Regulated exocytosis of synaptic vesicles is substantially faster than of endocrine dense core vesicles despite similar molecular machineries. The reasons for this difference are unknown and could be due to different regulatory proteins, different spatial arrangements, different vesicle sizes, or other factors. To address these questions, we take a reconstitution approach and compare regulated SNARE-mediated fusion of purified synaptic and dense core chromaffin and insulin vesicles using a single vesicle-supported membrane fusion assay. In all cases, Munc18 and complexin are required to restrict fusion in the absence of calcium. Calcium triggers fusion of all docked vesicles. Munc13 (C1C2MUN domain) is required for synaptic and enhanced insulin vesicle fusion, but not for chromaffin vesicles, correlating inversely with the presence of CAPS protein on purified vesicles. Striking disparities in calcium-triggered fusion rates are observed, increasing with curvature with time constants 0.23 s (synaptic vesicles), 3.3 s (chromaffin vesicles), and 9.1 s (insulin vesicles) and correlating with rate differences in cells. Regulated exocytosis of neuronal synaptic vesicles is substantially faster than that of endocrine dense core vesicles despite similar molecular machineries. Here authors compare SNARE-mediated fusion of purified synaptic vesicles with insulin vesicles and see disparities in calcium-triggered fusion rates.

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In vitro fusion of single synaptic and dense core vesicles reproduces key physiological properties

Electropolymerization has become a convenient method for synthesizing and characterizing complex organic copolymers having intrinsic electronic conductivity, including the donor (D)–acceptor (A) class of electronically conducting polymers (ECPs). This review begins with an introduction to the electrosynthesis of common second-generation ECPs. The information obtainable from electroanalytical studies, charge carriers such as polarons (positive and negative) and bipolarons (positive and negative) and doping will be discussed. The evolutionary chain of ECPs is then presented. ECPs comprising electron-rich D and electron-deficient A moieties have been shown to possess intrinsic electronic conductivity and unique optical and electronic properties. They are third generation ECPs and electropolymerization of mixtures of D and A leads to stoichiometrically controlled block copolymers. These D–A type ECPs are discussed on the basis of selected representative materials. Since the discovery of electropolymerization as a powerful tool to synthesize copolymers of conjugated monomers with a pre-determined ratio of D and A repeat units present in the polymer, the field of D–A type ECPs has grown considerably and the literature available since 2004 to 2021 is summarized and tabulated. Electronic and optical properties of the materials determined by computational chemistry are presented. The data obtained from electrochemical and optical methods are compared with those obtained from computational methods and reasons for discrepancies are given. The literature on the concept of electropolymerization extended to synthesizing triblock and many-block copolymers is reviewed. Finally, applications of D–A polymers in optoelectronic devices (organic solar cells and field-effect transistors) and in bio-imaging are explained quoting appropriate examples.

Implementing the donor–acceptor approach in electronically conducting copolymers via electropolymerization

The cell-to-cell transmission of pathological α-synuclein (α-syn) has been proposed to be a critical event in the development of synucleinopathies. Recent studies have begun to reveal the underlying molecular mechanism of α-syn propagation. As one of the central steps, α-syn secretion is reported to be Ca2+-dependent and mediated by unconventional exocytosis. However, the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) requirement and vesicle identity of α-syn secretion remain elusive. Here we found that α-syn secretion is SNARE-dependent by systematically knocking down Q-SNAREs and R-SNAREs in exocytosis pathways. α-Syn secretion was mainly mediated by syntaxin 4 (STX4) and synaptosomal-associated protein 23 (SNAP23), but did not require STX1 and SNAP25, in differentiated SH-SY5Y cells. On the other hand, vesicle-associated membrane protein 3 (VAMP3), VAMP7, and VAMP8 were all involved in α-syn secretion, most likely in overlapping pathways. Application of super-resolution microscopy revealed localization of both endogenous and overexpressed α-syn in endosomes, lysosomes, and autophagosomes in rat primary cortical neurons. α-Syn co-localized with microtubule-associated protein 1 light chain 3 (LC3) most extensively, suggesting its tight association with the autophagy pathway. Consistently, α-syn secretion was regulated by the autophagy-lysosome pathway. Collectively, our data suggest that α-syn secretion is SNARE-dependent and is mediated by multiple vesicular pathways including exocytosis of recycling endosomes, multivesicular bodies, autophagosomes, and lysosomes.

SNARE Proteins Mediate α-Synuclein Secretion via Multiple Vesicular Pathways

Triboelectric nanogenerators (TENG) are emerging as a potential technology in the wave energy harvesting domains due to their attractive characteristics like robust structure, ease of material selection, facile fabrication, high sensitivity, and high output. Since TENG enables the harvesting of random, multidirectional, low-frequency mechanical motions, its applicability can be easily extended to harvest the most underutilized renewable energy source - wave energy. This review article discusses the latest developments in marine energy harvesting and self-powered sensors using TENG. The study covers the basic understanding of TENG, its development pathways, working principle, and standard operational modes and focuses on the reported works on wave energy harvesting and self-powered sensing applications. Though various studies have been reported in lieu of wave energy harvesting, the immense possibilities of improvement of structure and materials do exist. More exploration of bionic structures and superhydrophobic materials for liquid-solid interface TENG will be a breakthrough in renewable energy harvesting. 

Triboelectric nanogenerators for marine energy harvesting and sensing applications

A low-concentration all-fluorinated electrolyte for stable lithium metal batteries.

Therapeutic strategies in ischemic cardiomyopathy: Focus on mitochondrial quality surveillance

Mitochondrial dysfunction has been regarded as a hallmark of diabetic cardiomyopathy. In addition to their canonical metabolic actions, mitochondria influence various other aspects of cardiomyocyte function, including oxidative stress, iron regulation, metabolic reprogramming, intracellular signaling transduction and cell death. These effects depend on the mitochondrial quality control (MQC) system, which includes mitochondrial dynamics, mitophagy and mitochondrial biogenesis. Mitochondria are not static entities, but dynamic units that undergo fission and fusion cycles to maintain their structural integrity. Increased mitochondrial fission elevates the number of mitochondria within cardiomyocytes, a necessary step for cardiomyocyte metabolism. Enhanced mitochondrial fusion promotes communication and cooperation between pairs of mitochondria, thus facilitating mitochondrial genomic repair and maintenance. On the contrary, erroneous fission or reduced fusion promotes the formation of mitochondrial fragments that contain damaged mitochondrial DNA and exhibit impaired oxidative phosphorylation. Under normal/physiological conditions, injured mitochondria can undergo mitophagy, a degradative process that delivers poorly structured mitochondria to lysosomes. However, defective mitophagy promotes the accumulation of nonfunctional mitochondria, which may induce cardiomyocyte death. A decline in the mitochondrial population due to mitophagy can stimulate mitochondrial biogenesis), which generates new mitochondrial offspring to maintain an adequate mitochondrial number. Energy crises or ATP deficiency also increase mitochondrial biogenesis, because mitochondrial DNA encodes 13 subunits of the electron transport chain (ETC) complexes. Disrupted mitochondrial biogenesis diminishes the mitochondrial mass, accelerates mitochondrial senescence and promotes mitochondrial dysfunction. In this review, we describe the involvement of MQC in the pathogenesis of diabetic cardiomyopathy. Besides, the potential targeted therapies that could be applied to improve MQC during diabetic cardiomyopathy are also discussed and accelerate the development of cardioprotective drugs for diabetic patients. 

Mitochondrial quality control mechanisms as molecular targets in diabetic heart.


 Disruption of the mitochondrial quality surveillance (MQS) system contributes to mitochondrial dysfunction in diabetic cardiomyopathy (DCM). In this study, we observed that cardiac expression of phosphoglycerate mutase 5 (PGAM5), a mitochondrial Ser/Thr protein phosphatase, is upregulated in mice with streptozotocin-induced DCM. Notably, DCM-related cardiac structural and functional deficits were negated in cardiomyocyte-specific
 Pgam5
 knockout (
 
 Pgam5
 CKO
 
 ) mice. Hyperglycemic stress impaired adenosine triphosphate production, reduced respiratory activity, and prolonged mitochondrial permeability transition pore opening in acutely isolated neonatal cardiomyocytes from control
 
 Pgam5
 f/f
 
 mice, and these effects were markedly prevented in cardiomyocytes from
 
 Pgam5
 CKO
 
 mice. Likewise, three main MQS-governed processes—namely, mitochondrial fission/fusion cycling, mitophagy, and biogenesis—were disrupted by hyperglycemia in
 
 Pgam5
 f/f
 
 , but not in
 
 Pgam5
 CKO
 
 , cardiomyocytes. On the basis of bioinformatics prediction of interaction between PGAM5 and prohibitin 2 (PHB2), an inner mitochondrial membrane-associated scaffolding protein, co-immunoprecipitation, and immunoblot assays demonstrated that PGAM5 dephosphorylates PHB2 on Ser91. Transfection of cardiomyocytes with phosphodefective or phosphomimetic Ser91 mutants of PHB2 confirmed a critical role for PGAM5-mediated dephosphorylation of PHB2 in mitochondrial dysfunction associated with hyperglycemic stress. Furthermore, knockin mice expressing phosphomimetic PHB2
 S91D
 were resistant to diabetes-induced cardiac dysfunction. Our findings highlight the PGAM-PHB2 axis as a novel and critical regulator of mitochondrial dysfunction in DCM.


PGAM5-Mediated PHB2 Dephosphorylation Contributes to Diabetic Cardiomyopathy by Disrupting Mitochondrial Quality Surveillance

Structural and Functional Analysis of the CAPS SNARE-Binding Domain Required for SNARE Complex Formation and Exocytosis.

The regulatory mechanisms involved in mitochondrial quality control (MQC) dysfunction during septic cardiomyopathy (SCM) remain incompletely characterized. Transmembrane BAX inhibitor motif containing 6 (TMBIM6) is an endoplasmic reticulum protein with Ca2+ leak activity that modulates cellular responses to various cellular stressors.In this study, we evaluated the role of TMBIM6 in SCM using cardiomyocyte-specific TMBIM6 knockout (TMBIM6CKO) and TMBIM6 transgenic (TMBIM6TG) mice.Myocardial TMBIM6 transcription and expression were significantly downregulated in wild-type mice upon LPS exposure, along with characteristic alterations in myocardial systolic/diastolic function, cardiac inflammation, and cardiomyocyte death. Notably, these alterations were further exacerbated in LPS-treated TMBIM6CKO mice, and largely absent in TMBIM6TG mice. In LPS-treated primary cardiomyocytes, TMBIM6 deficiency further impaired mitochondrial respiration and ATP production, while defective MQC was suggested by enhanced mitochondrial fission, impaired mitophagy, and disrupted mitochondrial biogenesis. Structural protein analysis, Co-IP, mutant TMBIM6 plasmid transfection, and molecular docking assays subsequently indicated that TMBIM6 exerts cardioprotection against LPS-induced sepsis by interacting with and preventing the oligomerization of voltage-dependent anion channel-1 (VDAC1), the major route of mitochondrial Ca2+ uptake.We conclude that the TMBIM6-VDAC1 interaction prevents VDAC1 oligomerization and thus sustains mitochondrial Ca2+ homeostasis as well as MQC, contributing to improved myocardial function in SCM. 

Hao Zhou

Papers

Therapeutic strategies in ischemic cardiomyopathy: Focus on mitochondrial quality surveillance

Mitochondrial quality control mechanisms as molecular targets in diabetic heart.

PGAM5-Mediated PHB2 Dephosphorylation Contributes to Diabetic Cardiomyopathy by Disrupting Mitochondrial Quality Surveillance

Structural and Functional Analysis of the CAPS SNARE-Binding Domain Required for SNARE Complex Formation and Exocytosis.

TMBIM6 prevents VDAC1 multimerization and improves mitochondrial quality control to reduce sepsis-related myocardial injury.