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The Journal of Cell Biology Apr 2022Genetic, environmental, and aging-related insults can promote the misfolding and subsequent aggregation of secreted proteins implicated in the pathogenesis of numerous... (Review)
Review
Genetic, environmental, and aging-related insults can promote the misfolding and subsequent aggregation of secreted proteins implicated in the pathogenesis of numerous diseases. This has led to considerable interest in understanding the molecular mechanisms responsible for regulating proteostasis in extracellular environments such as the blood and cerebrospinal fluid (CSF). Extracellular proteostasis is largely dictated by biological pathways comprising chaperones, folding enzymes, and degradation factors localized to the ER and extracellular space. These pathways limit the accumulation of nonnative, potentially aggregation-prone proteins in extracellular environments. Many reviews discuss the molecular mechanisms by which these pathways impact the conformational integrity of the secreted proteome. Here, we instead focus on describing the stress-responsive mechanisms responsible for adapting ER and extracellular proteostasis pathways to protect the secreted proteome from pathologic insults that challenge these environments. Further, we highlight new strategies to identify stress-responsive pathways involved in regulating extracellular proteostasis and describe the pathologic and therapeutic implications for these pathways in human disease.
Topics: Animals; Endoplasmic Reticulum; Extracellular Space; Humans; Molecular Chaperones; Proteostasis; Stress, Physiological; Unfolded Protein Response
PubMed: 35191945
DOI: 10.1083/jcb.202112104 -
International Journal of Molecular... Feb 2021Macrophages are present in nearly all vertebrate tissues, where they respond to a complex variety of regulatory signals to coordinate immune functions involved in tissue... (Review)
Review
Macrophages are present in nearly all vertebrate tissues, where they respond to a complex variety of regulatory signals to coordinate immune functions involved in tissue development, metabolism, homeostasis, and repair. Glycogen synthase kinase 3 (GSK3) is a ubiquitously expressed protein kinase that plays important roles in multiple pathways involved in cell metabolism. Dysregulation of GSK3 has been implicated in several prevalent metabolic disorders, and recent findings have highlighted the importance of GSK3 activity in the regulation of macrophages, especially with respect to the initiation of specific pathologies. This makes GSK3 a potential therapeutic target for the development of novel drugs to modulate immunometabolic responses. Here, we summarize recent findings that have contributed to our understanding of how GSK3 regulates macrophage function, and we discuss the role of GSK3 in the development of metabolic disorders and diseases.
Topics: Animals; Apoptosis; Glycogen Synthase Kinase 3; Humans; Inflammation; Lipid Metabolism; Macrophages; Unfolded Protein Response
PubMed: 33672232
DOI: 10.3390/ijms22042206 -
Antioxidants & Redox Signaling Apr 2020The geological record shows that as atmospheric O levels increased, it concomitantly coincided with the evolution of metazoans. More complex, higher organisms contain a... (Review)
Review
The geological record shows that as atmospheric O levels increased, it concomitantly coincided with the evolution of metazoans. More complex, higher organisms contain a more cysteine-rich proteome, potentially as a means to regulate homeostatic responses in a more O-rich environment. Regulation of redox-sensitive processes to control development is likely to be evolutionarily conserved. During early embryonic development, the conceptus is exposed to varying levels of O. Oxygen and redox-sensitive elements can be regulated to promote normal development, defined as changes to cellular mass, morphology, biochemistry, and function, suggesting that O is a developmental morphogen. During periods of O fluctuation, embryos are "reprogrammed," on the genomic and metabolic levels. Reprogramming imparts changes to particular redox couples (nodes) that would support specific post-translational modifications (PTMs), targeting the cysteine proteome to regulate protein function and development. Major developmental events such as stem cell expansion, proliferation, differentiation, migration, and cell fate decisions are controlled through oxidative PTMs of cysteine-based redox nodes. As such, timely coordinated redox regulation of these events yields normal developmental outcomes and viable species reproduction. Disruption of normal redox signaling can produce adverse developmental outcomes. Furthering our understanding of the redox-sensitive processes/pathways, the nature of the regulatory PTMs involved in development and periods of activation/sensitivity to specific developmental pathways would greatly support the theory of redox regulation of development, and would also provide rationale and direction to more fully comprehend poor developmental outcomes, such as dysmorphogenesis, functional deficits, and preterm embryonic death.
Topics: Animals; Biological Evolution; Environment; Humans; Oxidation-Reduction; Oxidative Stress; Oxygen; Protein Processing, Post-Translational
PubMed: 31891515
DOI: 10.1089/ars.2019.7976 -
Plant Signaling & Behavior Mar 2021Gamma-aminobutyric acid (GABA) is a ubiquitous four-carbon, non-protein amino acid. GABA has been widely studied in animal central nervous systems, where it acts as an... (Review)
Review
Gamma-aminobutyric acid (GABA) is a ubiquitous four-carbon, non-protein amino acid. GABA has been widely studied in animal central nervous systems, where it acts as an inhibitory neurotransmitter. In plants, it is metabolized through the GABA shunt pathway, a bypass of the tricarboxylic acid (TCA) cycle. Additionally, it can be synthesized through the polyamine metabolic pathway. GABA acts as a signal in -mediated plant gene transformation and in plant development, especially in pollen tube elongation (to enter the ovule), root growth, fruit ripening, and seed germination. It is accumulated during plant responses to environmental stresses and pathogen and insect attacks. A high concentration of GABA elevates plant stress tolerance by improving photosynthesis, inhibiting reactive oxygen species (ROS) generation, activating antioxidant enzymes, and regulating stomatal opening in drought stress. The transporters of GABA in plants are reviewed in this work. We summarize the recent research on GABA function and transporters with the goal of providing a review of GABA in plants.
Topics: GABA Plasma Membrane Transport Proteins; Metabolic Networks and Pathways; Plants; Signal Transduction; Stress, Physiological; gamma-Aminobutyric Acid
PubMed: 33404284
DOI: 10.1080/15592324.2020.1862565 -
Cellular and Molecular Life Sciences :... Dec 2020The metabolic complexity and flexibility commonly observed in brain tumors, especially glioblastoma, is fundamental for their development and progression. The ability of... (Review)
Review
The metabolic complexity and flexibility commonly observed in brain tumors, especially glioblastoma, is fundamental for their development and progression. The ability of tumor cells to modify their genetic landscape and adapt metabolically, subverts therapeutic efficacy, and inevitably instigates therapeutic resistance. To overcome these challenges and develop effective therapeutic strategies targeting essential metabolic processes, it is necessary to identify the mechanisms underlying heterogeneity and define metabolic preferences and liabilities of malignant cells. In this review, we will discuss metabolic diversity in brain cancer and highlight the role of cancer stem cells in regulating metabolic heterogeneity. We will also highlight potential therapeutic modalities targeting metabolic vulnerabilities and examine how intercellular metabolic signaling can shape the tumor microenvironment.
Topics: Brain Neoplasms; Genetic Heterogeneity; Glioblastoma; Glycolysis; Humans; Metabolism; Neoplastic Stem Cells; Signal Transduction; Tumor Microenvironment
PubMed: 32506168
DOI: 10.1007/s00018-020-03569-w -
American Journal of Physiology.... Oct 2020Mitochondrial-derived peptides (MDPs) are small bioactive peptides encoded by short open-reading frames (sORF) in mitochondrial DNA that do not necessarily have... (Review)
Review
Mitochondrial-derived peptides (MDPs) are small bioactive peptides encoded by short open-reading frames (sORF) in mitochondrial DNA that do not necessarily have traditional hallmarks of protein-coding genes. To date, eight MDPs have been identified, all of which have been shown to have various cyto- or metaboloprotective properties. The 12S ribosomal RNA () gene harbors the sequence for MOTS-c, whereas the other seven MDPs [humanin and small humanin-like peptides (SHLP) 1-6] are encoded by the 16S ribosomal RNA gene. Here, we review the evidence that endogenous MDPs are sensitive to changes in metabolism, showing that metabolic conditions like obesity, diabetes, and aging are associated with lower circulating MDPs, whereas in humans muscle MDP expression is upregulated in response to stress that perturbs the mitochondria like exercise, some mtDNA mutation-associated diseases, and healthy aging, which potentially suggests a tissue-specific response aimed at restoring cellular or mitochondrial homeostasis. Consistent with this, treatment of rodents with humanin, MOTS-c, and SHLP2 can enhance insulin sensitivity and offer protection against a range of age-associated metabolic disorders. Furthermore, assessing how mtDNA variants alter the functions of MDPs is beginning to provide evidence that MDPs are metabolic signal transducers in humans. Taken together, MDPs appear to form an important aspect of a retrograde signaling network that communicates mitochondrial status with the wider cell and to distal tissues to modulate adaptative responses to metabolic stress. It remains to be fully determined whether the metaboloprotective properties of MDPs can be harnessed into therapies for metabolic disease.
Topics: Animals; Energy Metabolism; Humans; Mitochondria; Mitochondrial Proteins; Peptides
PubMed: 32776825
DOI: 10.1152/ajpendo.00249.2020 -
Phytochemistry Sep 2022Microalgae are important primary producers and form the basis for the marine food web. As global climate changes, so do salinity levels that algae are exposed to. A...
Microalgae are important primary producers and form the basis for the marine food web. As global climate changes, so do salinity levels that algae are exposed to. A metabolic response of algal cells partly alleviates the resulting osmotic stress. Some metabolites involved in the response are well studied, but the full metabolic implications of adaptation remain unclear. Improved analytical methodology provides an opportunity for additional insight. We can now follow responses to stress in major parts of the metabolome and derive comprehensive charts of the resulting metabolic re-wiring. In this study, we subjected three species of diatoms to high salinity conditions and compared their metabolome to controls in an untargeted manner. The three well-investigated species with sequenced genomes Phaeodactylum tricornutum, Thalassiosira pseudonana, and Skeletonema marinoi were selected for our survey. The microalgae react to salinity stress with common adaptations in the metabolome by amino acid up-regulation, production of saccharides, and inositols. But also species-specific dysregulation of metabolites is common. Several metabolites previously not connected with osmotic stress reactions are identified, including 4-hydroxyproline, pipecolinic acid, myo-inositol, threonic acid, and acylcarnitines. This expands our knowledge about osmoadaptation and calls for further functional characterization of metabolites and pathways in algal stress physiology.
Topics: Acclimatization; Diatoms; Metabolome; Microalgae; Salinity
PubMed: 35671808
DOI: 10.1016/j.phytochem.2022.113267 -
Immunology Dec 2022The metabolic reprogramming during T cell activation and differentiation affects T cell fate and immune responses. Cell metabolism may serve as the driving force that... (Review)
Review
The metabolic reprogramming during T cell activation and differentiation affects T cell fate and immune responses. Cell metabolism may serve as the driving force that induces epigenetic modifications, contributing to regulating T cell differentiation. Persistent pathogen infection leads to T cell exhaustion, which is composed of two main subsets and with distinct metabolic characteristics. The progenitor exhausted T cells utilize mitochondrial fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) for energy, while terminally exhausted T cells mainly rely on glycolytic metabolism with impaired glycolysis and OXPHOS. Here, we compiled the latest research on how T cell metabolism defines differentiation, focusing on T cell exhaustion during chronic infections. In addition, metabolic-related factors including antigen stimulation signals strength, cytokines and epigenetics affecting T cell exhaustion were also reviewed. Furthermore, the intervention strategies on metabolism and epigenetics to reverse T cell exhaustion were discussed in detail, which may contribute to achieving the goal of prevention and treatment of T cell exhaustion.
Topics: T-Lymphocytes; Oxidative Phosphorylation; Glycolysis; Lymphocyte Activation; Cell Differentiation
PubMed: 36088582
DOI: 10.1111/imm.13575 -
Frontiers in Endocrinology 2023The ability to generate thermogenic fat could be a targeted therapy to thwart obesity and improve metabolic health. Brown and beige adipocytes are two types of... (Review)
Review
The ability to generate thermogenic fat could be a targeted therapy to thwart obesity and improve metabolic health. Brown and beige adipocytes are two types of thermogenic fat cells that regulate energy balance. Both adipocytes share common morphological, biochemical, and thermogenic properties. Yet, recent evidence suggests unique features exist between brown and beige adipocytes, such as their cellular origin and thermogenic regulatory processes. Beige adipocytes also appear highly plastic, responding to environmental stimuli and interconverting between beige and white adipocyte states. Additionally, beige adipocytes appear to be metabolically heterogenic and have substrate specificity. Nevertheless, obese and aged individuals cannot develop beige adipocytes in response to thermogenic fat-inducers, creating a key clinical hurdle to their therapeutic promise. Thus, elucidating the underlying developmental, molecular, and functional mechanisms that govern thermogenic fat cells will improve our understanding of systemic energy regulation and strive for new targeted therapies to generate thermogenic fat. This review will examine the recent advances in thermogenic fat biogenesis, molecular regulation, and the potential mechanisms for their failure.
Topics: Humans; Aged; Adipocytes; Adipose Tissue, Brown; Adipocytes, Beige; Energy Metabolism; Obesity
PubMed: 37020585
DOI: 10.3389/fendo.2023.1150059