ER membranes associated with mitochondria: Possible therapeutic targets in heart-associated diseases

Silva-Palacios, Alejandro; Zazueta, Cecilia; Pedraza‐Chaverrí, José

doi:10.1016/j.phrs.2020.104758

Cited by 47 publications

(36 citation statements)

References 198 publications

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“…Interestingly, in addition to being an essential mitochondrial fusion protein, Mfn2 was also a major tethering regulator of MAMs. [ 20 ] Particularly, although the formation of MAMs was increased upon Hcy induction, the expression of Mfn2 was downregulated in this study. It was also reported that Mfn2 acted as a tethering antagonist to prevent the potential toxicity caused by excessive proximity between ER and mitochondria.…”

Section: Discussionmentioning

confidence: 53%

“…[ 19 ] The inositol 1,4,5‐triphosphate receptor (IP3R)–glucose‐regulated protein 75 (Grp75)–voltage‐dependent anion channel (VDAC) cooperates in the propagation of the Ca 2+ between two organelles. [ 20 ] Ca 2+ released from IP3R crosses the outer mitochondrial membrane through VDAC and enters the intermembrane space before reaching the mitochondrial matrix through MCU. The MCU is present in the inner mitochondrial membrane and form a selective channel allowing Ca 2+ uptake into the mitochondrial matrix.…”

Section: Introductionmentioning

confidence: 99%

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Homocysteine induced a calcium‐mediated disruption of mitochondrial function and dynamics in endothelial cells

Chen

Qiu

et al. 2021

J Biochem & Molecular Tox

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Homocysteine (Hcy) is a sulfur‐containing amino acid that originated in methionine metabolism and the elevated level of Hcy in plasma is considered to be an independent risk factor for cardiovascular diseases (CVD). Endothelial dysfunction plays a major role in the development of CVD, while the potential mechanism of Hcy‐induced endothelial dysfunction is still unclear. Here, in Hcy‐treated endothelial cells, we observed the destruction of mitochondrial morphology and the decline of mitochondrial membrane potential. Meanwhile, the level of ATP was reduced and the reactive oxygen species was increased. The expressions of dynamin‐related protein 1 (Drp1) and phosphate‐Drp1 (Ser616) were upregulated, whereas the expression of mitofusin 2 was inhibited by Hcy treatment. These findings suggested that Hcy not only triggered mitochondrial dysfunction but also incurred an imbalance of mitochondrial dynamics in endothelial cells. The expression of mitochondrial calcium uniporter (MCU) was activated by Hcy, contributing to calcium transferring into mitochondria. Interestingly, the formation of mitochondria‐associated membranes (MAMs) was increased in endothelial cells after Hcy administration. The inositol 1,4,5‐triphosphate receptor (IP3R)–glucose‐regulated protein 75 (Grp75)–voltage‐dependent anion channel (VDAC) complex, which was enriched in MAMs, was also increased. The accumulation of mitochondrial calcium could be blocked by inhibiting with the IP3R inhibitor Xestospongin C (XeC) in Hcy‐treated cells. Then, we confirmed that the mitochondrial dysfunction and the increased mitochondrial fission induced by Hcy could be attenuated after Hcy and XeC co‐treatment. In conclusion, Hcy‐induced mitochondrial dysfunction and dynamics disorder in endothelial cells were mainly related to the increase of calcium as a result of the upregulated expressions of the MCU and the IP3R–Grp75–VDAC complex in MAMs.

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Section: Discussionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Homocysteine induced a calcium‐mediated disruption of mitochondrial function and dynamics in endothelial cells

Chen

Qiu

et al. 2021

J Biochem & Molecular Tox

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“…ER contact sites allow the direct exchange of macromolecules and serve as a platform for the recruitment of machinery that regulates biogenesis, division, and trafficking of organelles (Lee et al, 2020). Among the broad processes taking place at such interface are Ca 2+ homeostasis, lipid signaling, and organelle remodeling (Jing et al, 2020) as well as mitochondrial fusion/fission, autophagy, apoptosis, reactive oxygen species (ROS) signaling, and unfolded protein response (van Vliet et al, 2014;Silva-Palacios et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Relevance of Membrane Contact Sites in Cancer Progression

Gil-Hernández

Arroyo-Campuzano

Simoni‐Nieves

et al. 2021

Front. Cell Dev. Biol.

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Membrane contact sites (MCS) are typically defined as areas of proximity between heterologous or homologous membranes characterized by specific proteins. The study of MCS is considered as an emergent field that shows how crucial organelle interactions are in cell physiology. MCS regulate a myriad of physiological processes such as apoptosis, calcium, and lipid signaling, just to name a few. The membranal interactions between the endoplasmic reticulum (ER)–mitochondria, the ER–plasma membrane, and the vesicular traffic have received special attention in recent years, particularly in cancer research, in which it has been proposed that MCS regulate tumor metabolism and fate, contributing to their progression. However, as the therapeutic or diagnostic potential of MCS has not been fully revisited, in this review, we provide recent information on MCS relevance on calcium and lipid signaling in cancer cells and on its role in tumor progression. We also describe some proteins associated with MCS, like CERT, STIM1, VDAC, and Orai, that impact on cancer progression and that could be a possible diagnostic marker. Overall, these information might contribute to the understanding of the complex biology of cancer cells.

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“…The ER is an interconnected and continuous network formed by the nuclear envelope and is essentially associated with other organelles in all eukaryotic cells [49]. Structurally, the ER interacts with mitochondria at contact sites called mitochondria-associated membranes (MAMs), which facilitate interorganelle communication [50].…”

Section: Discussionmentioning

confidence: 99%

Melatonin suppresses ER stress-dependent proapoptotic effects via AMPK in bone mesenchymal stem cells during mitochondrial oxidative damage

et al. 2020

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Background Bone marrow mesenchymal stem cells (BMSCs) have been used as important cell-based tools for clinical applications. Oxidative stress-induced apoptosis causes a low survival rate after transplantation, and the underlying mechanisms remain unknown. The endoplasmic reticulum (ER) and mitochondria are vital organelles regulated by adenosine monophosphate (AMP)-activated protein kinase (AMPK), especially during oxidative stress injury. Melatonin exerts an antioxidant effect by scavenging free radicals. Here, we aimed to explore whether cytoprotective melatonin relieves ER stress-mediated mitochondrial dysfunction through AMPK in BMSCs after oxidative stress injury. Methods Mouse BMSCs were isolated and exposed to H2O2 in the absence or presence of melatonin. Thereafter, cell damage, oxidative stress levels, mitochondrial function, AMPK activity, ER stress-related proteins, and apoptotic markers were measured. Additionally, the involvement of AMPK and ER stress in the melatonin-mediated protection of BMSCs against H2O2-induced injury was investigated using pharmacologic agonists and inhibitors. Results Melatonin improved cell survival and restored mitochondrial function. Moreover, melatonin intimately regulated the phosphorylation of AMPK and molecules associated with ER stress pathways. AMPK activation and ER stress inhibition following melatonin administration improved the mitochondrial membrane potential (MMP), reduced mitochondria-initiated oxidative damage, and ultimately suppressed apoptotic signaling pathways in BMSCs. Cotreatment with N-acetyl-l-cysteine (NAC) significantly enhanced the antioxidant effect of melatonin. Importantly, pharmacological AMPK activation/ER stress inhibition promoted melatonin-induced cytoprotection, while pharmacological AMPK inactivation/ER stress induction conferred resistance to the effect of melatonin against H2O2 insult. Conclusions Our data also reveal a new, potentially therapeutic mechanism by which melatonin protects BMSCs from oxidative stress-mediated mitochondrial apoptosis, possibly by regulating the AMPK-ER stress pathway.

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ER membranes associated with mitochondria: Possible therapeutic targets in heart-associated diseases

Cited by 47 publications

References 198 publications

Homocysteine induced a calcium‐mediated disruption of mitochondrial function and dynamics in endothelial cells

Homocysteine induced a calcium‐mediated disruption of mitochondrial function and dynamics in endothelial cells

Relevance of Membrane Contact Sites in Cancer Progression

Melatonin suppresses ER stress-dependent proapoptotic effects via AMPK in bone mesenchymal stem cells during mitochondrial oxidative damage

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