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Nature Reviews. Molecular Cell Biology Jul 2023To coordinate, adapt and respond to biological signals, cells convey specific messages to other cells. An important aspect of cell-cell communication involves secretion... (Review)
Review
To coordinate, adapt and respond to biological signals, cells convey specific messages to other cells. An important aspect of cell-cell communication involves secretion of molecules into the extracellular space. How these molecules are selected for secretion has been a fundamental question in the membrane trafficking field for decades. Recently, extracellular vesicles (EVs) have been recognized as key players in intercellular communication, carrying not only membrane proteins and lipids but also RNAs, cytosolic proteins and other signalling molecules to recipient cells. To communicate the right message, it is essential to sort cargoes into EVs in a regulated and context-specific manner. In recent years, a wealth of lipidomic, proteomic and RNA sequencing studies have revealed that EV cargo composition differs depending upon the donor cell type, metabolic cues and disease states. Analyses of distinct cargo 'fingerprints' have uncovered mechanistic linkages between the activation of specific molecular pathways and cargo sorting. In addition, cell biology studies are beginning to reveal novel biogenesis mechanisms regulated by cellular context. Here, we review context-specific mechanisms of EV biogenesis and cargo sorting, focusing on how cell signalling and cell state influence which cellular components are ultimately targeted to EVs.
Topics: Proteomics; Biological Transport; Extracellular Vesicles; Protein Transport; Signal Transduction; Cell Communication
PubMed: 36765164
DOI: 10.1038/s41580-023-00576-0 -
Signal Transduction and Targeted Therapy May 2023Blood-brain barrier (BBB) is a natural protective membrane that prevents central nervous system (CNS) from toxins and pathogens in blood. However, the presence of BBB... (Review)
Review
Blood-brain barrier (BBB) is a natural protective membrane that prevents central nervous system (CNS) from toxins and pathogens in blood. However, the presence of BBB complicates the pharmacotherapy for CNS disorders as the most chemical drugs and biopharmaceuticals have been impeded to enter the brain. Insufficient drug delivery into the brain leads to low therapeutic efficacy as well as aggravated side effects due to the accumulation in other organs and tissues. Recent breakthrough in materials science and nanotechnology provides a library of advanced materials with customized structure and property serving as a powerful toolkit for targeted drug delivery. In-depth research in the field of anatomical and pathological study on brain and BBB further facilitates the development of brain-targeted strategies for enhanced BBB crossing. In this review, the physiological structure and different cells contributing to this barrier are summarized. Various emerging strategies for permeability regulation and BBB crossing including passive transcytosis, intranasal administration, ligands conjugation, membrane coating, stimuli-triggered BBB disruption, and other strategies to overcome BBB obstacle are highlighted. Versatile drug delivery systems ranging from organic, inorganic, and biologics-derived materials with their synthesis procedures and unique physio-chemical properties are summarized and analyzed. This review aims to provide an up-to-date and comprehensive guideline for researchers in diverse fields, offering perspectives on further development of brain-targeted drug delivery system.
Topics: Blood-Brain Barrier; Drug Delivery Systems; Brain; Biological Transport; Pharmaceutical Preparations; Biological Products
PubMed: 37231000
DOI: 10.1038/s41392-023-01481-w -
Annual Review of Plant Biology May 2023Plant hormones are a group of small signaling molecules produced by plants at very low concentrations that have the ability to move and function at distal sites. Hormone... (Review)
Review
Plant hormones are a group of small signaling molecules produced by plants at very low concentrations that have the ability to move and function at distal sites. Hormone homeostasis is critical to balance plant growth and development and is regulated at multiple levels, including hormone biosynthesis, catabolism, perception, and transduction. In addition, plants move hormones over short and long distances to regulate various developmental processes and responses to environmental factors. Transporters coordinate these movements, resulting in hormone maxima, gradients, and cellular and subcellular sinks. Here, we summarize the current knowledge of most of the characterized plant hormone transporters with respect to biochemical, physiological, and developmental activities. We further discuss the subcellular localizations of transporters, their substrate specificities, and the need for multiple transporters for the same hormone in the context of plant growth and development.
Topics: Plant Growth Regulators; Plant Development; Plants; Biological Transport; Membrane Transport Proteins; Hormones; Gene Expression Regulation, Plant
PubMed: 36889002
DOI: 10.1146/annurev-arplant-070722-015329 -
Cell Metabolism Jan 2024Mitochondria are central hubs of cellular metabolism and are tightly connected to signaling pathways. The dynamic plasticity of mitochondria to fuse, divide, and contact... (Review)
Review
Mitochondria are central hubs of cellular metabolism and are tightly connected to signaling pathways. The dynamic plasticity of mitochondria to fuse, divide, and contact other organelles to flux metabolites is central to their function. To ensure bona fide functionality and signaling interconnectivity, diverse molecular mechanisms evolved. An ancient and long-overlooked mechanism is the generation of mitochondrial-derived vesicles (MDVs) that shuttle selected mitochondrial cargoes to target organelles. Just recently, we gained significant insight into the mechanisms and functions of MDV transport, ranging from their role in mitochondrial quality control to immune signaling, thus demonstrating unexpected and diverse physiological aspects of MDV transport. This review highlights the origin of MDVs, their biogenesis, and their cargo selection, with a specific focus on the contribution of MDV transport to signaling across cell and organ barriers. Additionally, the implications of MDVs in peroxisome biogenesis, neurodegeneration, metabolism, aging, and cancer are discussed.
Topics: Mitochondria; Peroxisomes; Biological Transport
PubMed: 38171335
DOI: 10.1016/j.cmet.2023.11.014 -
Annual Review of Pharmacology and... Jan 2024Rapid removal of apoptotic cells by phagocytes, a process known as efferocytosis, is key for the maintenance of tissue homeostasis, the resolution of inflammation, and... (Review)
Review
Rapid removal of apoptotic cells by phagocytes, a process known as efferocytosis, is key for the maintenance of tissue homeostasis, the resolution of inflammation, and tissue repair. However, impaired efferocytosis can result in the accumulation of apoptotic cells, subsequently triggering sterile inflammation through the release of endogenous factors such as DNA and nuclear proteins from membrane permeabilized dying cells. Here, we review the molecular basis of the three key phases of efferocytosis, that is, the detection, uptake, and degradation of apoptotic materials by phagocytes. We also discuss how defects in efferocytosis due to the alteration of phagocytes and dying cells can contribute to the low-grade chronic inflammation that occurs during aging, described as inflammaging. Lastly, we explore opportunities in targeting and harnessing the efferocytic machinery to limit aging-associated inflammatory diseases.
Topics: Humans; Efferocytosis; Aging; Biological Transport; Inflammation; Nuclear Proteins
PubMed: 37585658
DOI: 10.1146/annurev-pharmtox-032723-110507 -
Experimental & Molecular Medicine Aug 2023Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. This process contributes to cellular and tissue damage in various human... (Review)
Review
Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. This process contributes to cellular and tissue damage in various human diseases, such as cardiovascular diseases, neurodegeneration, liver disease, and cancer. Although polyunsaturated fatty acids (PUFAs) in membrane phospholipids are preferentially oxidized, saturated/monounsaturated fatty acids (SFAs/MUFAs) also influence lipid peroxidation and ferroptosis. In this review, we first explain how cells differentially synthesize SFA/MUFAs and PUFAs and how they control fatty acid pools via fatty acid uptake and β-oxidation, impacting ferroptosis. Furthermore, we discuss how fatty acids are stored in different lipids, such as diacyl or ether phospholipids with different head groups; triglycerides; and cholesterols. Moreover, we explain how these fatty acids are released from these molecules. In summary, we provide an integrated view of the diverse and dynamic metabolic processes in the context of ferroptosis by revisiting lipidomic studies. Thus, this review contributes to the development of therapeutic strategies for ferroptosis-related diseases.
Topics: Humans; Lipid Metabolism; Ferroptosis; Lipidomics; Fatty Acids; Biological Transport
PubMed: 37612411
DOI: 10.1038/s12276-023-01077-y -
The Journal of Physiological Sciences :... Nov 2023Physiological roles of Cl, a major anion in the body, are not well known compared with those of cations. This review article introduces: (1) roles of Cl in bodily and... (Review)
Review
Physiological roles of Cl, a major anion in the body, are not well known compared with those of cations. This review article introduces: (1) roles of Cl in bodily and cellular functions; (2) the range of cytosolic Cl concentration ([Cl]); (3) whether [Cl] could change with cell volume change under an isosmotic condition; (4) whether [Cl] could change under conditions where multiple Cl transporters and channels contribute to Cl influx and efflux in an isosmotic state; (5) whether the change in [Cl] could be large enough to act as signals; (6) effects of Cl on cytoskeletal tubulin polymerization through inhibition of GTPase activity and tubulin polymerization-dependent biological activity; (7) roles of cytosolic Cl in cell proliferation; (8) Cl-regulatory mechanisms of ciliary motility; (9) roles of Cl in sweet/umami taste receptors; (10) Cl-regulatory mechanisms of with-no-lysine kinase (WNK); (11) roles of Cl in regulation of epithelial Na transport; (12) relationship between roles of Cl and H in body functions.
Topics: Chlorides; Tubulin; Ion Transport; Biological Transport; Sodium; Chloride Channels
PubMed: 37968609
DOI: 10.1186/s12576-023-00889-x -
Nature Communications Oct 2023Niemann-Pick C1-like 1 (NPC1L1) is essential for intestinal cholesterol absorption. Together with the cholesterol-rich and Flotillin-positive membrane microdomain,...
Niemann-Pick C1-like 1 (NPC1L1) is essential for intestinal cholesterol absorption. Together with the cholesterol-rich and Flotillin-positive membrane microdomain, NPC1L1 is internalized via clathrin-mediated endocytosis and transported to endocytic recycling compartment (ERC). When ERC cholesterol level decreases, NPC1L1 interacts with LIMA1 and moves back to plasma membrane. However, how cholesterol leaves ERC is unknown. Here, we find that, in male mice, intracellular bile acids facilitate cholesterol transport to other organelles, such as endoplasmic reticulum, in a non-micellar fashion. When cholesterol level in ERC is decreased by bile acids, the NPC1L1 carboxyl terminus that previously interacts with the cholesterol-rich membranes via the ALAL residues dissociates from membrane, exposing the QKR motif for LIMA1 recruitment. Then NPC1L1 moves back to plasma membrane. This study demonstrates an intracellular cholesterol transport function of bile acids and explains how the substantial amount of cholesterol in NPC1L1-positive compartments is unloaded in enterocytes during cholesterol absorption.
Topics: Animals; Male; Mice; Biological Transport; Cell Membrane; Cholesterol; Intestinal Absorption; Membrane Transport Proteins
PubMed: 37833289
DOI: 10.1038/s41467-023-42179-5 -
International Journal of Molecular... Mar 2024The cornea is an avascular, transparent tissue that allows light to enter the visual system. Accurate vision requires proper maintenance of the cornea's integrity and... (Review)
Review
The cornea is an avascular, transparent tissue that allows light to enter the visual system. Accurate vision requires proper maintenance of the cornea's integrity and structure. Due to its exposure to the external environment, the cornea is prone to injury and must undergo proper wound healing to restore vision. Aquaporins (AQPs) are a family of water channels important for passive water transport and, in some family members, the transport of other small molecules; AQPs are expressed in all layers of the cornea. Although their functions as water channels are well established, the direct function of AQPs in the cornea is still being determined and is the focus of this review. AQPs, primarily AQP1, AQP3, and AQP5, have been found to play an important role in maintaining water homeostasis, the corneal structure in relation to proper hydration, and stress responses, as well as wound healing in all layers of the cornea. Due to their many functions in the cornea, the identification of drug targets that modulate the expression of AQPs in the cornea could be beneficial to promote corneal wound healing and restore proper function of this tissue crucial for vision.
Topics: Humans; Cornea; Aquaporins; Corneal Injuries; Biological Transport; Water
PubMed: 38612559
DOI: 10.3390/ijms25073748 -
Nature Communications Aug 2023Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible for generating most of the energy needed to sustain contraction....
Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible for generating most of the energy needed to sustain contraction. Dysfunctional mitochondria are normally degraded via intracellular degradation pathways that converge on the lysosome. Here, we identified an alternative mechanism to eliminate mitochondria when lysosomal function is compromised. We show that lysosomal inhibition leads to increased secretion of mitochondria in large extracellular vesicles (EVs). The EVs are produced in multivesicular bodies, and their release is independent of autophagy. Deletion of the small GTPase Rab7 in cells or adult mouse heart leads to increased secretion of EVs containing ubiquitinated cargos, including intact mitochondria. The secreted EVs are captured by macrophages without activating inflammation. Hearts from aged mice or Danon disease patients have increased levels of secreted EVs containing mitochondria indicating activation of vesicular release during cardiac pathophysiology. Overall, these findings establish that mitochondria are eliminated in large EVs through the endosomal pathway when lysosomal degradation is inhibited.
Topics: Animals; Mice; Lysosomes; Mitochondria; Biological Transport; Extracellular Vesicles; Multivesicular Bodies
PubMed: 37596294
DOI: 10.1038/s41467-023-40680-5