Trapping Approach Research Articles

A Kinetic Trapping Approach for Facile Access to 3FaxNeu5Ac and a Photo-Cross-Linkable Sialyltransferase Probe.

Sialic acid (Neu5Ac) is installed onto glycoconjugates by sialyltransferases (STs) using cytidine monophosphate-Neu5Ac (CMP-β-d-Neu5Ac) as their donor. The only class of cell-active ST inhibitors are those based on a 3FaxNeu5Ac scaffold, which is metabolically converted into CMP-3FaxNeu5Ac within cells. It is essential for the fluorine to be axial, yet stereoselective installation of fluorine in this specific orientation is challenging. Sialic acid aldolase can convert 3-fluoropyruvate and 2-acetamido-2-deoxy-d-mannopyranose (ManNAc) to 3FNeu5Ac, but stereocontrol of the fluorine in the product has not been possible. We hypothesized that the 3Fax kinetic product of a sialic acid aldolase reaction could be trapped by coupling with CMP-sialic acid synthetase to yield CMP-3FaxNeu5Ac. Here, we report that highly active CMP-sialic acid synthetase and short reaction times produce exclusively CMP-3FaxNeu5Ac. Removal of CMP from CMP-3FaxNeu5Ac under acidic conditions unexpectedly led to 3-fluoro-β-d-Neu5Ac 2-phosphate (3FaxNeu5Ac-2P). Alkaline phosphatase successfully converted 3FaxNeu5Ac-2P to 3FaxNeu5Ac, enabling stereochemically controlled access to 3FaxNeu5Ac, which is effective in lowering the sialoglycan ligands for Siglecs on cells. Moreover, our kinetic trapping approach could be used to access CMP-3FaxNeu5Ac with modifications at the C5, C9, or both positions, which enabled the chemoenzymatic synthesis of a photo-cross-linkable version of CMP-3FaxNeu5Ac that selectively photo-cross-linked to ST6GAL1 over two other STs.

In-situ confining selenium within bubble - like carbon nanoshells for ultra-stable Li-Se batteries.

Lithium-selenium (Li-Se) batteries are promising energy storage devices. However, the long-term durability and high-rate performance of the Se cathode have been limited by significant volume expansion and the troublesome shuttle effect of polyselenides during repeated charging/discharging processes. To revolutionize these issues, we applied a top-down strategy through the in-situ trapping of amorphous Se within bubble-like carbon (BLC) frameworks, which can radically minimize the presence of surface-absorbed Se while enhancing Se loading capacity. This ingenious technique successfully encapsulates all Se species within carbon nanoshells, creating a distinct half-filled core-shell structure known as Se@void@BLC. This in-situ trapping approach ensures the efficient management of Se volume changes during repeated discharge and charge cycles. Moreover, an extraordinary Se loading capacity of up to 65.6 wt% is reached. Using the Se@void@BLC as cathode for Li-Se battery, we achieve a high initial Columbic efficiency of 84.2 %, a high reversible capacity of 585 mAh g-1 , and an ultralow capacity decay of only 0.0037 % per cycle during 4000 cycles at 10 A g-1 .

A confined self-assembly approach towards chiral photonic materials with circularly polarized structural colors for information storage and encryption

Chiroptical materials with tunable circular polarization performances have gained wide interest because of promising applications in optical devices and information communication. However, limited by their intrinsic chirality, such materials suffer from serious deficiencies in dynamical manipulation on circularly polarized light (CPL). Here, we demonstrate a kinetic trapping approach to capture multi-domain cholesteric mesophases for polarization-dependent structural coloration. The resultant photonic structures depicted by limited solvent evaporation display light control from selective left-handed circularly polarized light reflection to dual reflection, as a result of forming highly tilted and distorted domains with a phase-retardation effect. Notably, a positive linear correlation is established between the circular polarization behavior and structural orientation regulated by the solvent evaporation. The tunable circular polarization structural colors enable the application of the photonic materials for complex encryption in terms of polychromatic coding arrays. The confined-anisotropic-fabrication method of photonic structures paves a foundation toward advanced functional materials with promising applications in light science and technology.

New topological rainbow trapping approach for phononic beam-foundation systems

Rainbow trapping is of great significance for frequency-based wave splitting and broadband wave attenuation. By recognizing the deficiency of prevailing gradient rainbow reflection devices in terms of energy concentration and broadband vibration isolation, we design a new topological rainbow trapping device by introducing a topological protected interface mode (TPIM) into the prevailing gradient rainbow device. Therefore, a topological rainbow trapping beam composed of a homogenous beam rested on an alternate and gradient foundation is constructed. Using theoretical and numerical analysis, we perform a unit-cell band structure analysis. The dependence of bandgap region and group velocity on the reference foundation stiffness is investigated. With the help of the topological phase transition and Zak phase analysis, we successfully predict and demonstrate TPIM. A quantitative evaluation of the advancement of topological rainbow devices upon the prevailing gradient device in vibration amplification and broadband wave attenuation is also presented. We believe that the robust one-dimensional topological rainbow trapping beam will be useful in many applications, such as energy harvesting, wave splitting, and vibration control.

A complex network regulating malate contents during fruit ripening in climacteric fruits.

This article is a Commentary on Wang et al. (2023), 239: 1014–1034.

Elucidating mechanisms of cytoskeletal ensemble synergy using optical tweezers.

Development of cytoskeletal reconstitution assays that reflect a physiologically relevant environment has been a challenge for the biophysics field. In particular, optical trapping approaches to investigate motor protein dynamics have typically consisted of a reductionist geometry of a single motor and single filament. These assays not only do not capture the structural hierarchy in which motors with crosslinking ability function, but they also cannot capture the emergent mechanics that develop from ensembles of cytoskeletal proteins. It is becoming increasingly clear that the sum of protein single molecule properties may not always equal the resulting mechanics of the overall ensemble. Thus, to probe the molecular determinants of force generation, communication, and synergy of hierarchical cytoskeletal mechanics with high resolution, an optical trapping approach was developed that probes multiple motors and filaments in an ensemble. Using this method, we interrogate actomyosin mechanics to elucidate myosin II ensemble synergy and force regulation within a bundled actin assembly.

Numerical Simulations of Double-Well Optical Potentials in All-Dielectric Nanostructures for Manipulation of Small Nanoparticles in Aqueous Media

The manipulation of molecules placed in close proximity to a liquid is crucial for understanding their interactions, as in the study of antibiotics against bacteria. This can, in principle, be realized with plasmonic optical tweezers, but the heating of metals leads to the denaturing of biomolecules. In this work, we demonstrate that slotted all-dielectric nanodisks made of amorphous silicon (a-Si) exhibit double-well optical potentials, which can be used to stably trap dielectric nanoparticles with radii as small as 15 nm using infrared wavelengths where there is no optical loss (no heating) for a-Si. The latter is important to avoid heating the surrounding environment, which in turn, generates fluid convection currents that would compromise optical trapping. The trapping of one and two nanoparticles (even with different morphologies) in water is demonstrated in numerical results for an all-dielectric nanostructure, which can be obtained with standard materials and nanofabrication methods. The trapping forces are only slightly affected by the morphology of the small dielectric nanoparticles, thus indicating that the trapping approach may be applied to a variety of biomolecules.

King Rail ( Rallus elegans ) response to audio playback: implications for population estimation, monitoring methodology, and trapping approach

Conspecific audio can be broadcast to improve detection probability (detectability) of secretive marsh bird species for population monitoring purposes and as a lure to more effectively trap individuals. Our primary objective was to describe King Rail (<em>Rallus elegans</em>) detectability as a function of distance and so determine if the distance sampling assumption of perfect detectability immediately adjacent to survey points was violated during call-broadcast surveys. We also described what factors affected King Rail detectability during audio broadcast surveys, and how and when this species was detected, and compared effectiveness of various King Rail call recordings used during trapping attempts. To accomplish these objectives, we experimentalized trapping efforts, radio-tagged 12 King Rails, and conducted repeated call-broadcast surveys for each radio-tagged individual in Michigan and Ohio, USA during the 2020 and 2021 breeding seasons. We found that King Rail detectability during 81 surveys was 0.39, which violates the aforementioned distance sampling assumption and necessitates a correction factor. Detectability within survey segments varied among survey periods, though overall detectability remained relatively constant, even after call-broadcast surveys in our study area typically end (post-survey period: 15 June to 10 July), which indicates that King Rail monitoring could effectively continue later than currently occurs. We found that grunt calls resulted in more captures than kek calls and that a multi-call track was most effective at trapping King Rails. Our findings could improve King Rail population estimates and increase success during trapping efforts, and may inform similar efforts for other secretive marsh birds.

PS-B02-7: THE LONG NON-CODING RNA CAREN IMPROVES CARDIAC DYSFUNCTION IN AGED MICE

Background: Heart failure (HF) is the predominant cause of hospitalization and amongst the leading causes of death in developed countries. Especially, the prevalence of HFpEF is increasing and its prognosis is not improving. Our understanding of HFpEF pathophysiology is incomplete and optimal treatment remains uncertain. Under such circumstance, recently, it has been reported that some lncRNAs expressed in heart play important roles in cardiac development and disease. Methods and Results: Using a gene trapping approach in mouse embryonic stem cells, we identified Caren (for cardiomyocyte-enriched noncoding transcript), a cytoplasmic lncRNA abundantly expressed in cardiomyocytes. Caren overexpression in cardiomyocytes activated mitochondrial biogenesis by upregulating of Tfam protein and attenuated TAC-induced activation of Ataxia Telangiectasia Mutated (ATM), a key regulator of DNA Damage Response (DDR). Moreover, TAC operated mice treated with AAV6-Caren relieved reduction of fractional shortening (%FS) and improved dilatation of left ventricular. Next, proteomics analysis revealed that Histidine triad nucleotide-binding protein1 (Hint1) which activates the ATM-DDR pathway was reduced in Caren transgenic mice. Moreover, 24-month-old WT mice treated with AAV6-Caren diminished systolic and dilatation capacity were improved. And electron microscopy analysis revealed that mitochondrial cristae were restored and the numbers of mitochondria were increased in the heart of 24-month-old WT mice treated with AAV6-Caren compared with the mice treated with AAV6-GFP as control. Conclusion: A cytoplasmic lncRNA Caren improves not only systolic function but also diastolic function in failing / aged heart by suppressing the ATM-DDR pathway and activating mitochondrial bioenergetics.

A geometric trapping approach to global regularity for 2D Navier–Stokes on manifolds

A geometric trapping approach to global regularity for 2D Navier–Stokes on manifolds

Avoid Suspicious Route of Blackhole Nodes in MANET’s: Using A Cooperative Trapping

Mobile Ad hoc Network (MANET) is decentralized wireless network and can communicate without existing infrastructure in many areas. MANET is vulnerable to various attacks that affect its performance such as blackhole attack. Blackhole attacker, inject fault routing information to persuade the source node to select the path with malicious node as the shortest path. To eliminate malicious nodes from launching any collaborative attack. A cooperative Trapping Approach (CTA) was proposed based on modifying Ad-hoc On-demand Distance Vector (AODV) routing protocol and trapping the malicious nodes by responding to the trap request message. The approach aims to eliminate and rule out both single and collaborative malicious blackhole nodes from any attack. The approach realizes a backward tracking mechanism to perform the elimination process. The proposed algorithm (CTA) was executed using NS-2 network simulator. The performance metrics that has been considered to evaluate the performance of the proposed algorithm such as throughput, end to end delay, packet delivery ratio, and consuming energy. The experimental results have shown the performance metrics of the proposed approach outperformed other state of at algorithms.

King Rail (Rallus elegans) response to audio playback: implications for population estimation, monitoring methodology, and trapping approach

King Rail (Rallus elegans) response to audio playback: implications for population estimation, monitoring methodology, and trapping approach

PTP4A2 promotes lysophagy by dephosphorylation of VCP/p97 at Tyr805

ABSTRACT Overexpression of PTP4A phosphatases are associated with advanced cancers, but their biological functions are far from fully understood due to limited knowledge about their physiological substrates. VCP is implicated in lysophagy via collaboration with specific cofactors in the ELDR complex. However, how the ELDR complex assembly is regulated has not been determined. Moreover, the functional significance of the penultimate and conserved Tyr805 phosphorylation in VCP has not been established. Here, we use an unbiased substrate trapping and mass spectrometry approach and identify VCP/p97 as a bona fide substrate of PTP4A2. Biochemical studies show that PTP4A2 dephosphorylates VCP at Tyr805, enabling the association of VCP with its C-terminal cofactors UBXN6/UBXD1 and PLAA, which are components of the ELDR complex responsible for lysophagy, the autophagic clearance of damaged lysosomes. Functionally, PTP4A2 is required for cellular homeostasis by promoting lysophagy through facilitating ELDR-mediated K48-linked ubiquitin conjugate removal and autophagosome formation on the damaged lysosomes. Deletion of Ptp4a2 in vivo compromises the recovery of glycerol-injection induced acute kidney injury due to impaired lysophagy and sustained lysosomal damage. Taken together, our data establish PTP4A2 as a critical regulator of VCP and uncover an important role for PTP4A2 in maintaining lysosomal homeostasis through dephosphorylation of VCP at Tyr805. Our study suggests that PTP4A2 targeting could be a potential therapeutic approach to treat cancers and other degenerative diseases by modulating lysosomal homeostasis and macroautophagy/autophagy. Abbreviations: AAA+: ATPases associated with diverse cellular activities; AKI: acute kidney injury; CBB: Coomassie Brilliant Blue; CRISPR: clustered regularly interspaced short palindromic repeats; ELDR: endo-lysosomal damage response; GFP: green fluorescent protein; GST: ‎glutathione S-transferase; IHC: immunohistochemistry; IP: immunoprecipitation; LAMP1: lysosomal-associated membrane protein 1; LC-MS: liquid chromatography-mass spectrometry; LGALS3/Gal3: galectin 3; LLOMe: L-leucyl-L-leucine methyl ester; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; PLAA: phospholipase A2, activating protein; PTP4A2: protein tyrosine phosphatase 4a2; PUB: NGLY1/PNGase/UBA- or UBX-containing protein; PUL: PLAP, Ufd3, and Lub1; TFEB: transcription factor EB; UBXN6/UBXD1: UBX domain protein 6; UPS: ubiquitin-proteasome system; VCP/p97: valosin containing protein; VCPIP1: valosin containing protein interacting protein 1; YOD1: YOD1 deubiquitinase.

Examination of Charge Modifications of an Endolysosomal Trapping Inhibitor in an Antagonistic NTSR1-Targeted Construct for Colon Cancer.

Many low-molecular weight targeted radiotherapeutics (TRTs) are capable of rapidly achieving exceptional tumor to non-target ratios shortly after administration. However, the low tumor residence time of many TRTs limits therapeutic dose delivery and has become the Achilles heel to their clinical translation. To combat the tumor efflux of these otherwise promising agents, we have previously presented a strategy of equipping low-molecular weight TRTs with irreversible cysteine cathepsin inhibitors (e.g., E-64 analogues). These inhibitors are capable of forming irreversible adducts with cysteine proteases within the endolysosomal compartments of cells. Using these endolysosomal trapping agents (ETs), the receptor-targeted constructs are able to increase tumor retention and, thus, deliverable therapeutic doses. In this study, we examine this approach in the development of agents targeting the neurotensin receptor subtype 1 (NTSR1), a receptor overexpressed in numerous cancers. Using an antagonistic NTSR1-targeting vector, we explore the impact of charge modification of the ETs on the in vitro and in vivo biological performance of the constructs using HT-29 colon cancer models. Four ETs (based on the epoxysuccinyl peptide E-64) with various charge states were synthesized and incorporated into the structures of the NTSR1-targeted antagonist. These four 177Lu-labeled, ET-enhanced, NTSR1-targeted agents (177Lu-NA-ET1-4), along with the structurally analogous 177Lu-3BP-227, currently in clinical trials, underwent a battery of in vitro assays using HT-29 xenograft colon cancer cells to examine their NTSR1 binding, internalization and efflux, inhibition, and adduct formation properties. The biodistribution profile of these constructs was studied in an HT-29 mouse model. Charge modification of the terminal carboxylic acid and arginine of the ETs had deleterious effects on inhibition kinetics and in vitro adduct formation. Contrastingly, deletion of the arginine resulted in a modest increase in inhibition kinetics. Incorporation of ETs into the NTSR1-targeted agents was well-tolerated with minimal impact on the in vivo NTSR1 targeting but resulted in increased renal uptake. This study demonstrates that the ETs can be successfully incorporated into antagonistic NTSR1-targeted constructs without compromising their adduct formation capabilities. Based on these results, further exploration of the endolysosomal trapping approach is warranted in NTSR1- and other receptor-targeted antagonistic constructs.

Characterization of radicals in polysorbate 80 using electron paramagnetic resonance (EPR) spectroscopy and spin trapping

Polysorbates are an important class of nonionic surfactants that are widely used to stabilize biopharmaceuticals. The degradation of polysorbate 20 and 80 and the related particle formation in biologics are heavily discussed in the pharmaceutical community. Although a lot of experimental effort was spent in the detailed study of potential degradation pathways, the underlying mechanisms are only sparsely understood. Besides enzymatic hydrolysis, another proposed mechanism is associated with radical-induced (auto)oxidation of polysorbates. To characterize the types and the origin of the involved radicals and their propagation in bulk material as well as in diluted polysorbate 80 solutions, we applied electron paramagnetic resonance (EPR) spectroscopy using a spin trapping approach. The prerequisite for a meaningful experiment using spin traps is an understanding of the trapping rate, which is an interplay of (i) the presence of the spin trap at the scene of action, (ii) the specific reactivity of the selected spin trap with a certain radical as well as (iii) the stability of the formed spin adducts (a slow decay rate). We discuss whether and to which extent these criteria are fulfilled regarding the identification of different radical classes that might be involved in polysorbate oxidative degradation processes. The ratio of different radicals for different scenarios was determined for various polysorbate 80 quality grades in bulk material and in aqueous solution, showing differences in the ratio of present radicals. Possible correlations between the radical content and product parameters such as the quality grade, the manufacturing date, the manufacturer, the initial peroxide content according to the certificate of analysis of polysorbate 80 are discussed.

Subtle Effects of Experimental Grassland Fragmentation on Density, Species Composition and Functional Dispersion of Gastropods

The fragmentation of continuous habitats has significant consequences for species and for the functional diversity of plant and animal communities. Fragmentation effects can be indirect, can occur at different spatial scales and may vary over years. Small fragmentation-related effects may only be detected in standardized, controlled field experiments accounting for the natural variation in environmental conditions and in remnants of habitat. Using a non-invasive trapping approach, we examined the responses of terrestrial gastropods (snails and slugs) to small-scale habitat fragmentation in a controlled experiment conducted in three species-rich, nutrient-poor calcareous grasslands in the Jura Mountains, Switzerland, over four years. We found site-specific differences in species richness, individual density, and species composition. Experimental grassland fragmentation did not significantly affect species richness or density, but affected functional dispersion (a measure of functional diversity) in the final year, indicating that fragmentation-related changes may occur with a time delay. Similarly, experimental fragmentation influenced the mean shell size of the snail assemblage and the proportions of individuals with certain life-history traits or habitat preferences in some years. The observed fragmentation effects were subtle and varied over time, underlining the importance of controlled field experiments.

Cytosolic glutaredoxin 1 is upregulated in AMD and controls retinal pigment epithelial cells proliferation via β-catenin

Thioredoxin (Trx) family proteins are key players in redox signaling. Here, we have analyzed glutaredoxin (Grx) 1 and Grx2 in age-related macular degeneration (AMD) and in retinal pigment epithelial (ARPE-19) cells. We hypothesized that these redoxins regulate cellular functions and signaling circuits such as cell proliferation, Wnt signaling and VEGF release that have been correlated to the pathophysiology of AMD. ARPE-19 cells were transfected with specific siRNAs to silence the expression of Grx1 and Grx2 and were analyzed for proliferation/viability, migration capacity, β-catenin activation, and VEGF release. An active site-mutated C-X-X-S Grx1 was utilized to trap interacting proteins present in ARPE-19 cell extracts. In both, AMD retinas and in ARPE-19 cells incubated under hypoxia/reoxygenation conditions, Grx1 showed an increased nuclear localization. Grx1-silenced ARPE-19 cells showed a significantly reduced proliferation and migration rate. Our trapping approach showed that Grx1 interacts with β-catenin in a dithiol-disulfide exchange reaction. Knock-down of Grx1 led to a reduction in both total and active β-catenin levels. These findings add redox control to the regulatory mechanisms of β-catenin signaling in the retinal pigment epithelium and open the door to novel therapeutic approaches in AMD that is currently treated with VEGF-inhibitors.

Proteomics, phylogenetics, and co‐expression analyses indicate novel interactions in the plastid CLP chaperone‐protease system

The chloroplast CLPC1 chaperone delivers and unfolds substrates to the stromal CLPPRT protease complex for degradation. We previously used an in vivo trapping approach to identify a dozen interactors with CLPC1 in Arabidopsis thaliana.This was achieved by expressing a STREPII‐tagged copy of CLPC1 mutated in its Walker B domains (CLPC1‐TRAP) followed by affinity purification and mass spectrometry. To screen for additional interactors, we carried out a far more sensitive and comprehensive in vivo protein trapping analysis. This identified 59 highly enriched CLPC1 protein interactors, in particular proteins in families of unknown functions (DUF760, DUF179, DUF3143, UVR‐DUF151, HugZ/DUF2470), as well as the UVR domain proteins EXE1 and EXE2 implicated in singlet oxygen damage and signaling. Phylogenetic and functional domain analyses identified other members of these families. These protein families appear to localize (nearly) exclusively to plastids. Several of these DUF proteins are of very low abundance as determined through the Arabidopsis PeptideAtlas http://www.peptideatlas.org/builds/arabidopsis/ showing that enrichment in the CLPC1‐TRAP was extremely selective. Evolutionary rate covariation indicated that the HugZ/DUF2470 family co‐evolved with the plastid CLP machinery suggesting functional and/or physical interactions. mRNA‐based co‐expression networks showed that all 12 CLP protease subunits tightly co‐expressed as a single cluster with deep connections to DUF760‐3. Co‐expression modules for other trapped proteins suggested specific functions in biological processes, e.g. UVR2 and UVR3 were associated with extra‐plastidic degradation, whereas DUF760‐6 is likely involved in senescence. This study provides a strong foundation for discovery of substrate selection by the chloroplast CLP protease system.

Proteomics, phylogenetics, and coexpression analyses indicate novel interactions in the plastid CLP chaperone-protease system

The chloroplast chaperone CLPC1 unfolds and delivers substrates to the stromal CLPPRT protease complex for degradation. We previously used an in vivo trapping approach to identify interactors with CLPC1 in Arabidopsis thaliana by expressing a STREPII-tagged copy of CLPC1 mutated in its Walker B domains (CLPC1-TRAP) followed by affinity purification and mass spectrometry. To create a larger pool of candidate substrates, adaptors, or regulators, we carried out a far more sensitive and comprehensive in vivo protein trapping analysis. We identified 59 highly enriched CLPC1 protein interactors, in particular proteins belonging to families of unknown functions (DUF760, DUF179, DUF3143, UVR-DUF151, HugZ/DUF2470), as well as the UVR domain proteins EXE1 and EXE2 implicated in singlet oxygen damage and signaling. Phylogenetic and functional domain analyses identified other members of these families that appear to localize (nearly) exclusively to plastids. In addition, several of these DUF proteins are of very low abundance as determined through the Arabidopsis PeptideAtlas http://www.peptideatlas.org/builds/arabidopsis/ showing that enrichment in the CLPC1-TRAP was extremely selective. Evolutionary rate covariation indicated that the HugZ/DUF2470 family coevolved with the plastid CLP machinery suggesting functional and/or physical interactions. Finally, mRNA-based coexpression networks showed that all 12 CLP protease subunits tightly coexpressed as a single cluster with deep connections to DUF760-3. Coexpression modules for other trapped proteins suggested specific functions in biological processes, e.g., UVR2 and UVR3 were associated with extraplastidic degradation, whereas DUF760-6 is likely involved in senescence. This study provides a strong foundation for discovery of substrate selection by the chloroplast CLP protease system.

Abstract 9218: The Long Non-Coding Rna Caren Improves Cardiac Dysfunction in Aged Mice

Background: Heart failure (HF) is the predominant cause of hospitalization and amongst the leading causes of death in developed countries. Especially, the prevalence of HFpEF is increasing and its prognosis is not improving. Our understanding of HFpEF pathophysiology is incomplete and optimal treatment remains uncertain. Under such circumstance, recently, it has been reported that some lncRNAs expressed in heart play important roles in cardiac development and disease. Methods and Results: Using a gene trapping approach in mouse embryonic stem cells, we identified Caren (for car diomyocyte- en riched noncoding transcript), a cytoplasmic lncRNA abundantly expressed in cardiomyocytes. Caren overexpression in cardiomyocytes activated mitochondrial biogenesis by upregulating of Tfam protein and attenuated TAC-induced activation of Ataxia Telangiectasia Mutated (ATM), a key regulator of DNA Damage Response (DDR). Moreover, TAC operated mice treated with AAV6- Caren relieved reduction of fractional shortening (%FS) and improved dilatation of left ventricular. Next, proteomics analysis revealed that Histidine triad nucleotide-binding protein1 (Hint1) which activates the ATM-DDR pathway was reduced in Caren transgenic mice. Moreover, 24-month-old WT mice treated with AAV6- Caren diminished systolic and dilatation capacity were improved. And electron microscopy analysis revealed that mitochondrial cristae were restored and the numbers of mitochondria were increased in the heart of 24-month-old WT mice treated with AAV6- Caren compared with the mice treated with AAV6-GFP as control. Conclusion: A cytoplasmic lncRNA Caren improves not only systolic function but also diastolic function in failing / aged heart by suppressing the ATM-DDR pathway and activating mitochondrial bioenergetics.