Mitochondrial degradation: Mitophagy and beyond.

Mitochondria are central hubs of cellular metabolism that also play key roles in signaling and disease. It is therefore fundamentally important that mitochondrial quality and activity are tightly regulated. Mitochondrial degradation pathways contribute to quality control of mitochondrial networks and can also regulate the metabolic profile of mitochondria to ensure cellular homeostasis. Here, we cover the many and varied ways in which cells degrade or remove their unwanted mitochondria, ranging from mitophagy to mitochondrial extrusion. The molecular signals driving these varied pathways are discussed, including the cellular and physiological contexts under which the different degradation pathways are engaged.

Unconventional initiation of PINK1/Parkin mitophagy by Optineurin.

Cargo sequestration is a fundamental step of selective autophagy in which cells generate a double-membrane structure termed an "autophagosome" on the surface of cargoes. NDP52, TAX1BP1, and p62 bind FIP200, which recruits the ULK1/2 complex to initiate autophagosome formation on cargoes. How OPTN initiates autophagosome formation during selective autophagy remains unknown despite its importance in neurodegeneration. Here, we uncover an unconventional path of PINK1/Parkin mitophagy initiation by OPTN that does not begin with FIP200 binding or require the ULK1/2 kinases. Using gene-edited cell lines and in vitro reconstitutions, we show that OPTN utilizes the kinase TBK1, which binds directly to the class III phosphatidylinositol 3-kinase complex I to initiate mitophagy. During NDP52 mitophagy initiation, TBK1 is functionally redundant with ULK1/2, classifying TBK1's role as a selective autophagy-initiating kinase. Overall, this work reveals that OPTN mitophagy initiation is mechanistically distinct and highlights the mechanistic plasticity of selective autophagy pathways.

ATG4 family proteins drive phagophore growth independently of the LC3/GABARAP lipidation system.

The sequestration of damaged mitochondria within double-membrane structures termed autophagosomes is a key step of PINK1/Parkin mitophagy. The ATG4 family of proteases are thought to regulate autophagosome formation exclusively by processing the ubiquitin-like ATG8 family (LC3/GABARAPs). We discover that human ATG4s promote autophagosome formation independently of their protease activity and of ATG8 family processing. ATG4 proximity networks reveal a role for ATG4s and their proximity partners, including the immune-disease protein LRBA, in ATG9A vesicle trafficking to mitochondria. Artificial intelligence-directed 3D electron microscopy of phagophores shows that ATG4s promote phagophore-ER contacts during the lipid-transfer phase of autophagosome formation. We also show that ATG8 removal during autophagosome maturation does not depend on ATG4 activity. Instead, ATG4s can disassemble ATG8-protein conjugates, revealing a role for ATG4s as deubiquitinating-like enzymes. These findings establish non-canonical roles of the ATG4 family beyond the ATG8 lipidation axis and provide an AI-driven framework for rapid 3D electron microscopy.

Rebellious autophagy proteins bypass ATG8 lipidation, taking their own path to autophagic degradation.

LC3/GABARAP (hereafter ATG8) conjugation machineries have long been thought to play an essential role in autophagy by driving ATG8 lipidation on autophagosomal membranes. In this issue, Ohnstad et al (2020) describe an ATG8 lipidation bypass pathway which governs autophagy-dependent turnover of NBR1, highlighting that there is more than one road to autophagic degradation.

A unifying model for the role of the ATG8 system in autophagy.

The formation of autophagosomes and their fusion with lysosomes are key events that underpin autophagic degradation of cargoes. The core ATG8 system, which consists of the ATG8 family of ubiquitin-like proteins and the machineries that conjugate them onto autophagosomal membranes, are among the most-studied autophagy components. Despite the research focus on the core ATG8 system, there are conflicting reports regarding its essential roles in autophagy. Here, we reconcile prior observations of the core ATG8 system into a unifying model of their function that aims to consider apparently conflicting discoveries. Bypass pathways of autophagy that function independently of the core ATG8 system are also discussed.

Enhanced second harmonic generation of gold nanostars: optimizing multipolar radiation to improve nonlinear properties.

We report a detailed investigation on the second harmonic generation (SHG) emission from single 150 nm diameter non-centrosymmetric gold nanoparticles. Polarization-resolved analysis together with scanning electron microscopy images shows that these nanostructures exhibit a unique polarization-sensitive SHG that depends strongly on the particle's shape. An analytical approach based on multipolar analysis is introduced to link SHG properties to the nanoparticles' shape. Those multipolar modes can be probed using polarization-resolved SHG. This multipolar analysis offers a physical picture of the relation between shape (size, symmetries, defects, etc.) and nonlinear polarized optical efficiency.

Characterization and mechanisms of anti-influenza virus metabolites isolated from the Vietnamese medicinal plant Polygonum chinense.

BACKGROUND: Polygonum chinense Linn. is a common medicinal plant in Southeast Asia and has been used in traditional medicine in Vietnam. The plant contains phytochemicals with various biological properties; however, its antiviral effect has not yet been demonstrated. This study was aimed to evaluate the anti-influenza virus activity of crude extracts of P. chinense, to characterize antiviral metabolites therefrom and to investigate their mechanisms of antiviral action. METHODS: The methanol (MeOH) extract and organic solvent layers of P. chinense were prepared by extraction and partition with relevant solvents. The ethyl acetate (EtOAc) layer showing antiviral activity was chromatographed repeatedly on SiO2 and Sephadex LH-20 columns to give eight pure metabolites. Their chemical structures were determined by NMR and MS spectral data. Anti-influenza virus activity of the eight metabolites against virus strains A/Puerto Rico/8/34 (H1N1, PR8), A/Hong Kong/8/68 (H3N2, HK) and B/Lee/40 (Lee) was evaluated on the basis of cytopathic effect (CPE) and plaque inhibition assays. Time-of-addition, confocal microscopy and neuraminidase inhibition assay were performed for mode-of-action studies of active ingredients. RESULTS: The MeOH extract of P. chinense showed anti-influenza virus activity with EC50 values ranging from 38.4 to 55.5 µg/mL in a CPE inhibition assay. Among the eight pure metabolites isolated from P. chinense, ellagic acid (PC5), methyl gallate (PC7) and caffeic acid (PC8) significantly inhibited viral replication in a dose-dependent manner in both plaque inhibition and CPE inhibition assays with EC50 values ranging from 14.7 to 81.1 µg/mL and CC50 values higher than 300 µg/mL. Mode-of-action studies suggested that PC5 and PC7 suppress virus entry into or replication in cells, while PC8 targets influenza viral neuraminidase, even oseltamivir-resistant one. CONCLUSION: These results demonstrated that P. chinense and its metabolites possess effective anti-influenza virus activities. The botanical materials of P. chinense could be a promising multitargeted inhibitor of influenza A and B viruses and applied to development of a novel herbal medicine.

Exposure of the inner mitochondrial membrane triggers apoptotic mitophagy.

During apoptosis mediated by the intrinsic pathway, BAX/BAK triggers mitochondrial permeabilization and the release of cytochrome-c, followed by a dramatic remodelling of the mitochondrial network that results in mitochondrial herniation and the subsequent release of pro-inflammatory mitochondrial components. Here, we show that mitochondrial herniation and subsequent exposure of the inner mitochondrial membrane (IMM) to the cytoplasm, initiates a unique form of mitophagy to deliver these damaged organelles to lysosomes. IMM-induced mitophagy occurs independently of canonical PINK1/Parkin signalling and is driven by ubiquitination of the IMM. Our data suggest IMM-induced mitophagy is an additional safety mechanism that cells can deploy to contain damaged mitochondria. It may have particular relevance in situations where caspase activation is incomplete or inhibited, and in contexts where PINK1/Parkin-mitophagy is impaired or overwhelmed.

Control of mitophagy initiation and progression by the TBK1 adaptors NAP1 and SINTBAD.

Mitophagy preserves overall mitochondrial fitness by selectively targeting damaged mitochondria for degradation. The regulatory mechanisms that prevent PTEN-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase Parkin (PINK1/Parkin)-dependent mitophagy and other selective autophagy pathways from overreacting while ensuring swift progression once initiated are largely elusive. Here, we demonstrate how the TBK1 (TANK-binding kinase 1) adaptors NAP1 (NAK-associated protein 1) and SINTBAD (similar to NAP1 TBK1 adaptor) restrict the initiation of OPTN (optineurin)-driven mitophagy by competing with OPTN for TBK1. Conversely, they promote the progression of nuclear dot protein 52 (NDP52)-driven mitophagy by recruiting TBK1 to NDP52 and stabilizing its interaction with FIP200. Notably, OPTN emerges as the primary recruiter of TBK1 during mitophagy initiation, which in return boosts NDP52-mediated mitophagy. Our results thus define NAP1 and SINTBAD as cargo receptor rheostats, elevating the threshold for mitophagy initiation by OPTN while promoting the progression of the pathway once set in motion by supporting NDP52. These findings shed light on the cellular strategy to prevent pathway hyperactivity while still ensuring efficient progression.

Management of Unruptured Intracranial Aneurysms and Brain Arteriovenous Malformations.

OBJECTIVE: Managing a patient with an unruptured brain aneurysm or brain arteriovenous malformation (AVM) can lead to uncertainty about preventive treatment. While the bleeding risks are low, the morbidity or mortality associated with a hemorrhagic event is not insignificant. The objective of this article is to review the natural history of these vascular entities, the risk factors for hemorrhage, preventive treatment options, and the risks of treatment. LATEST DEVELOPMENTS: Randomized trials to inform preventive treatment strategies for unruptured intracranial aneurysms and brain AVMs are ongoing. Higher angiographic obliteration rates of unruptured intracranial aneurysms have been reported with the flow-diversion technique compared with alternative standard techniques. One randomized trial for unruptured brain AVMs showed a higher rate of morbidity and mortality in patients who underwent interventional treatment compared with observation. ESSENTIAL POINTS: The decision to treat a patient with a brain aneurysm should consider patient factors, the patient's life expectancy, aneurysm anatomical factors, and treatment risks. Patients with unruptured brain AVMs should be observed in light of recent clinical trial data or enrolled in an ongoing clinical trial.

Recent Advances in Conjugated Polymer-Based Biosensors for Virus Detection.

Nowadays, virus pandemics have become a major burden seriously affecting human health and social and economic development. Thus, the design and fabrication of effective and low-cost techniques for early and accurate virus detection have been given priority for prevention and control of such pandemics. Biosensors and bioelectronic devices have been demonstrated as promising technology to resolve the major drawbacks and problems of the current detection methods. Discovering and applying advanced materials have offered opportunities to develop and commercialize biosensor devices for effectively controlling pandemics. Along with various well-known materials such as gold and silver nanoparticles, carbon-based materials, metal oxide-based materials, and graphene, conjugated polymer (CPs) have become one of the most promising candidates for preparation and construction of excellent biosensors with high sensitivity and specificity to different virus analytes owing to their unique π orbital structure and chain conformation alterations, solution processability, and flexibility. Therefore, CP-based biosensors have been regarded as innovative technologies attracting great interest from the community for early diagnosis of COVID-19 as well as other virus pandemics. For providing precious scientific evidence of CP-based biosensor technologies in virus detection, this review aims to give a critical overview of the recent research related to use of CPs in fabrication of virus biosensors. We emphasize structures and interesting characteristics of different CPs and discuss the state-of-the-art applications of CP-based biosensors as well. In addition, different types of biosensors such as optical biosensors, organic thin film transistors (OTFT), and conjugated polymer hydrogels (CPHs) based on CPs are also summarized and presented.

Tailored synthesis of NdMnxFe1-xO3 perovskite nanoparticles with oxygen-vacancy defects for lithium-ion battery anodes.

In this study, we synthesize nanostructured NdMnxFe1-xO3 perovskites using a facile method to produce materials for the high-working-efficiency anodes of Li-ion batteries. A series of characterization assessments (e.g., X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and electron microscopy) were conducted, and the results confirmed the efficacious partial replacement of Fe ions with Mn ions in the NdFeO3 perovskite structure, occurrence of both amorphous and crystalline structures, presence of oxygen vacancies (VO), and interconnection between nanoparticles. The possibility of Mn ion replacement significantly affects the size, amount of VO, and ratio of amorphous phase in NdMnxFe1-xO3 perovskites. The NdMnxFe1-xO3 perovskite with x = 0.3 presents a notable electrochemical performance, including low charge transfer resistance, durable Coulombic efficiency, first-rate capacity reservation, high pseudo-behavior, and elongated 150-cycle service life, whereas no discernible capacity deterioration is observed. The reversible capacity of the anode after the 150th-cylcle was 713 mAh g-1, which represents a high-capacity value. The outstanding electrochemical efficiency resulted from the optimum presence of VO, interconnection between the nanoparticles, and distinctive properties of the NdFeO3 perovskite. The interconnection between nanoparticles was advantageous for forming a large electrolyte-electrode contact area, improving Li-ion diffusion rates, and enhancing pseudocapacitive effect. The attributes of perovskite crystals, coexistence of Mn and Fe throughout the charge/discharge process, and optimum VO precluded the electrode devastation that caused the Li2O-phase decomposition catalysis, enabling favorable reversible Li storage.

Recent Advances and Progress of Conducting Polymer-Based Hydrogels in Strain Sensor Applications.

Conducting polymer-based hydrogels (CPHs) are novel materials that take advantage of both conducting polymers and three-dimensional hydrogels, which endow them with great electrical properties and excellent mechanical features. Therefore, CPHs are considered as one of the most promising platforms for employing wearable and stretchable strain sensors in practical applications. Herein, we provide a critical review of distinct features and preparation technologies and the advancements in CPH-based strain sensors for human motion and health monitoring applications. The fundamentals, working mechanisms, and requirements for the design of CPH-based strain sensors with high performance are also summarized and discussed. Moreover, the recent progress and development strategies for the implementation of CPH-based strain sensors are pointed out and described. It has been surmised that electronic skin (e-skin) sensors are the upward tendency in the development of CPHs for wearable strain sensors and human health monitoring. This review will be important scientific evidence to formulate new approaches for the development of CPH-based strain sensors in the present and in the future.

Plant mitophagy: Beware of Friendly or you might get eaten.

Mitophagy is a selective garbage disposal pathway that rids cells of excess or damaged mitochondria. In this issue, Ma et al. uncover a role for Friendly in driving depolarisation-induced mitophagy in plants and highlight a physiological role for mitophagy during plant development.

ATG4s: above and beyond the Atg8-family protein lipidation system.

The sole proteases of the macroautophagy/autophagy machinery, the ATG4s, contribute to autophagosome formation by cleaving Atg8-family protein members (LC3/GABARAPs) which enables Atg8-family protein lipidation and de-lipidation. Our recent work reveals that ATG4s can also promote phagophore growth independently of their protease activity and of Atg8-family proteins. ATG4s and their proximity partners including ARFIP2 and LRBA function to promote trafficking of ATG9A to mitochondria during PINK1-PRKN mitophagy. Through the development of a 3D electron microscopy framework utilizing FIB-SEM and artificial intelligence (termed AIVE: Artificial Intelligence-directed Voxel Extraction), we show that ATG4s promote ER-phagophore contacts during the lipid-transfer phase of autophagosome biogenesis, which requires ATG2B and ATG9A to support phagophore growth. We also discovered that ATG4s are not essential for removal of Atg8-family proteins from autolysosomes, but they can function as deubiquitinase-like enzymes to counteract the conjugation of Atg8-family proteins to other proteins, a process that we have termed ATG8ylation (also known as LC3ylation). These discoveries demonstrate the duality of the ATG4 family in driving autophagosome formation by functioning as both autophagy proteases and trafficking factors, while simultaneously raising questions about the putative roles of ATG8ylation in cell biology.

Development of Antimicrobial MgO-CuO/Activated Carbon Fiber.

Activated carbon fiber (ACF) is widely used as an adsorption fiber in air purification systems. In this study, MgO and CuO nanoparticles were immobilized on ACF with enhancement of (3-aminopropyl)triethoxysilane (APTES). The obtained fibers' coating efficiency, structural deformation, and antimicrobial activities were investigated. The MgO-CuO/APTES/ACF fiber (DA-MC) sample showed high antimicrobial activity (<90%) against both Escherichia coli and Staphylococcus aureus after 24-hour treatment. DA-MC also showed the highest coating efficiency, with no observed structural deformation. The presence of APTES and curing step at high temperature is believed to increase the coating efficiency and thus result in the high antimicrobial activity and also protect the ACF from deformation.

Development of Antimicrobial CuO/(3-aminopropyl)Triethoxysilane Activated Carbon Fiber.

CuO nanoparticles (NPs) have been used for the antimicrobial agent against different pathogenic microorganisms. In this study, CuO NPs are immobilized on the surface of activated carbon fiber (ACF) with the enhancement of (3-aminopropyl)triethoxysilane (APTES) as an organic binder. The obtained fibers are evaluated by coating efficiency, structural deformation, and antimicrobial activities. In the results, APTES can improve the immobilization of CuO on the surface of ACF. Also, the curing of silane layers at high temperature leads to the high coating efficiencies as well as structural reinforcement. The samples with drying step after APTES coating step (denoted as DA-CuO) have the highest antimicrobial activity against both Escherichia coli and Staphylococcus aureus after 24 hours treatment, respectively.

Insights on autophagosome-lysosome tethering from structural and biochemical characterization of human autophagy factor EPG5.

Pivotal to the maintenance of cellular homeostasis, macroautophagy (hereafter autophagy) is an evolutionarily conserved degradation system that involves sequestration of cytoplasmic material into the double-membrane autophagosome and targeting of this transport vesicle to the lysosome/late endosome for degradation. EPG5 is a large-sized metazoan protein proposed to serve as a tethering factor to enforce autophagosome-lysosome/late endosome fusion specificity, and its deficiency causes a severe multisystem disorder known as Vici syndrome. Here, we show that human EPG5 (hEPG5) adopts an extended "shepherd's staff" architecture. We find that hEPG5 binds preferentially to members of the GABARAP subfamily of human ATG8 proteins critical to autophagosome-lysosome fusion. The hEPG5-GABARAPs interaction, which is mediated by tandem LIR motifs that exhibit differential affinities, is required for hEPG5 recruitment to mitochondria during PINK1/Parkin-dependent mitophagy. Lastly, we find that the Vici syndrome mutation Gln336Arg does not affect the hEPG5's overall stability nor its ability to engage in interaction with the GABARAPs. Collectively, results from our studies reveal new insights into how hEPG5 recognizes mature autophagosome and establish a platform for examining the molecular effects of Vici syndrome disease mutations on hEPG5.

A human apolipoprotein L with detergent-like activity kills intracellular pathogens.

Activation of cell-autonomous defense by the immune cytokine interferon-γ (IFN-γ) is critical to the control of life-threatening infections in humans. IFN-γ induces the expression of hundreds of host proteins in all nucleated cells and tissues, yet many of these proteins remain uncharacterized. We screened 19,050 human genes by CRISPR-Cas9 mutagenesis and identified IFN-γ-induced apolipoprotein L3 (APOL3) as a potent bactericidal agent protecting multiple non-immune barrier cell types against infection. Canonical apolipoproteins typically solubilize mammalian lipids for extracellular transport; APOL3 instead targeted cytosol-invasive bacteria to dissolve their anionic membranes into human-bacterial lipoprotein nanodiscs detected by native mass spectrometry and visualized by single-particle cryo-electron microscopy. Thus, humans have harnessed the detergent-like properties of extracellular apolipoproteins to fashion an intracellular lysin, thereby endowing resident nonimmune cells with a mechanism to achieve sterilizing immunity.

A Novel Photocatalyst Composite of Magnesium Aminoclay and TiO2 Immobilized into Activated Carbon Fiber (ACF) Matrix for Pollutant Removal.

Titanium dioxide (TiO2) is a semiconductor photocatalyst widely applied in numerous fields due to possessing prominent photocatalytic properties. However, its practical applications in the form of nanoparticles or powders still have remained several limitations. Recently, novel photocatalytic porous composites have been discovered to be potential alternative approaches. In the present study, nanostructured magnesium-aminoclay-based TiO2 (MgAC-TiO2) was successfully deposited on an activated carbon fiber (ACF) matrix using the sol-gel approach followed by calcination at 350°C in an air atmosphere. The structure and photocatalytic activity of this as-prepared photocatalyst composite were characterized by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), the Brunauer-Emmett-Teller (BET), and UV-vis diffuse reflectance spectral analysis. The photocatalytic activity of MgAC-TiO2/ACF was investigated under batch conditions for the removal of methylene blue (MB) in solution under UV irradiation and dark conditions. The results revealed that MB is absorbed by MgAC-TiO2/ACF and that its photodecomposition occurs under UV irradiation. The addition of MgAC can prevent the sintering of TiO2 act as a dispersing agent to create a high specific surface area, and thus enhance photocatalytic efficiency. In addition, ACF in the MgAC-TiO2/ACF composite can additionally improve the photocatalytic activity by hindering electron-hole recombination, which is known as a synergetic effect, and thereby enhancing the photodegradation and removal efficiency of MB.