ZFHX3 knockdown dysregulates mitochondrial adaptations to tachypacing in atrial myocytes through enhanced oxidative stress and calcium overload

2020 ◽  
Author(s):  
Baigalmaa Lkhagva ◽  
Yung‐Kuo Lin ◽  
Yao‐Chang Chen ◽  
Wan‐Li Cheng ◽  
Satoshi Higa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Calcium Overload ◽  
Atrial Myocytes ◽  
Mitochondrial Adaptations

Abstract MP124: De-palmitoylation of Cysteine 202 of Cyclophilin-D by Calcium is Important for the Activation of the Permeability Transition Pore

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Georgios Amanakis ◽  
Junhui Sun ◽  
Maria Fergusson ◽  
Chengyu Liu ◽  
Jeff D Molkentin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Calcium Overload ◽  
Mitochondrial Calcium ◽  
Cyclophilin D ◽  
Perfused Heart ◽  
Knock Out

Cyclophilin-D (CypD) is a well-known regulator of the mitochondrial permeability transition pore (PTP), the main effector of cardiac ischemia/reperfusion (I/R) injury characterized by oxidative stress and calcium overload. However, the mechanism by which CypD activates PTP is poorly understood. Cysteine 202 of CypD (C202) is highly conserved across species and can undergo redox-sensitive post-translational modifications, such as S-nitrosylation and oxidation. To study the importance of C202, we developed a knock-in mouse model using CRISPR where CypD-C202 was mutated to a serine (C202S). Hearts from these mice are protected against I/R injury. We found C202 to be abundantly S-palmitoylated under baseline conditions while C202 was de-palmitoylated during ischemia in WT hearts. To further investigate the mechanism of de-palmitoylation during ischemia, we considered the increase of matrix calcium, oxidative stress and uncoupling of ATP synthesis from the electron transport chain. We tested the effects of these conditions on the palmitoylation of CypD in isolated cardiac mitochondria. The palmitoylation of CypD was assessed using a resin-assisted capture (Acyl-RAC). We report that oxidative stress (phenylarsenide) and uncoupling (CCCP) had no effect on CypD palmitoylation (p>0.05, n=3 and n=7 respectively). However, calcium overload led to de-palmitoylation of CypD to the level observed at the end ischemia (1±0.10 vs 0.63±0.09, p=0.012, n=9). To further test the hypothesis that calcium regulates S-palmitoylation of CypD we measured S-palmitoylation of CypD in non-perfused heart lysates from global germline mitochondrial calcium uniporter knock-out mice (MCU-KO), which have reduced mitochondrial calcium and we found an increase in S-palmitoylation of CypD (WT 1±0.04 vs MCU-KO 1.603±0.11, p<0.001, n=6). The data are consistent with the hypothesis that C202 is important for the CypD mediated activation of PTP. Ischemia leads to increased matrix calcium which in turn promotes the de-palmitoylation of CypD on C202. The now free C202 can further be oxidized during reperfusion leading to the activation of PTP. Thus, S-palmitoylation and oxidation of CypD-C202 possibly target CypD to the PTP, making them potent regulators of cardiac I/R injury.

Epigallocatechin-3-gallate induced primary cultures of rat hippocampal neurons death linked to calcium overload and oxidative stress

2009 ◽  
Vol 379 (6) ◽  
pp. 551-564 ◽  
Author(s):  
Shu-Ting Yin ◽  
Ming-Liang Tang ◽  
Hong-Min Deng ◽  
Tai-Ran Xing ◽  
Ju-Tao Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hippocampal Neurons ◽  
Primary Cultures ◽  
Calcium Overload ◽  
And Oxidative Stress

scholarly journals MOFs-based nanoagent enables dual mitochondrial damage in synergistic antitumor therapy via oxidative stress and calcium overload

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Weier Bao ◽  
Ming Liu ◽  
Jiaqi Meng ◽  
Siyuan Liu ◽  
Shuang Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Near Infrared ◽  
Calcium Influx ◽  
Calcium Overload ◽  
Tumor Xenograft ◽  
Great Promise ◽  
Antitumor Therapy ◽  
Nir Light ◽  
Metal Organic

AbstractTargeting subcellular organelle with multilevel damage has shown great promise for antitumor therapy. Here, we report a core-shell type of nanoagent with iron (III) carboxylate metal-organic frameworks (MOFs) as shell while upconversion nanoparticles (UCNPs) as core, which enables near-infrared (NIR) light-triggered synergistically reinforced oxidative stress and calcium overload to mitochondria. The folate decoration on MOFs shells enables efficient cellular uptake of nanoagents. Based on the upconversion ability of UCNPs, NIR light mediates Fe3+-to-Fe2+ reduction and simultaneously activates the photoacid generator (pHP) encapsulated in MOFs cavities, which enables release of free Fe2+ and acidification of intracellular microenvironment, respectively. The overexpressed H2O2 in mitochondria, highly reactive Fe2+ and acidic milieu synergistically reinforce Fenton reactions for producing lethal hydroxyl radicals (•OH) while plasma photoacidification inducing calcium influx, leading to mitochondria calcium overload. The dual-mitochondria-damage-based therapeutic potency of the nanoagent has been unequivocally confirmed in cell- and patient-derived tumor xenograft models in vivo.

scholarly journals TPEN REDUCES CALCIUM OVERLOAD, OXIDATIVE STRESS AND EXHIBITS PROTECTIVE EFFECTS IN PACED HL-1 CELLS

Heart ◽  
2012 ◽  
Vol 98 (Suppl 2) ◽  
pp. E116.2-E117
Author(s):  
Zhou Mo ◽  
Xu Wen-jing ◽  
Sun Li-ping ◽  
Lin Chao-lan ◽  
Zhang Ying-ying ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Calcium Overload ◽  
Protective Effects

scholarly journals Fibroblast Growth Factor 21 Protects Against Atrial Remodeling via Reducing Oxidative Stress

2021 ◽  
Vol 8 ◽  
Author(s):  
Miao Chen ◽  
Jiawei Zhong ◽  
Zhen Wang ◽  
Hongfei Xu ◽  
Heng Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Atrial Fibrillation ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 21 ◽  
Atrial Remodeling ◽  
Protective Effects ◽  
Fibroblast Growth ◽  
Atrial Myocytes ◽  
Antioxidant Genes

Aim: The structural and electrical changes in the atrium, also known as atrial remodeling, are the main characteristics of atrial fibrillation (AF). Fibroblast growth factor 21 (Fgf21) is an important endocrine factor, which has been shown to play an important role in cardiovascular diseases. However, the effects of Fgf21 on atrial remodeling have not been addressed yet. The purpose of the present study is to evaluate the effects of Fgf21 on atrial remodeling.Methods and Results: Adult mice were treated with Ang II, and randomly administrated with or without Fgf21 for 2 weeks. The susceptibility to AF was assessed by electrical stimulation and optical mapping techniques. Here, we found that Fgf21 administration attenuated the inducibility of atrial fibrillation/atrial tachycardia (AF/AT), improved epicardial conduction velocity in the mice atria. Mechanistically, Fgf21 protected against atrial fibrosis and reduced oxidative stress of the atria. Consistently, in vitro study also demonstrated that Fgf21 blocked the upregulation of collagen by Tgf-β in fibroblasts and attenuated tachypacing-induced oxidative stress including reactive oxygen species (ROS), Tgf-β, and ox-CaMKII in atrial myocytes. We further found that Fgf21 attenuated oxidative stress by inducing antioxidant genes, such as SOD2 and UCP3. Fgf21 also improved tachypacing-induced myofibril degradation, downregulation of L-type calcium channel, and upregulation of p-RyR2, which implicated protective effects of Fgf21 on structural and electrical remodeling in the atria. Moreover, Nrf2 was identified as a downstream of Fgf21 and partly mediated Fgf21-induced antioxidant gene expression in atrial myocytes.Conclusion: Fgf21 administration effectively suppressed atrial remodeling by reducing oxidative stress, which provides a novel therapeutic insight for AF.

scholarly journals Noise-Induced Hearing Loss: Updates on Molecular Targets and Potential Interventions

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Huanyu Mao ◽  
Yan Chen
Keyword(s):  
Oxidative Stress ◽  
Hearing Loss ◽  
Auditory Nerve ◽  
Molecular Targets ◽  
Cell Loss ◽  
Calcium Overload ◽  
Glutamate Excitotoxicity ◽  
Noise Induced Hearing Loss ◽  
Hair Cell Loss ◽  
Synaptic Ribbon

Noise overexposure leads to hair cell loss, synaptic ribbon reduction, and auditory nerve deterioration, resulting in transient or permanent hearing loss depending on the exposure severity. Oxidative stress, inflammation, calcium overload, glutamate excitotoxicity, and energy metabolism disturbance are the main contributors to noise-induced hearing loss (NIHL) up to now. Gene variations are also identified as NIHL related. Glucocorticoid is the only approved medication for NIHL treatment. New pharmaceuticals targeting oxidative stress, inflammation, or noise-induced neuropathy are emerging, highlighted by the nanoparticle-based drug delivery system. Given the complexity of the pathogenesis behind NIHL, deeper and more comprehensive studies still need to be fulfilled.

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