IP3R1/GRP75/VDAC1 complex mediates endoplasmic reticulum stress-mitochondrial oxidative stress in diabetic atrial remodeling

Yuan, Ming; Gong, Mengqi; He, Jinli; Xie, Bingxin; Zhang, Zhiwei; Meng, Lei; Tse, Gary; Zhao, Yungang; Bao, Qiankun; Zhang, Yue; Yuan, Meng; Liu, Xing; Luo, Cunjin; Wang, Rui; Li, Guangping; Liu, Tong

doi:10.1016/j.redox.2022.102289

Cited by 67 publications

(45 citation statements)

References 42 publications

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“…The selective activation of ATF6 with AA147 increased the expression of catalase and suppressed oxidative stress and apoptosis in mouse neurons following cardiac arrest. Interestingly, NRF2/HO-1 activation was also demonstrated as a feature of AA147 treatment [102]. Overall, these findings indicate an antioxidant role for ATF6.…”

Section: Atf6 In Response To Oxidative Stressmentioning

confidence: 55%

Unfolding the Interactions between Endoplasmic Reticulum Stress and Oxidative Stress

Ong

Logue

2023

Antioxidants

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Oxidative stress is caused by an imbalance in cellular redox state due to the accumulation of reactive oxygen species (ROS). While homeostatic levels of ROS are important for cell physiology and signaling, excess ROS can induce a variety of negative effects ranging from damage to biological macromolecules to cell death. Additionally, oxidative stress can disrupt the function of redox-sensitive organelles including the mitochondria and endoplasmic reticulum (ER). In the case of the ER, the accumulation of misfolded proteins can arise due to oxidative stress, leading to the onset of ER stress. To combat ER stress, cells initiate a highly conserved stress response called the unfolded protein response (UPR). While UPR signaling, within the context of resolving ER stress, is well characterised, how UPR mediators respond to and influence oxidative stress is less defined. In this review, we evaluate the interplay between oxidative stress, ER stress and UPR signaling networks. Specifically, we assess how UPR signaling mediators can influence antioxidant responses.

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Section: Atf6 In Response To Oxidative Stressmentioning

confidence: 55%

Unfolding the Interactions between Endoplasmic Reticulum Stress and Oxidative Stress

Ong

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2023

Antioxidants

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“…[82][83][84][85] Furthermore, ROS accumulation in MAMs can also alter the GRP75-mediated tethering of IP 3 R and VDAC. [80,86,87] The opening of these Ca 2+ channels can drive the upregulation of electron transport chain components, in turn leading to altered ROS generation. In line with the idea that H 2 O 2 could be transferred directly between organelles at the mitochondria-ER interface, it was shown that aquaporin AQP11 is an ER resident peroxiporin (H 2 O 2 channel) which partially localizes to MAMs.…”

Section: Redox Regulation At Mitochondria-er Mcs Is An Example Of Howmentioning

confidence: 99%

Controlling contacts—Molecular mechanisms to regulate organelle membrane tethering

et al. 2022

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In recent years, membrane contact sites (MCS), which mediate interactions between virtually all subcellular organelles, have been extensively characterized and shown to be essential for intracellular communication. In this review essay, we focus on an emerging topic: the regulation of MCS. Focusing on the tether proteins themselves, we discuss some of the known mechanisms which can control organelle tethering events and identify apparent common regulatory hubs, such as the VAP interface at the endoplasmic reticulum (ER). We also highlight several currently hypothetical concepts, including the idea of tether oligomerization and redox regulation playing a role in MCS formation. We identify gaps in our current understanding, such as the identity of the majority of kinases/phosphatases involved in tether modification and conclude that a holistic approach-incorporating the formation of multiple MCS, regulated by interconnected regulatory modulators-may be required to fully appreciate the true complexity of these fascinating intracellular communication systems.

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“…Recent studies show mitochondrial metabolism, the most predominant functional site of energy metabolism in cardiomyocytes, plays an important role in the development of AF ( Brown et al, 2021 ; Yuan et al, 2022 ). It also regulates the oxidative phosphorylation of various metabolites and influences the contraction and ion homeostasis of myocardial tissues ( Avula et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Multiple targets related to mitochondrial function unveiled by metabolomics and proteomics profiles of hearts from atrial fibrillation patients

Liu

Wang

et al. 2023

Front. Physiol.

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Background: The prominent mitochondrial metabolic changes of the atrium reportedly have significant impact on electrical signals and structural remodeling which play important roles in the occurrence and development of atrial fibrillation (AF). However, the mechanism is not completely known.Objective: This study was aimed to explore the mitochondrial metabolism reprogrammed in AF patients by integrating metabolomics as well as proteomics of human atrium tissues.Methods and Results: Left atrial tissue samples were harvested from 10 non-valvular AF patients and 10 matched samples from healthy donors for transplantation. In metabolomics analysis, 113 metabolites were upregulated and 10 metabolites were downregulated in AF, where multiple pathways related to mitochondrial energy metabolism were enriched. Correlation analysis between the differentially expressed proteins and metabolites identified several hub proteins related to mitochondrial function including Glycerol-3-phosphate dehydrogenase 2 (GPD2), Synemin (SYNM), Plectin (PLEC), with MCC score of 27, 17, 16, respectively, which have the most interactions with the dysregulated metabolites and ranked at the top in network string interactions scored by MCC method. All 330 differentially expressed proteins including 225 upregulated and 105 downregulated molecules were revealed and analyzed, which identified the downregulation of GPD2 (p = 0.02 and FC = 0.77), PLEC (p < 0.001 and FC = 0.71) and SYNM (p = 0.04 and FC = 0.76) in AF patients. Gene Set Variation Analysis (GSEA) showed mitochondrial metabolism-associated pathways including oxidative phosphorylation (NES: −1.73) and ATP biosynthetic process (NES: −2.29), were dramatically diversified in human AF. In GSVA, the expression levels of GPD2, PLEC, and SYNM were demonstrated to be associated with multiple metabolic pathways related to mitochondrial function (e.g., lipid metabolism and AMP activated protein kinase signaling) and cardiac structural and electrical remodeling (e.g., contractile fiber, ion homeostasis), which were proven vital in the development and maintenance of AF.Conclusion: In all, this study provides new insights into understanding the mechanisms of AF progression, especially the reprogramming mitochondrial metabolism, and identifies several genes related to mitochondrial function as novel targets for AF, which may be involved in the occurrence and development of AF.

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IP3R1/GRP75/VDAC1 complex mediates endoplasmic reticulum stress-mitochondrial oxidative stress in diabetic atrial remodeling

Cited by 67 publications

References 42 publications

Unfolding the Interactions between Endoplasmic Reticulum Stress and Oxidative Stress

Unfolding the Interactions between Endoplasmic Reticulum Stress and Oxidative Stress

Controlling contacts—Molecular mechanisms to regulate organelle membrane tethering

Multiple targets related to mitochondrial function unveiled by metabolomics and proteomics profiles of hearts from atrial fibrillation patients

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