal.1987.252.3.F365 -
The Journal of Experimental Biology Dec 2015Pacific hagfish, Eptatretus stoutii, can recover from 36 h of anoxia at 10°C. Such anoxia tolerance demands the mobilization of anaerobic fuels and the removal of...
Pacific hagfish, Eptatretus stoutii, can recover from 36 h of anoxia at 10°C. Such anoxia tolerance demands the mobilization of anaerobic fuels and the removal of metabolic wastes--processes that require a functional heart. The purpose of this study was to measure the metabolic response of the excised, cannulated hagfish heart to anoxia using direct calorimetry. These experiments were coupled with measurements of cardiac pH and metabolite concentrations, at multiple time points, to monitor acid-base balance and anaerobic ATP production. We also exposed hagfish to anoxia to compare the in vitro responses of the excised hearts with the in vivo responses. The calorimetry results revealed a significant reduction in the rate of metabolic heat production over the first hour of anoxia exposure, and a recovery over the subsequent 6 h. This response is likely attributable to a rapid anoxia-induced depression of aerobic ATP-production pathways followed by an upregulation of anaerobic ATP-production pathways such that the ATP production rate was restored to that measured in normoxia. Glycogen-depletion measurements suggest that metabolic processes were initially supported by glycolysis but that an alternative fuel source was used to support the sustained rates of ATP production. The maintenance of intracellular pH during anoxia indicates a remarkable ability of the myocytes to buffer/regulate protons and thus protect cardiac function. Altogether, these results illustrate that the low metabolic demand of the hagfish heart allows for near-routine levels of cardiac metabolism to be supported anaerobically. This is probably a significant contributor to the hagfish's exceptional anoxia tolerance.
Topics: Acid-Base Equilibrium; Adenosine Triphosphate; Anaerobiosis; Animals; Cell Hypoxia; Glycolysis; Hagfishes; Hydrogen-Ion Concentration; Myocardium
PubMed: 26486366
DOI: 10.1242/jeb.125070 -
Journal of Dairy Science Oct 2023The dairy industry depends upon the cow's successful lactation for economic profitability. Heat stress compromises the economic sustainability of the dairy industry by... (Review)
Review
The dairy industry depends upon the cow's successful lactation for economic profitability. Heat stress compromises the economic sustainability of the dairy industry by reducing milk production and increasing the risk of metabolic and pathogenic disease. Heat stress alters metabolic adaptations, such as nutrient mobilization and partitioning, that support the energetic demands of lactation. Metabolically inflexible cows are unable to enlist the necessary homeorhetic shifts that provide the needed nutrients and energy for milk synthesis, thereby impairing lactation performance. Mitochondria provide the energetic foundation that enable a myriad of metabolically demanding processes, such as lactation. Changes in an animal's energy requirements are met at the cellular level through alterations in mitochondrial density and bioenergetic capacity. Mitochondria also act as central stress modulators and coordinate tissues' energetic responses to stress by integrating endocrine signals, through mito-nuclear communication, into the cellular stress response. In vitro heat insults affect mitochondria through a compromise in mitochondrial integrity, which is linked to a decrease in mitochondrial function. However, limited evidence exists linking the in vivo metabolic effects of heat stress with parameters of mitochondrial behavior and function in lactating animals. This review summarizes the literature describing the cellular and subcellular effects of heat stress, with a focus on the effect of heat stress on mitochondrial bioenergetics and cellular dysfunction in livestock. Implications for lactation performance and metabolic health are also discussed.
Topics: Female; Cattle; Animals; Lactation; Mitochondria; Milk; Energy Metabolism; Heat-Shock Response
PubMed: 37210354
DOI: 10.3168/jds.2023-23340 -
Gene Nov 2013Flag leaf is one of the key photosynthesis organs during rice reproductive stage. A time course microarray analysis of rice flag leaf was done after 40°C treatment for...
Flag leaf is one of the key photosynthesis organs during rice reproductive stage. A time course microarray analysis of rice flag leaf was done after 40°C treatment for 0 min, 20 min, 60 min, 2h, 4h, and 8h. The identified significant heat responsive genes were mainly involved in transcriptional regulation, transport, protein binding, antioxidant, and stress response. KMC analysis discovered the time-dependent gene expression pattern under heat. MapMan analysis demonstrated that, under heat treatment, Hsp genes and genes involved in glycolysis and ubiquitin-proteasome were enhanced, and genes involved in TCA, carotenoid, dihydroflavonol and anthocyanin metabolisms and light-reaction in the photosynthesis were widely repressed. Meanwhile, some rate-limiting enzyme genes in shikimate, lignin, and mevalonic acid metabolisms were up-regulated, revealing the importance of maintaining specific secondary metabolites under heat stress. The present study increased our understanding of heat response in rice flag leaf and provided good candidate genes for crop improvement.
Topics: Adaptation, Physiological; Gene Expression Profiling; Gene Expression Regulation, Plant; Heat-Shock Response; Hot Temperature; Metabolic Networks and Pathways; Oryza; Plant Leaves; Plant Proteins; Transcriptome
PubMed: 23994682
DOI: 10.1016/j.gene.2013.08.048 -
Biochimica Et Biophysica Acta. General... Aug 2018Paclitaxel, a widely used antimicrotubular agent, predominantly eliminates rapidly proliferating cancer cells, while slowly proliferating and quiescent cells can survive...
Paclitaxel, a widely used antimicrotubular agent, predominantly eliminates rapidly proliferating cancer cells, while slowly proliferating and quiescent cells can survive the treatment, which is one of the main reasons for tumor recurrence and non-responsiveness to the drug. To improve the efficacy of chemotherapy, biomarkers need to be developed to enable monitoring of tumor responses. In this study we considered the auto-fluorescent metabolic cofactors NAD(P)H and FAD as possible indicators of cancer cell response to therapy with paclitaxel. It was found that, among the tested parameters (the fluorescence intensity-based redox ratio FAD/NAD(P)H, and the fluorescence lifetimes of NAD(P)H and FAD), the fluorescence lifetime of NAD(P)H is the most sensitive in tracking the drug response, and is capable of indicating heterogeneous cellular responses both in cell monolayers and in multicellular tumor spheroids. We observed that metabolic reorganization to a more oxidative state preceded the morphological manifestation of cell death and developed faster in cells that were more responsive to the drug. Our results suggest that noninvasive, label-free monitoring of the drug-induced metabolic changes by noting the NAD(P)H fluorescence lifetime is a valuable approach to characterize the responses of cancer cells to anti-cancer treatments and, therefore, to predict the effectiveness of chemotherapy.
Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Biomarkers; Flavin-Adenine Dinucleotide; Humans; Microscopy, Fluorescence, Multiphoton; NADP; Neoplasms; Oxidation-Reduction; Paclitaxel; Tumor Cells, Cultured
PubMed: 29719197
DOI: 10.1016/j.bbagen.2018.04.021 -
Circulation Research Sep 2010Obesity is a major problem worldwide that increases risk for a wide range of diseases, including diabetes and heart disease. As such, it is increasingly important to... (Review)
Review
Obesity is a major problem worldwide that increases risk for a wide range of diseases, including diabetes and heart disease. As such, it is increasingly important to understand how excess adiposity can perturb normal metabolic functions. It is now clear that this disruption involves not only pathways controlling lipid and glucose homeostasis but also integration of metabolic and immune response pathways. Under conditions of nutritional excess, this integration can result in a metabolically driven, low-grade, chronic inflammatory state, referred to as "metaflammation," that targets metabolically critical organs and tissues to adversely affect systemic homeostasis. Endoplasmic reticulum dysfunction is another important feature of chronic metabolic disease that is also linked to both metabolic and immune regulation. A thorough understanding of how these pathways intersect to maintain metabolic homeostasis, as well as how this integration is altered under conditions of nutrient excess, is important to fully understand, and subsequently treat, chronic metabolic diseases.
Topics: Adipokines; Animals; Diabetes Complications; Endoplasmic Reticulum; Energy Metabolism; Humans; Inflammation; Inflammation Mediators; Lipid Metabolism; Obesity; Signal Transduction; Stress, Physiological; Unfolded Protein Response
PubMed: 20814028
DOI: 10.1161/CIRCRESAHA.110.225698 -
Cells May 2020Metabolic reprogramming is a hallmark of cancer cells in response to targeted therapy. Decreased glycolytic activity with enhanced mitochondrial respiration secondary to...
Metabolic reprogramming is a hallmark of cancer cells in response to targeted therapy. Decreased glycolytic activity with enhanced mitochondrial respiration secondary to imatinib has been shown in imatinib-sensitive gastrointestional stromal tumors (GIST). However, the role of energy metabolism in imatinib-resistant GIST remains poorly characterized. Here, we investigated the effect of imatinib treatment on glycolysis and oxidative phosphorylation (OXPHOS), as well as the effect of inhibition of these energy metabolisms on cell viability in imatinib-resistant and -sensitive GIST cell lines. We observed that imatinib treatment increased OXPHOS in imatinib-sensitive, but not imatinib-resistant, GIST cells. Imatinib also reduced the expression of mitochondrial biogenesis activators (peroxisome proliferator-activated receptor coactivator-1 alpha (PGC1α), nuclear respiratory factor 2 (NRF2), and mitochondrial transcription factor A (TFAM)) and mitochondrial mass in imatinib-sensitive GIST cells. Lower TFAM levels were also observed in imatinib-sensitive GISTs than in tumors from untreated patients. Using the Seahorse system, we observed bioenergetics diversity among the GIST cell lines. One of the acquired resistant cell lines (GIST 882R) displayed a highly metabolically active phenotype with higher glycolysis and OXPHOS levels compared with the parental GIST 882, while the other resistant cell line (GIST T1R) had a similar basal glycolytic activity but lower mitochondrial respiration than the parental GIST T1. Further functional assays demonstrated that GIST 882R was more vulnerable to glycolysis inhibition than GIST 882, while GIST T1R was more resistant to OXPHOS inhibition than GIST T1. These findings highlight the diverse energy metabolic adaptations in GIST cells that allow them to survive upon imatinib treatment and reveal the potential of targeting the metabolism for GIST therapy.
Topics: Antimycin A; Cell Death; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Energy Metabolism; Gastrointestinal Stromal Tumors; Gene Expression Regulation, Neoplastic; Glycolysis; Gossypol; Humans; Imatinib Mesylate; Oligomycins; Organelle Biogenesis; Oxidative Phosphorylation; Phenotype; Pyruvates
PubMed: 32466502
DOI: 10.3390/cells9061333 -
MBio Dec 2022Small alarmone hydrolases (SAHs) are alarmone metabolizing enzymes found in both metazoans and bacteria. In metazoans, the SAH homolog Mesh1 is reported to function in...
Small alarmone hydrolases (SAHs) are alarmone metabolizing enzymes found in both metazoans and bacteria. In metazoans, the SAH homolog Mesh1 is reported to function in cofactor metabolism by hydrolyzing NADPH to NADH. In bacteria, SAHs are often identified in genomes with toxic alarmone synthetases for self-resistance. Here, we characterized a bacterial orphan SAH, i.e., without a toxic alarmone synthetase, in the phytopathogen Xanthomonas campestris pv. (SAH) and found that it metabolizes both cellular alarmones and cofactors. , SAH displays abilities to hydrolyze multiple nucleotides, including pppGpp, ppGpp, pGpp, pppApp, and NADPH. , X. campestris pv. cells lacking accumulated higher levels of cellular (pp)pGpp and NADPH compared to wild-type cells upon amino acid starvation. In addition, X. campestris pv. mutants lacking were more sensitive to killing by Pseudomonas during interbacterial competition. Interestingly, loss of also resulted in reduced growth in amino acid-replete medium, a condition that did not induce (pp)pGpp or pppApp accumulation. Further metabolomic characterization revealed strong depletion of NADH levels in the X. campestris pv. mutant lacking , suggesting that NADPH/NADH regulation is an evolutionarily conserved function of both bacterial and metazoan SAHs and Mesh1. Overall, our work demonstrates a regulatory role of bacterial SAHs as tuners of stress responses and metabolism, beyond functioning as antitoxins. Small alarmone hydrolases (SAHs) comprise a widespread family of alarmone metabolizing enzymes. In metazoans, SAHs have been reported to control multiple aspects of physiology and stress resistance through alarmone and NADPH metabolisms, but their physiological functions in bacteria is mostly uncharacterized except for a few reports as antitoxins. Here, we identified an SAH functioning independently of toxins in the phytopathogen Xanthomonas campestris pv. . We found that SAH hydrolyzed multiple alarmones and NADPH , and X. campestris pv. mutants lacking displayed increased alarmone levels during starvation, loss of interspecies competitive fitness, growth defects, and strong reduction in NADH. Our findings reveal the importance of NADPH hydrolysis by a bacterial SAH. Our work is also the first report of significant physiological roles of bacterial SAHs beyond functioning as antitoxins and suggests that SAHs have far broader physiological roles and share similar functions across domains of life.
Topics: Animals; Guanosine Pentaphosphate; Hydrolases; Bacterial Proteins; NADP; NAD; Bacteria; Amino Acids; Xanthomonas campestris
PubMed: 36472432
DOI: 10.1128/mbio.02422-22