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The Journal of Cell Biology Oct 2023Mitochondria are dynamic organelles regulated by fission and fusion processes. The fusion of membranes requires elaborative coordination of proteins and lipids and is...
Mitochondria are dynamic organelles regulated by fission and fusion processes. The fusion of membranes requires elaborative coordination of proteins and lipids and is particularly crucial for the function and quality control of mitochondria. Phosphatidic acid (PA) on the mitochondrial outer membrane generated by PLD6 facilitates the fusion of mitochondria. However, how PA promotes mitochondrial fusion remains unclear. Here, we show that a mitochondrial outer membrane protein, NME3, is required for PLD6-induced mitochondrial tethering or clustering. NME3 is enriched at the contact interface of two closely positioned mitochondria depending on PLD6, and NME3 binds directly to PA-exposed lipid packing defects via its N-terminal amphipathic helix. The PA binding function and hexamerization confer NME3 mitochondrial tethering activity. Importantly, nutrient starvation enhances the enrichment efficiency of NME3 at the mitochondrial contact interface, and the tethering ability of NME3 contributes to fusion efficiency. Together, our findings demonstrate NME3 as a tethering protein promoting selective fusion between PLD6-remodeled mitochondria for quality control.
Topics: Humans; Mitochondria; Mitochondrial Dynamics; Mitochondrial Membranes; Mitochondrial Proteins; NM23 Nucleoside Diphosphate Kinases; Phosphatidic Acids; Phospholipase D
PubMed: 37584589
DOI: 10.1083/jcb.202301091 -
Plants (Basel, Switzerland) Oct 2023Nuclear fusion is essential for the sexual reproduction of various organisms, including plants, animals, and fungi. During the life cycle of flowering plants, nuclear...
Nuclear fusion is essential for the sexual reproduction of various organisms, including plants, animals, and fungi. During the life cycle of flowering plants, nuclear fusion occurs three times: once during female gametogenesis and twice during double fertilization, when two sperm cells fertilize the egg and the central cell. Haploid nuclei migrate in an actin filament-dependent manner to become in close contact and, then, two nuclei fuse. The nuclear fusion process in plant reproduction is achieved through sequential nuclear membrane fusion events. Recent molecular genetic analyses using showed the conservation of nuclear membrane fusion machinery between plants and the budding yeast . These include the heat-shock protein 70 in the endoplasmic reticulum and the conserved nuclear membrane proteins. Analyses of the mutants of these components show that the completion of the sperm nuclear fusion at fertilization is essential for proper embryo and endosperm development.
PubMed: 37896071
DOI: 10.3390/plants12203608 -
ACS Omega May 2024Cells inhabit a mechanical microenvironment that they continuously sense and adapt to. The plasma membrane (PM), serving as the boundary of the cell, plays a pivotal... (Review)
Review
Cells inhabit a mechanical microenvironment that they continuously sense and adapt to. The plasma membrane (PM), serving as the boundary of the cell, plays a pivotal role in this process of adaptation. In this Review, we begin by examining well-studied processes where mechanoregulation proves significant. Specifically, we highlight examples from the immune system and stem cells, besides discussing processes involving fibroblasts and other cell types. Subsequently, we discuss the common molecular players that facilitate the sensing of the mechanical signal and transform it into a chemical response covering integrins YAP/TAZ and Piezo. We then review how this understanding of molecular elements is leveraged in drug discovery and tissue engineering alongside a discussion of the methodologies used to measure mechanical properties. Focusing on the processes of endocytosis, we discuss how cells may respond to altered membrane mechanics using endo- and exocytosis. Through the process of depleting/adding the membrane area, these could also impact membrane mechanics. We compare pathways from studies illustrating the involvement of endocytosis in mechanoregulation, including clathrin-mediated endocytosis (CME) and the CLIC/GEEC (CG) pathway as central examples. Lastly, we review studies on cell-cell fusion during myogenesis, the mechanical integrity of muscle fibers, and the reported and anticipated roles of various molecular players and processes like endocytosis, thereby emphasizing the significance of mechanoregulation at the PM.
PubMed: 38799362
DOI: 10.1021/acsomega.4c01962 -
Science Advances Oct 2023The clinical potential of miRNA-based liquid biopsy has been largely limited by the heterogeneous sources in plasma and tedious assay processes. Here, we develop a...
The clinical potential of miRNA-based liquid biopsy has been largely limited by the heterogeneous sources in plasma and tedious assay processes. Here, we develop a precise and robust one-pot assay called dual-surface-protein-guided orthogonal recognition of tumor-derived exosomes and in situ profiling of microRNAs (SORTER) to detect tumor-derived exosomal miRNAs and enhance the diagnostic accuracy of prostate cancer (PCa). The SORTER uses two allosteric aptamers against exosomal marker CD63 and tumor marker EpCAM to create an orthogonal labeling barcode and achieve selective sorting of tumor-specific exosome subtypes. Furthermore, the labeled barcode on tumor-derived exosomes initiated targeted membrane fusion with liposome probes to import miRNA detection reagents, enabling in situ sensitive profiling of tumor-derived exosomal miRNAs. With a signature of six miRNAs, SORTER differentiated PCa and benign prostatic hyperplasia with an accuracy of 100%. Notably, the diagnostic accuracy reached 90.6% in the classification of metastatic and nonmetastatic PCa. We envision that the SORTER will promote the clinical adaptability of miRNA-based liquid biopsy.
Topics: Male; Humans; Exosomes; Membrane Proteins; MicroRNAs; Prostatic Neoplasms; Biomarkers, Tumor
PubMed: 37792944
DOI: 10.1126/sciadv.adi1556 -
Advanced Science (Weinheim,... Nov 2023Extracellular vesicles (EVs), involved in essential physiological and pathological processes of the organism, have emerged as powerful tools for disease treatment owing... (Review)
Review
Extracellular vesicles (EVs), involved in essential physiological and pathological processes of the organism, have emerged as powerful tools for disease treatment owing to their unique natural biological characteristics and artificially acquired advantages. However, the limited targeting ability, insufficient production yield, and low drug-loading capability of natural simplex EVs have greatly hindered their development in clinical translation. Therefore, the establishment of multifunctional hybrid membrane nanovesicles (HMNVs) with favorable adaptability and flexibility has become the key to expanding the practical application of EVs. This timely review summarizes the current progress of HMNVs for biomedical applications. Different HMNVs preparation strategies including physical, chemical, and chimera approaches are first discussed. This review then individually describes the diverse types of HMNVs based on homologous or heterologous cell membrane substances, a fusion of cell membrane and liposome, as well as a fusion of cell membrane and bacterial membrane. Subsequently, a specific emphasis is placed on the highlight of biological applications of the HMNVs toward various diseases with representative examples. Finally, ongoing challenges and prospects of the currently developed HMNVs in clinical translational applications are briefly presented. This review will not only stimulate broad interest among researchers from diverse disciplines but also provide valuable insights for the development of promising nanoplatforms in precision medicine.
Topics: Extracellular Vesicles; Drug Delivery Systems; Liposomes; Cell Membrane; Precision Medicine
PubMed: 37749882
DOI: 10.1002/advs.202303617 -
Annual Review of Virology Sep 2023Nuclear egress of herpesvirus capsids across the intact nuclear envelope is an exceptional vesicle-mediated nucleocytoplasmic translocation resulting in the delivery of... (Review)
Review
Nuclear egress of herpesvirus capsids across the intact nuclear envelope is an exceptional vesicle-mediated nucleocytoplasmic translocation resulting in the delivery of herpesvirus capsids into the cytosol. Budding of the (nucleo)capsid at and scission from the inner nuclear membrane (INM) is mediated by the viral nuclear egress complex (NEC) resulting in a transiently enveloped virus particle in the perinuclear space followed by fusion of the primary envelope with the outer nuclear membrane (ONM). The dimeric NEC oligomerizes into a honeycomb-shaped coat underlining the INM to induce membrane curvature and scission. Mutational analyses complemented structural data defining functionally important regions. Questions remain, including where and when the NEC is formed and how membrane curvature is mediated, vesicle formation is regulated, and directionality is secured. The composition of the primary enveloped virion and the machinery mediating fusion of the primary envelope with the ONM is still debated. While NEC-mediated budding apparently follows a highly conserved mechanism, species and/or cell type-specific differences complicate understanding of later steps.
Topics: Viral Proteins; Herpesviridae; Nuclear Envelope; Capsid Proteins; Capsid; Cell Nucleus; Virus Release
PubMed: 37040797
DOI: 10.1146/annurev-virology-111821-105518 -
Particle and Fibre Toxicology Jul 2023Exposure to particulate matter (PM) with an aerodynamic diameter less than 2.5 μm (PM) is a risk factor for developing pulmonary diseases and the worsening of ongoing...
BACKGROUND
Exposure to particulate matter (PM) with an aerodynamic diameter less than 2.5 μm (PM) is a risk factor for developing pulmonary diseases and the worsening of ongoing disease. Mitochondrial fission and fusion are essential processes underlying mitochondrial homeostasis in health and disease. We examined the role of mitochondrial fission and fusion in PM-induced alveolar epithelial cell damage and lung injury. Key genes in these processes include dystrophin-related protein 1 (DRP1) and optic atrophy 1 (OPA1) respectively.
METHODS
Alveolar epithelial (A549) cells were treated with PM (32 µg/ml) in the presence and absence of Mdivi-1 (10µM, a DRP1 inhibitor) or BGP-15 (10µM, an OPA1 activator). Results were validated using DRP1-knockdown (KD) and OPA1-overexpression (OE). Mice were injected intraperitoneally with Mdivi-1 (20 mg/kg), BGP-15 (20 mg/kg) or distilled water (control) one hour before intranasal instillation of PM (7.8 mg/kg) or distilled water for two consecutive days.
RESULTS
PM exposure of A549 cells caused oxidative stress, enhanced inflammation, necroptosis, mitophagy and mitochondrial dysfunction indicated by abnormal mitochondrial morphology, decreased mitochondrial membrane potential (ΔΨm), reduced mitochondrial respiration and disrupted mitochondrial fission and fusion. Regulating mitochondrial fission and fusion pharmacologically using Mdivi-1 and BGP-15 and genetically using DRP1-KD and OPA1-OE prevented PM-induced celluar damage in A549 cells. Mdivi-1 and BGP-15 attenuated PM-induced acute lung injury in mice.
CONCLUSION
Increased mitochondrial fission and decreased mitochondrial fusion may underlie PM-induced alveolar epithelial cell damage in vitro and lung injury in vivo.
Topics: Mice; Animals; Particulate Matter; Mitochondrial Dynamics; Alveolar Epithelial Cells; Lung Injury; Water
PubMed: 37464447
DOI: 10.1186/s12989-023-00534-w -
Cancer Metastasis Reviews Dec 2023Metastatic progression is regulated by metastasis promoter and suppressor genes. NME1, the prototypic and first described metastasis suppressor gene, encodes a... (Review)
Review
Metastatic progression is regulated by metastasis promoter and suppressor genes. NME1, the prototypic and first described metastasis suppressor gene, encodes a nucleoside diphosphate kinase (NDPK) involved in nucleotide metabolism; two related family members, NME2 and NME4, are also reported as metastasis suppressors. These proteins physically interact with members of the GTPase dynamin family, which have key functions in membrane fission and fusion reactions necessary for endocytosis and mitochondrial dynamics. Evidence supports a model in which NDPKs provide GTP to dynamins to maintain a high local GTP concentration for optimal dynamin function. NME1 and NME2 are cytosolic enzymes that provide GTP to dynamins at the plasma membrane, which drive endocytosis, suggesting that these NMEs are necessary to attenuate signaling by receptors on the cell surface. Disruption of NDPK activity in NME-deficient tumors may thus drive metastasis by prolonging signaling. NME4 is a mitochondrial enzyme that interacts with the dynamin OPA1 at the mitochondria inner membrane to drive inner membrane fusion and maintain a fused mitochondrial network. This function is consistent with the current view that mitochondrial fusion inhibits the metastatic potential of tumor cells whereas mitochondrial fission promotes metastasis progression. The roles of NME family members in dynamin-mediated endocytosis and mitochondrial dynamics and the intimate link between these processes and metastasis provide a new framework to understand the metastasis suppressor functions of NME proteins.
Topics: Humans; NM23 Nucleoside Diphosphate Kinases; Dynamins; Neoplasms; Cell Membrane; Guanosine Triphosphate
PubMed: 37353690
DOI: 10.1007/s10555-023-10118-x -
Journal of Clinical Medicine Sep 2023Dysferlinopathy is a disease caused by a dysferlin deficiency due to mutations in the gene. Dysferlin is a membrane protein in the sarcolemma and is involved in... (Review)
Review
Dysferlinopathy is a disease caused by a dysferlin deficiency due to mutations in the gene. Dysferlin is a membrane protein in the sarcolemma and is involved in different functions, such as membrane repair and vesicle fusion, T-tubule development and maintenance, Ca signalling, and the regulation of various molecules. Miyoshi Myopathy type 1 (MMD1) and Limb-Girdle Muscular Dystrophy 2B/R2 (LGMD2B/LGMDR2) are two possible clinical presentations, yet the same mutations can cause both presentations in the same family. They are therefore grouped under the name dysferlinopathy. Onset is typically during the teenage years or young adulthood and is characterized by a loss of Achilles tendon reflexes and difficulty in standing on tiptoes or climbing stairs, followed by a slow progressive loss of strength in limb muscles. The MRI pattern of patient muscles and their biopsies show various fibre sizes, necrotic and regenerative fibres, and fat and connective tissue accumulation. Recent tools were developed for diagnosis and research, especially to evaluate the evolution of the patient condition and to prevent misdiagnosis caused by similarities with polymyositis and Charcot-Marie-Tooth disease. The specific characteristic of dysferlinopathy is dysferlin deficiency. Recently, mouse models with patient mutations were developed to study genetic approaches to treat dysferlinopathy. The research fields for dysferlinopathy therapy include symptomatic treatments, as well as antisense-mediated exon skipping, myoblast transplantation, and gene editing.
PubMed: 37762951
DOI: 10.3390/jcm12186011 -
Biomolecules Sep 2023Retinal neurons that form ribbon-style synapses operate over a wide dynamic range, continuously relaying visual information to their downstream targets. The remarkable...
Retinal neurons that form ribbon-style synapses operate over a wide dynamic range, continuously relaying visual information to their downstream targets. The remarkable signaling abilities of these neurons are supported by specialized presynaptic machinery, one component of which is syntaxin3B. Syntaxin3B is an essential t-SNARE protein of photoreceptors and bipolar cells that is required for neurotransmitter release. It has a light-regulated phosphorylation site in its N-terminal domain at T14 that has been proposed to modulate membrane fusion. However, a direct test of the latter has been lacking. Using a well-controlled in vitro fusion assay, we found that a phosphomimetic T14 syntaxin3B mutation leads to a small but significant enhancement of SNARE-mediated membrane fusion following the formation of the t-SNARE complex. While the addition of Munc18a had only a minimal effect on membrane fusion mediated by SNARE complexes containing wild-type syntaxin3B, a more significant enhancement was observed in the presence of Munc18a when the SNARE complexes contained a syntaxin3B T14 phosphomimetic mutant. Finally, we showed that the retinal-specific complexins (Cpx III and Cpx IV) inhibited membrane fusion mediated by syntaxin3B-containing SNARE complexes in a dose-dependent manner. Collectively, our results establish that membrane fusion mediated by syntaxin3B-containing SNARE complexes is regulated by the T14 residue of syntaxin3B, Munc18a, and Cpxs III and IV.
Topics: Membrane Fusion; Synapses; Synaptic Transmission; Retina; SNARE Proteins; Protein Binding
PubMed: 37892145
DOI: 10.3390/biom13101463