Circadian Clocks Make Metabolism Run Sinturel, Flore; Petrenko, Volodymyr; Dibner, Charna
Journal of molecular biology,
05/2020, Letnik:
432, Številka:
12
Journal Article
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Most organisms adapt to the 24-h cycle of the Earth's rotation by anticipating the time of the day through light-dark cycles. The internal time-keeping system of the circadian clocks has been ...developed to ensure this anticipation. The circadian system governs the rhythmicity of nearly all physiological and behavioral processes in mammals. In this review, we summarize current knowledge stemming from rodent and human studies on the tight interconnection between the circadian system and metabolism in the body. In particular, we highlight recent advances emphasizing the roles of the peripheral clocks located in the metabolic organs in regulating glucose, lipid, and protein homeostasis at the organismal and cellular levels. Experimental disruption of circadian system in rodents is associated with various metabolic disturbance phenotypes. Similarly, perturbation of the clockwork in humans is linked to the development of metabolic diseases. We discuss recent studies that reveal roles of the circadian system in the temporal coordination of metabolism under physiological conditions and in the development of human pathologies.
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•Central and peripheral clocks coordinate mammalian physiology.•Circadian oscillators are modulated by metabolic cycles.•Peripheral clocks regulate glucose, lipid, and protein homeostasis.•Circadian desynchrony promotes the development of metabolic pathologies in humans.
Voltage-dependent anion-selective channels (VDAC) are pore-forming proteins located in the outer mitochondrial membrane. Three isoforms are encoded by separate genes in mammals (VDAC1-3). These ...proteins play a crucial role in the cell, forming the primary interface between mitochondrial and cellular metabolisms. Research on the role of VDACs in the cell is a rapidly growing field, but the function of VDAC3 remains elusive. The high-sequence similarity between isoforms suggests a similar pore-forming structure. Electrophysiological analyzes revealed that VDAC3 works as a channel; however, its gating and regulation remain debated. A comparison between VDAC3 and VDAC1-2 underlines the presence of a higher number of cysteines in both isoforms 2 and 3. Recent mass spectrometry data demonstrated that the redox state of VDAC3 cysteines is evolutionarily conserved. Accordingly, these residues were always detected as totally reduced or partially oxidized, thus susceptible to disulfide exchange. The deletion of selected cysteines significantly influences the function of the channel. Some cysteine mutants of VDAC3 exhibited distinct kinetic behavior, conductance values and voltage dependence, suggesting that channel activity can be modulated by cysteine reduction/oxidation. These properties point to VDAC3 as a possible marker of redox signaling in the mitochondrial intermembrane space. Here, we summarize our current knowledge about VDAC3 predicted structure, physiological role and regulation, and possible future directions in this research field.
It is unclear how microangiopathic changes in skeletal muscle vary among systemic vascular pathologies. We therefore analyzed the capillary fine structure in skeletal muscle from patients with ...arterial hypertension (HYPT), diabetes mellitus type 2 (T2DM) or intermittent claudication - peripheral arterial disease (IC/PAD). Tablet-based image analysis (TBIA) was carried out to largely re-evaluate 5,000 transmission electron micrographs of capillaries from 126 vastus lateralis biopsies of 75 individuals (HYPT, T2DM or IC/PAD patients as well as healthy individuals before and after endurance exercise training) used in previous morphometric studies, but assessed using stereological counting grids of different sizes. Serial block-face scanning electron microscopy (SBFSEM) of mouse skeletal muscle was used for validation of the particular fine structural events observed in human biopsies. The peri-capillary basement membrane (BM) was 38.5 and 45.5% thicker (
< 0.05) in T2DM and IC/PAD patients than in the other groups. A 17.7-39.6% lower (
< 0.05) index for intraluminal endothelial cell (EC) surface enlargement by projections was exclusively found in T2DM patients by TBIA morphometry. The proportion of capillaries with disrupted BM between pericytes (PC) and EC was higher (
< 0.05) in HYPT (33.2%) and T2DM (38.7%) patients than in the control group. Empty EC-sockets were more frequent (
< 0.05) in the three patient groups (20.6% in HYPT, 27.1% in T2DM, 30.0% in IC/PAD) than in the healthy individuals. SBFSEM confirmed that EC-sockets may exhibit close proximity to the capillary lumen. Our comparative morphometric analysis demonstrated that structural arrangement of skeletal muscle capillaries is more affected in T2DM than in HYPT or IC/PAD, although some similar elements of remodeling were found. The increased frequency of empty EC-sockets in the three patient groups indicates that the PC-EC interaction is commonly disturbed in these systemic vascular pathologies.
Despite the number of cellular and pathological mitoNEET-related processes, very few details are known about the mechanism of action of the protein. The recently discovered existence of a link ...between NEET proteins and cancer pave the way to consider mitoNEET and its Fe-S clusters as suitable targets to inhibit cancer cell proliferation. Here, we will review the variety of spectroscopic techniques that have been applied to study mitoNEET in an attempt to explain the drastic difference in clusters stability and reactivity observed for the two redox states, and to elucidate the cellular function of the protein. In particular, the extensive NMR assignment and the characterization of first coordination sphere provide a molecular fingerprint helpful to assist the design of drugs able to impair cellular processes or to directly participate in redox reactions or protein-protein recognition mechanisms.
Abstract
Cross-Linking Immunoprecipitation associated to high-throughput sequencing (CLIP-seq) is a technique used to identify RNA directly bound to RNA-binding proteins across the entire ...transcriptome in cell or tissue samples. Recent technological and computational advances permit the analysis of many CLIP-seq samples simultaneously, allowing us to reveal the comprehensive network of RNA-protein interaction and to integrate it to other genome-wide analyses. Therefore, the design and quality management of the CLIP-seq analyses are of critical importance to extract clean and biological meaningful information from CLIP-seq experiments. The application of CLIP-seq technique to Argonaute 2 (Ago2) protein, the main component of the microRNA (miRNA)-induced silencing complex, reveals the direct binding sites of miRNAs, thus providing insightful information about the role played by miRNA(s). In this review, we summarize and discuss the most recent computational methods for CLIP-seq analysis, and discuss their impact on Ago2/miRNA-binding site identification and prediction with a regard toward human pathologies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
—RNA polymerase III synthesizes a wide range of noncoding RNAs shorter than 400 nucleotides in length. These RNAs are involved in protein synthesis (tRNA, 5S rRNA, and 7SL RNA), maturation, and ...splicing of different types of RNA (RPR, MRP RNA, and U6 snRNA), regulation of transcription (7SK RNA), replication (Y RNA), and intracellular transport (vault RNA). BC200 and BC1 RNA genes are transcribed by RNA polymerase III in neurons only where these RNAs regulate protein synthesis. Mutations in the regulatory elements of the genes transcribed by RNA polymerase III as well as in transcription factors of this RNA polymerase are associated with the development of a number of diseases, primarily oncological and neurological. In this regard, the mechanisms of regulation of the expression of the genes containing various RNA polymerase III promoters were actively studied. This review describes the structural and functional classification of polymerase III promoters, as well as the factors involved in the regulation of promoters of different types. A number of examples demonstrate the role of the described factors in the pathogenesis of human diseases.
► LXR are members of the nuclear receptor superfamily. ► Numerous natural and synthetic molecules could module LXR activity. ► LXR are promising pharmacological targets in human diseases. ► ...Atherosclerosis, diabetes, Alzheimer, skin disorders, and cancers could be targeted. ► Development of selective liver X modulators (SLiMs) is a challenge.
Liver X receptors (LXR) are members of the nuclear receptor family. As activated transcription factors, their putative association with human diseases makes them promising pharmacological targets because of the large potential to develop ligands. LXR are mainly considered as intracellular cholesterol “sensors” whose activation leads to decreased plasma cholesterol. They also modulate numerous physiological functions: fatty acid synthesis and metabolism, glucose homeostasis, steroidogenesis, immunity, and neurological homeostasis. LXR-deficiency in mouse results in several phenotypes mimicking pathological conditions in humans. This review will be focused on the various natural and synthetic LXR agonists and antagonists. Putative clinical targets including atherosclerosis, diabetes, Alzheimer’s disease, skin disorders, and cancer will be covered.
Editorial: GPER and Human Pathologies Jacquot, Yves; Kampa, Marilena; Lindsey, Sarah H
Frontiers in endocrinology (Lausanne),
11/2021, Letnik:
12
Journal Article
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