scholarly journals Binding Features and Functions of ATG3

2021 ◽  
Vol 9 ◽  
Author(s):  
Dongmei Fang ◽  
Huazhong Xie ◽  
Tao Hu ◽  
Hao Shan ◽  
Min Li
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Current Knowledge ◽  
Ischemia Reperfusion ◽  
Cellular Tissue ◽  
Dependent Manner ◽  
Conjugation System ◽  
Autophagosome Formation ◽  
Binding Partners ◽  
Independent Functions ◽  
Evolutionarily Conserved

Autophagy is an evolutionarily conserved catabolic process that is essential for maintaining cellular, tissue, and organismal homeostasis. Autophagy-related (ATG) genes are indispensable for autophagosome formation. ATG3 is one of the key genes involved in autophagy, and its homologs are common in eukaryotes. During autophagy, ATG3 acts as an E2 ubiquitin-like conjugating enzyme in the ATG8 conjugation system, contributing to phagophore elongation. ATG3 has also been found to participate in many physiological and pathological processes in an autophagy-dependent manner, such as tumor occurrence and progression, ischemia–reperfusion injury, clearance of pathogens, and maintenance of organelle homeostasis. Intriguingly, a few studies have recently discovered the autophagy-independent functions of ATG3, including cell differentiation and mitosis. Here, we summarize the current knowledge of ATG3 in autophagosome formation, highlight its binding partners and binding sites, review its autophagy-dependent functions, and provide a brief introduction into its autophagy-independent functions.

Abstract 1394: Sublethal Levels of Aldehydes Augmented Cardiac Anti-Oxidant Defense through Activation of eIF2 α -ATF4 Pathway via GCN2 Kinase

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Takaharu Katayama ◽  
Motoaki Sano ◽  
Jin Endo ◽  
Kentaro Hayashida ◽  
Tomohiro Matsuhashi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Special Importance ◽  
Dependent Manner ◽  
Protein Levels

[Introduction] Despite an increase in the levels of aldehydes, the heart from aldehyde dehydrogenase ( ALDH ) 2*2 -transgenic (Tg) mice, loss of function model of ALDH, exhibited a greater tolerance to oxidative stress via activation of amino acid metabolism leading to glutathione biosynthesis. This study was designed to identify the signaling cascades responsible for the activation of amino acid metabolism by aldehydes. [Methods & Results] (1) Phosphorylation of α -subunit of eukaryotic translation initiation factor 2 (eIF2 α ) and subsequent translational activation of ATF4 have been shown to induce amino acid metabolism as a common response to a wide variety of stressors. Consistent with this, phosphorylation levels of eIF2 α and protein expression of ATF4 were increased in ALDH2*2 -Tg hearts. (2) Among four eIF2 α kinases, general control non-depressible (GCN)2 kinase, a sensor for amino acid insufficiency, was activated in ALDH2*2 -Tg heart. (3) Quantification of intracellular amino acid demonstrated that free histidine concentration in ALDH2*2 -Tg heart was selectively reduced by 50% compared to that in non-Tg littermates. (4) To clarify the functional significance of observed reduction in histidine, ALDH2*2 -Tg mice were fed a high histidine diet. The phosphorylation levels of eIF2 α and the protein levels of ATF4 were diminished by 50% in ALDH2*2 -Tg mice fed the high histidine diet, in agreement with the normalization of histidine concentration. Accordingly, both enhanced tolerance to ischemia-reperfusion injury and elevated levels of glutathione were partially diminished in the heart from ALDH2*2 -Tg mice fed the high histidine diet compared to ALDH2*2 -Tg mice fed normal chow. (5) In culture, exposure to 4-hydroxy-2-nonenal (4-HNE) phosphorylated GCN2 and eIF2 α and increased protein levels of ATF4 in a time-dependent manner. (6) siRNA-mediated knockdown of GCN2 abrogated 4-HNE-induced induction of amino acid metabolic genes. [Conclusions] Activation of eIF2 α -ATF4 pathway via GCN2 kinase might be of special importance in the transcriptional control that coordinately promotes amino acid metabolism in response to aldehydes. Intracellular depletion of free histidine is at least partly involved in the activation of GCN2 kinase by aldehydes.

scholarly journals What we need to know about lipid-associated injury in case of renal ischemia-reperfusion

2018 ◽  
Vol 315 (6) ◽  
pp. F1714-F1719 ◽  
Author(s):  
Pauline Erpicum ◽  
Pascal Rowart ◽  
Jean-Olivier Defraigne ◽  
Jean-Marie Krzesinski ◽  
François Jouret
Keyword(s):  
Energy Demand ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Current Knowledge ◽  
Ischemia Reperfusion ◽  
Acid Oxidation ◽  
Metabolic Switch ◽  
Cell Functions ◽  
Associated Injury ◽  
Cortex Area

Renal segmental metabolism is reflected by the complex distribution of the main energy pathways along the nephron, with fatty acid oxidation preferentially used in the cortex area. Ischemia/reperfusion injury (IRI) is due to the restriction of renal blood flow, rapidly leading to a metabolic switch toward anaerobic conditions. Subsequent unbalance between energy demand and oxygen/nutrient delivery compromises kidney cell functions, resulting in a complex inflammatory cascade including the production of reactive oxygen species (ROS). Renal IRI especially involves lipid accumulation. Lipid peroxidation is one of the major events of ROS-associated tissue injury. Here, we briefly review the current knowledge of renal cell lipid metabolism in normal and ischemic conditions. Next, we focus on renal lipid-associated injury, with emphasis on its mechanisms and consequences during the course of IRI. Finally, we discuss preclinical observations aiming at preventing and/or attenuating lipid-associated IRI.

scholarly journals Mitofusin 2 Exerts a Protective Role in Ischemia Reperfusion Injury Through Increasing Autophagy

2018 ◽  
Vol 46 (6) ◽  
pp. 2311-2324 ◽  
Author(s):  
Cheng Peng ◽  
Wei Rao ◽  
Lei Zhang ◽  
Fan Gao ◽  
Hao Hui ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Protective Role ◽  
Cell Counting ◽  
Autophagic Flux ◽  
Autophagosome Formation ◽  
Mitofusin 2 ◽  
Differentiated Cells

Background/Aims: Autophagy is essential for maintaining cellular homeostasis and the survival of terminally differentiated cells as neurons. In this study, we aim to investigate whether mitofusin 2, a mitochondrial fusion protein, mediates autophagy in cerebral ischemia/reperfusion (I/R) injury. Methods: Primary cultured neurons were treated with oxygen-glucose deprivation/reperfusion to mimic cerebral I/R injury in vitro. Autophagosomes were visualized upon TEM. Autophagy-markers were then detected to monitor autophagy by western-blot and real-time PCR, and the autophagic flux was tracked with a mRFP-GFP-LC3 construct by fluorescence as well as autophagy inhibitors and agonists. The up- and downregulation of Mfn2 were through transfecting a lentivirusexpression vector respectively. And neuronal injury was detected by cell counting kit and TUNEL assay. Results: Results showed I/R increased autophagosome formation and inhibited autolysosome degradation. Furthermore, use of autophagy related agents demonstrated that I/R injury was caused by insufficient autophagy and aggravated by impaired autophagic degradation. The results also indicated that mitofusin 2 could ameliorate I/R injury through increasing autophagosome formation and promoting the fusion of autophagosomes and lysosomes. In contrast, downregulation of mitofusin 2 aggravated the I/R injury by inhibiting autophagosome formation and the fusion of autophagosomes and lysosomes. Additionly, mitofusin 2 overexpression did not lead to autolysosome accumulation induced by I/R. Conclusions: In summary, this study explicitly demonstrated that mitofusin 2 could ameliorate I/R injury mainly through promoting autophagy, which represented a potential novel strategy for neuroprotection against cerebral I/R damage.

scholarly journals Bilirubin acts as a multipotent guardian of cardiovascular integrity: more than just a radical idea

2018 ◽  
Vol 315 (3) ◽  
pp. H429-H447 ◽  
Author(s):  
Andrew C. Bulmer ◽  
Bhavisha Bakrania ◽  
Eugene F. Du Toit ◽  
Ai-Ching Boon ◽  
Paul J. Clark ◽  
...  
Keyword(s):  
Clinical Medicine ◽  
Ischemia Reperfusion Injury ◽  
Current Knowledge ◽  
Ischemia Reperfusion ◽  
Chronic Obstructive ◽  
Protective Properties ◽  
Physiological Importance ◽  
Bilirubin Excretion ◽  
Chronic Obstructive Pulmonary Diseases ◽  
Atherosclerotic Process

Bilirubin, a potentially toxic catabolite of heme and indicator of hepatobiliary insufficiency, exhibits potent cardiac and vascular protective properties. Individuals with Gilbert’s syndrome (GS) may experience hyperbilirubinemia in response to stressors including reduced hepatic bilirubin excretion/increased red blood cell breakdown, with individuals usually informed by their clinician that their condition is of little consequence. However, GS appears to protect from all-cause mortality, with progressively elevated total bilirubin associated with protection from ischemic heart and chronic obstructive pulmonary diseases. Bilirubin may protect against these diseases and associated mortality by reducing circulating cholesterol, oxidative lipid/protein modifications, and blood pressure. In addition, bilirubin inhibits platelet activation and protects the heart from ischemia-reperfusion injury. These effects attenuate multiple stages of the atherosclerotic process in addition to protecting the heart during resultant ischemic stress, likely underpinning the profound reduction in cardiovascular mortality in hyperbilirubinemic GS. This review outlines our current knowledge of and uses for bilirubin in clinical medicine and summarizes recent progress in revealing the physiological importance of this poorly understood molecule. We believe that this review will be of significant interest to clinicians, medical researchers, and individuals who have GS.

Abstract 16991: Cardiosphere-derived Cell Exosomes Confer Acute Cardioprotection Following Ischemia-reperfusion Injury Through Macrophage Polarization (Best of Basic Science Abstract)

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Geoffrey de Couto ◽  
Nupur Makkar ◽  
Eduardo Marbán
Keyword(s):  
Noncoding Rna ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Dose Finding ◽  
Random Allocation ◽  
Dependent Manner ◽  
Phagocytic Capacity ◽  
Cardioprotective Effects ◽  
Wistar Kyoto

Introduction: Cardiosphere-Derived Cells (CDCs) exert both regenerative and cardioprotective effects following ischemic insult to the myocardium. The regenerative effects are mimicked by human CDC exosomes (CDC exo ), secreted nanovesicular entities that contain CDC-specific payloads of protein and noncoding RNA. Here we demonstrate that, CDC exo reduce infarct size and macrophage (Mf) infiltration when infused via the intracoronary route following ischemia/reperfusion (I/R) injury. Methods & Results: To examine the safety and efficacy of CDC exo , we performed a dose-finding study in Wistar-Kyoto rats (aged 8-12 weeks). Exosomes were precipitated from conditioned media collected from human CDCs or Fibroblasts [Fb, as a control] grown in serum-free media for 15 days. Exosome protein quantity, surface marker expression, and particle number were assessed prior to delivery. For in vivo analyses, rats underwent 45 minutes of ischemia followed by 20 minutes of reperfusion, then intracoronary infusion by random allocation of either Fb exosomes (Fb exo ) or CDC exo . Two days later, histological analysis revealed that CDC exo reduced infarct mass (CDC exo : 6.38% vs. Fb exo : 13.32%; p<0.05) and CD68 + Mf infiltration (CDC exo : 183.5/FOV vs. Fb exo : 302.1/FOV; p<0.05). In vitro, Mf uptake of exosomes and polarization based on gene expression profile ( Arg1, Vegfa, Il4ra ) occurred in a time-dependent manner. The phagocytic capacity of CDC exo -primed Mf was elevated relative to Fb exo -, M1-, or M2-polarized Mf (CDC exo : 76.8%; Fb exo : 38.3%; M1: 52.2%; M2: 33.9%; p<0.05). Conclusions: CDC exo are cardioprotective when delivered via the intracoronary route 20 min post-I/R. These data demonstrate that exosomes secreted by CDCs (but not by fibroblasts) recapitulate the cardioprotective effects of CDCs (cellular postconditioning; Kanazawa et al, Circ HF 2015; de Couto et al, JCI 2015). Like CDCs, CDC exo modulate the Mf infiltrate in the heart post-I/R and distinctively polarize Mf. The data support the conjecture that CDC exo mediate the cardioprotective effects of CDCs via effects on Mf.

Hydrogen Sulfide Reduces Renal Ischemia-Reperfusion Injury by Enhancing Autophagy and Reducing Oxidative Stress

2021 ◽  
Author(s):  
Hui Li ◽  
Shuaiwei Wang ◽  
Shuangshuang An ◽  
Biao Gao ◽  
Tieshan Teng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Sulfide ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Beclin 1 ◽  
Dependent Manner ◽  
Protein Levels ◽  
Renal Ischemia Reperfusion Injury

Abstract Background Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury. Hydrogen sulfide (H2S) exerts a protective effect in renal IRI. The present study was carried out to investigate the effects of exogenous H2S on renal IRI by regulating autophagy in mice. Methods Mice were randomly assigned to control, IRI, and NaHS (28, 56 and 100 µmol/kg) groups. Renal IRI was induced by clamping the bilateral renal pedicles for with non-traumatic arterial clamp for 45 min and then reperfused for 24 h. Mice were administered intraperitoneally with NaHS 20 min prior to renal ischemia. Sham group mice underwent the same procedures without clamping. Serum and kidney tissues were harvested 24 h after reperfusion for functional, histological, oxidative stress, and autophagic determination. Results Compared with the control group, the concentrations of serum creatinine (Scr), blood urea nitrogen (BUN), and malondialdehyde (MDA), the protein levels of LC3II/I, Beclin-1, and P62, as well as the number of autophagosomes were significantly increased, but the activity of superoxide dismutase (SOD) was decreased after renal IRI. NaHS pretreatment dramatically attenuated renal IRI-induced renal dysfunction, histological changes, MDA concentration, and p62 expression in a dose-dependent manner. However, NaHS increased the SOD activity and the protein levels of LC3II/I and Beclin-1. Conclusions These results indicate that exogenous H2S protects the kidney from IRI through enhancement of autophagy and reduction of oxidative stress. Novel H2S donors could be developed in the treatment of renal IRI.

Protection of the reperfused heart by L-propionylcarnitine

1991 ◽  
Vol 71 (4) ◽  
pp. 1518-1522 ◽  
Author(s):  
J. A. Leipala ◽  
R. Bhatnagar ◽  
E. Pineda ◽  
S. Najibi ◽  
K. Massoumi ◽  
...  
Keyword(s):  
Lactate Dehydrogenase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Membrane Integrity ◽  
Creatine Phosphate ◽  
Left Ventricular ◽  
Optimal Time ◽  
Dependent Manner ◽  
Cell Membrane Integrity ◽  
Developed Pressure

The effects of L-propionylcarnitine on mechanical function, creatine phosphate and ATP content, and lactate dehydrogenase leakage were studied in isolated perfused rat hearts exposed to global no-flow ischemia for 30 min followed by reperfusion for 20 min. Five and 10 mM L-propionylcarnitine resulted in a 100% recovery of left ventricular-developed pressure, whereas the recovery was only 40% in the hearts perfused without this agent. Ischemia-reperfusion caused a 85% loss of creatine phosphate and a 77% loss of ATP, which was prevented by 10 mM L-propionylcarnitine. Five millimolar L-propionylcarnitine protected the heart from the loss of creatine phosphate but not from the loss of ATP. Ten millimolar L-propionylcarnitine failed to improve the postischemic left ventricular-developed pressure, when it was added to the perfusate only after ischemia. L-propionylcarnitine alleviated the decrease of coronary flow in the reperfused hearts. Lactate dehydrogenase leakage was aggravated in the beginning of the reperfusion period by 10 mM L-propionylcarnitine. This adverse effect was, however, transient. L-Propionylcarnitine provides protection for the postischemic reperfused heart in a dose-dependent manner. The optimal time for administration is before the ischemic insult. High doses of this compound may perturb cell membrane integrity. Moreover, the present data point to an intracellular, metabolic, and perhaps anaplerotic mechanism of action of L-propionylcarnitine in cardiac ischemia-reperfusion injury.

scholarly journals Safflower Yellow B Protects Brain against Cerebral Ischemia Reperfusion Injury through AMPK/NF-kB Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Shibin Du ◽  
Youliang Deng ◽  
Hongjie Yuan ◽  
Yanyan Sun
Keyword(s):  
Brain Injury ◽  
Cerebral Ischemia ◽  
Pc12 Cells ◽  
Inflammatory Cytokines ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Dependent Manner ◽  
Secondary Damage

Inflammation had showed its important role in the pathogenesis of cerebral ischemia and secondary damage. Safflower yellow B (SYB) had neuroprotective effects against oxidative stress-induced brain injuries, but the mechanisms were still largely unknown to us. In this study, we tried to investigate the anti-inflammation effects of SYB and the possible roles of AMPK/NF-κB signaling pathway on these protective effects. In vivo, brain ischemia/reperfusion (I/R) was induced by transient middle cerebral artery occlusion for 2 h and reperfusion for 20 h. Neurofunctional evaluation, infarction area, and brain water contents were measured. Brain injury markers and inflammatory cytokines levels were measured by ELISA kits. In vitro, cell viability, apoptosis, and LDH leakage were measured after I/R in PC12 cells. The expression and phosphorylation levels of AMPK, NF-κB p65, and P-IκB-α in cytoplasm and nuclear were measured by Western blotting. SiRNA experiment was performed to certify the role of AMPK. The results showed SYB reduced infarct size, improved neurological outcomes, and inhibited brain injury after I/R. In vitro test, SYB treatment alleviated PC12 cells injury and apoptosis and inhibited the inflammatory cytokines (IL-1, IL-6, TNF-α, and COX-2) in a dose-dependent manner. SYB treatment induced AMPK phosphorylation and inhibited NF-κB p65 nuclear translocation both in brain and in PC12 cells. Further studies also showed that the inhibition of NF-κB activity of SYB was through AMPK. In conclusion, SYB protected brain I/R injury through reducing expression of inflammatory cytokines and this effect might be partly due to the inhibition of NF-κB mediated by AMPK.

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