Amphisomes are intermediate/hybrid organelles produced through the fusion of endosomes with autophagosomes within cells. Amphisome formation is an essential step during a sequential maturation ...process of autophagosomes before their ultimate fusion with lysosomes for cargo degradation. This process is highly regulated with multiple protein machineries, such as SNAREs, Rab GTPases, tethering complexes, and ESCRTs, are involved to facilitate autophagic flux to proceed. In neurons, autophagosomes are robustly generated in axonal terminals and then rapidly fuse with late endosomes to form amphisomes. This fusion event allows newly generated autophagosomes to gain retrograde transport motility and move toward the soma, where proteolytically active lysosomes are predominantly located. Amphisomes are not only the products of autophagosome maturation but also the intersection of the autophagy and endo-lysosomal pathways. Importantly, amphisomes can also participate in non-canonical functions, such as retrograde neurotrophic signaling or autophagy-based unconventional secretion by fusion with the plasma membrane. In this review, we provide an updated overview of the recent discoveries and advancements on the molecular and cellular mechanisms underlying amphisome biogenesis and the emerging roles of amphisomes. We discuss recent developments towards the understanding of amphisome regulation as well as the implications in the context of major neurodegenerative diseases, with a comparative focus on Alzheimer's disease and Parkinson's disease.
Mitochondrial dysfunction is a central aspect of aging and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. ...Mitochondria are the main cellular energy powerhouses, supplying most of ATP by oxidative phosphorylation, which is required to fuel essential neuronal functions. Efficient removal of aged and dysfunctional mitochondria through mitophagy, a cargo-selective autophagy, is crucial for mitochondrial maintenance and neuronal health. Mechanistic studies into mitophagy have highlighted an integrated and elaborate cellular network that can regulate mitochondrial turnover. In this review, we provide an updated overview of the recent discoveries and advancements on the mitophagy pathways and discuss the molecular mechanisms underlying mitophagy defects in Alzheimer's disease and other age-related neurodegenerative diseases, as well as the therapeutic potential of mitophagy-enhancing strategies to combat these disorders.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Neurons are highly polarized and post-mitotic cells with the specific requirements of neurotransmission accompanied by high metabolic demands that create a unique challenge for the maintenance of ...cellular homeostasis. Thus, neurons rely heavily on autophagy that constitutes a key quality control system by which dysfunctional cytoplasmic components, protein aggregates, and damaged organelles are sequestered within autophagosomes and then delivered to the lysosome for degradation. While mature lysosomes are predominantly located in the soma of neurons, the robust, constitutive biogenesis of autophagosomes occurs in the synaptic terminal via a conserved pathway that is required to maintain synaptic integrity and function. Following formation, autophagosomes fuse with late endosomes and then are rapidly and efficiently transported by the microtubule-based cytoplasmic dynein motor along the axon toward the soma for lysosomal clearance. In this review, we highlight the recent knowledge of the roles of autophagy in neuronal health and disease. We summarize the available evidence about the normal functions of autophagy as a protective factor against neurodegeneration and discuss the mechanism underlying neuronal autophagy regulation. Finally, we describe how autophagy function is affected in major neurodegenerative diseases with a special focus on Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mitochondria have a number of essential roles in neuronal function. Their complex mobility patterns within neurons are characterized by frequent changes in direction. Mobile mitochondria can become ...stationary or pause in regions that have a high metabolic demand and can move again rapidly in response to physiological changes. Defects in mitochondrial transport are implicated in the pathogenesis of several major neurological disorders. Research into the mechanisms that regulate mitochondrial transport is thus an important emerging frontier.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Mitochondrial dysfunction is one of the earliest and most prominent features in the brains of Alzheimer's disease (AD) patients. Recent studies suggest that mitochondrial dysfunction plays a pivotal ...role in the pathogenesis of AD. Neurons are metabolically active cells, causing them to be particularly dependent on mitochondrial function for survival and maintenance. As highly dynamic organelles, mitochondria are characterized by a balance of fusion and fission, transport, and mitophagy, all of which are essential for maintaining mitochondrial integrity and function. Mitochondrial dynamics and mitophagy can therefore be identified as key pathways in mitochondrial quality control. Tremendous progress has been made in studying changes in these key aspects of mitochondrial biology in the vulnerable neurons of AD brains and mouse models, and the potential underlying mechanisms of such changes. This review highlights recent findings on alterations in the mitochondrial dynamics and mitophagy in AD and discusses how these abnormalities impact mitochondrial quality control and thus contribute to mitochondrial dysfunction in AD.
Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare plasma dyscrasia without standard treatment. This phase II prospective trial evaluates ...the safety and response of 12 cycles of low dose lenalidomide (10 mg) plus dexamethasone (Rdex) in patients with newly diagnosed POEMS syndrome. Forty‐one patients (28 men) were enrolled and the median age at diagnosis was 49 years (range, 21‐70 years). Twenty‐one patients (46%) achieved complete hematologic response and the neurologic response rate was 95%. The median serum vascular endothelial growth factor (VEGF) declined from 5155 pg/mL (range, 534‐14 328 pg/mL) to 832 pg/mL (95‐6254 pg/mL) after therapy. The overall VEGF response rate was 83%, and the median time to response was 2 months, with a mean VEGF reduction of 43% at the first month. In terms of clinical response, Rdex substantially relieved extravascular volume overload, organomegaly, and pulmonary hypertension. No treatment‐related deaths occurred and no patients suffered from lenalidomide‐related grade 3 or above adverse events. After a median follow‐up of 34 months, median overall survival (OS) and progression‐free survival (PFS) were not reached, with an estimated 3‐year OS and PFS of 90% and 75%, respectively. In conclusion, Rdex was active with high hematologic, VEGF and organ response rate and well tolerated for patients with newly diagnosed POEMS syndrome. This trial was registered at www.clinicaltrials.gov as #NCT01816620.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
N6‐Methyladenosine (m6A), one of the post‐transcriptional modifications of RNA, is important in hepatocellular carcinoma (HCC). However, the mechanism of its regulation remains elusive. We here show ...that exposure of HCC cells to sulfatide significantly reduced the total mRNA m6A modification. Interestingly, METTL3 protein was robustly acetylated and the binding of METTL3 to MTF1 mRNA, METTL14 or WTAP was weakened in cells treated with sulfatide. Further investigation of the METTL3 complex revealed recruitment of the deacetylase scaffold SIN3B, but a diminished level of histone deacetylase HDAC2, which might enhance the acetylation of METTL3. The m6A abundance in MTF1 mRNA was markedly decreased in cells after sulfatide treatment. The expression of MTF1, a zinc‐dependent transcription factor, was significantly strengthened with reduced m6A modification. Sulfatide prolonged the half‐life of MTF1 mRNA, while the mutation (A to C) on 7 methylation sites in the 3’UTR of MTF1 mRNA enhanced MTF1 mRNA stability. 3‐deaza‐adenosine, an m6A methylation inhibitor, significantly reduced the m6A modification of MTF1 mRNA but extended its half‐life time. Importantly, overexpression of MTF1 prompted HCC cell proliferation and was associated with poor prognosis. In conclusion, the METTL3‐METTL14‐WTAP complex was regulated by acetylation induced by sulfatide to control MTF1 m6A methylation and its mRNA transcription, which was important for the tumor growth and migration of HCC.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Rechargeable aqueous Zn‐I2 batteries (ZIB) are regarded as a promising energy storage candidate. However, soluble polyiodide shuttling and rampant Zn dendrite growth hamper its commercial ...implementation. Herein, a hetero‐polyionic hydrogel is designed as the electrolyte for ZIBs. On the cathode side, iodophilic polycationic hydrogel (PCH) effectively alleviates the shuttle effect and facilitates the redox kinetics of iodine species. Meanwhile, polyanionic hydrogel (PAH) toward Zn metal anode uniformizes Zn2+ flux and prevents surface corrosion by electrostatic repulsion of polyiodides. Consequently, the Zn symmetric cells with PAH electrolyte demonstrate remarkable cycling stability over 3000 h at 1 mA cm–2 (1 mAh cm–2) and 800 h at 10 mA cm–2 (5 mAh cm–2). Moreover, the Zn‐I2 full cells with PAH‐PCH hetero‐polyionic hydrogel electrolyte deliver a low‐capacity decay of 0.008 ‰ per cycle during 18 000 cycles at 8 C. This work sheds light on hydrogel electrolytes design for long‐life conversion‐type aqueous batteries.
A hetero‐polyionic hydrogel electrolyte is developed to realize cycle‐stable Zn‐I2 batteries with fast kinetics. Polyanionic hydrogel with high zincophilicity uniformizes Zn2+ flux and retards polyiodides/SO42– transport, leading to a dendrite‐free and corrosion‐free Zn anode. Iodophilic polycationic hydrogel alleviates the shuttling of polyiodides and boosts the reaction kinetics at hydrogel/carbon interface for iodine species.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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•A facile CVD method was employed to introduce Mo doping on BiVO4 photoanode.•Mo doping will induce the reconstruction of BiVO4 surface, thereby forming a homojunction.•Oxygen ...vacancies will be generated by Mo doping, which is beneficial for OER reaction.•The CoPi/Graphene/Mo:BiVO4 photoanode exhibits excellent OER activity.•This work provide a promising strategy for designing high-performance BiVO4 photoelectrodes.
Fabrication junction and doping are the two major methods to improve the charge separation and transfer efficiency of BiVO4 (BVO) photoanode to boost its photoelectrochemical water splitting performance. Most of the reported methods require complicated fabrication steps, therefore increasing the usage of hazardous chemicals and cost as well. Herein, we report a BiVO4 homojunction with abundant oxygen vacancies fabricated by a surface crystal orientation reconstruction induced by one step Mo doping method. After Mo doping, a few nanometer BVO with crystal orientation of (121) is formed on BVO (110) surface with abundant oxygen vacancies on BVO photoanode. Mo doped BiVO4 photoanode (Mo:BVO) exhibits an obvious improvement of photocurrent (∼1.63 folds) compared with the pristine BVO. Using graphene as the hole extraction layer and CoPi as the cocatalysts, CoPi/Gr/Mo:BVO photoanode shows a high oxygen evolution reaction (OER) activity with the onset potential of 0.3 V vs. RHE and photocurrent of 4.36 mA cm−2 at 1.23 V vs. RHE under AM 1.5 G illumination. This work provides a promising strategy for the design of high-performance BiVO4 photoelectrodes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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