SIGMAR1/Sigma-1 receptor ablation impairs autophagosome clearance

Yang, Huan; Shen, Hongtao; Li, Jing; Guo, Lian‐Wang

doi:10.1080/15548627.2019.1586248

Cited by 62 publications

(45 citation statements)

References 68 publications

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“…where damaged mitochondria are degraded by hydrolases. 4,64 As such, disturbed lysosomal function or impaired mitophagosome-lysosome fusion can alter mitophagic flux outcomes. 6 Here, we found that mitophagic flux blockade resulted from impairments in mitophagosome-lysosome fusion and lysosomal degradation ability in compression-exposed human NP cells.…”

Section: Discussionmentioning

confidence: 99%

The mitochondria‐targeted anti‐oxidant MitoQ protects against intervertebral disc degeneration by ameliorating mitochondrial dysfunction and redox imbalance

et al. 2020

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Objective Mitochondrial dysfunction, oxidative stress and nucleus pulposus (NP) cell apoptosis are important contributors to the development and pathogenesis of intervertebral disc degeneration (IDD). Here, we comprehensively evaluated the effects of mitochondrial dynamics, mitophagic flux and Nrf2 signalling on the mitochondrial quality control, ROS production and NP cell survival in in vitro and ex vivo compression models of IDD and explored the effects of the mitochondria‐targeted anti‐oxidant MitoQ and its mechanism. Material and methods Human NP cells were exposed to mechanical compression to mimic pathological conditions. Results Compression promoted oxidative stress, mitochondrial dysfunction and NP cell apoptosis. Mechanistically, compression disrupted the mitochondrial fission/fusion balance, inducing fatal fission. Concomitantly, PINK1/Parkin‐mediated mitophagy was activated, whereas mitophagic flux was blocked. Nrf2 anti‐oxidant pathway was insufficiently activated. These caused the damaged mitochondria accumulation and persistent oxidative damage. Moreover, MitoQ restored the mitochondrial dynamics balance, alleviated the impairment of mitophagosome‐lysosome fusion and lysosomal function and enhanced the Nrf2 activity. Consequently, damaged mitochondria were eliminated, redox balance was improved, and cell survival increased. Additionally, MitoQ alleviated IDD in an ex vivo rat compression model. Conclusions These findings suggest that comodulation of mitochondrial dynamics, mitophagic flux and Nrf2 signalling alleviates sustained mitochondrial dysfunction and oxidative stress and represents a promising therapeutic strategy for IDD; furthermore, our results provide evidence that MitoQ might serve as an effective therapeutic agent for this disorder.

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Section: Discussionmentioning

confidence: 99%

The mitochondria‐targeted anti‐oxidant MitoQ protects against intervertebral disc degeneration by ameliorating mitochondrial dysfunction and redox imbalance

et al. 2020

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“…Autophagy plays an important role in cardiac fibrosis, as well as in other fibrotic diseases [ 50 ]. Zhang et al [ 51 ] reported that the tribbles pseudokinase 3 (TRIB3) mediates autophagy impairment by not only suppressing autophagic degradation but also promoting the activation of hepatic stellate cells (HSCs).…”

Section: Discussionmentioning

confidence: 99%

Stimulation of Sigma‐1 Receptor Protects against Cardiac Fibrosis by Alleviating IRE1 Pathway and Autophagy Impairment

et al. 2021

Oxidative Medicine and Cellular Longevity

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Sigma-1 receptor (Sig1R), a chaperone in the endoplasmic reticulum (ER) membrane, has been implicated in cardiac hypertrophy; however, its role in cardiac fibroblast activation has not been established. This study investigated the possible association between Sig1R and this activation by subjecting mice to sham, transverse aortic constriction (TAC), and TAC plus fluvoxamine (an agonist of Sig1R) treatments. Cardiac function and fibrosis were evaluated four weeks later by echocardiography and histological staining. In an in vitro study, neonatal rat cardiac fibroblasts were treated with fluvoxamine or NE-100 (an antagonist of Sig1R) in the presence or absence of transforming growth factor beta1 (TGF-β1). Fibrotic markers, ER stress pathways, and autophagy were then investigated by qPCR, western blotting, immunofluorescence, confocal microscopy, and transmission electron microscopy. Fluvoxamine treatment reduced cardiac fibrosis, preserved cardiac function, and attenuated cardiac fibroblast activation. Inhibition of the IRE1/XBP1 pathway, a branch of ER stress, by a specific inhibitor of IRE1 endonuclease activity, attenuated the pathological process. Fluvoxamine stimulation of Sig1R restored autophagic flux in cardiac fibroblasts, indicating that Sig1R appears to play a protective role in the activation of cardiac fibroblasts by inhibiting the IRE1 pathway and restoring autophagic flux. Sig1R may therefore represent a therapeutic target for cardiac fibrosis.

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“…Accordingly, loss-of-function mutations and Sig-1R deficiency are associated with defective autophagy, leading to accumulation of autophagic vacuoles. In contrast, reexpressing Sig-1R in the null background or its activation restores/induces autophagic activity (Vollrath et al, 2014;MacVicar et al, 2015;Christ et al, 2019;Yang et al, 2019;Christ et al, 2020). Sig-1R is not likely a core component of the general physiological autophagy machinery but it seems needed for cellular stress-induced autophagy (MacVicar et al, 2015).…”

Section: Intreraction With Master Unfolded Protein Response Regulatorsmentioning

confidence: 99%

Repurposing Sigma-1 Receptor Ligands for COVID-19 Therapy?

Vela

2020

Front. Pharmacol.

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Outbreaks of emerging infections, such as COVID-19 pandemic especially, confront health professionals with the unique challenge of treating patients. With no time to discover new drugs, repurposing of approved drugs or in clinical development is likely the only solution. Replication of coronaviruses (CoVs) occurs in a modified membranous compartment derived from the endoplasmic reticulum (ER), causes host cell ER stress and activates pathways to facilitate adaptation of the host cell machinery to viral needs. Accordingly, modulation of ER remodeling and ER stress response might be pivotal in elucidating CoV-host interactions and provide a rationale for new therapeutic, host-based antiviral approaches. The sigma-1 receptor (Sig-1R) is a ligand-operated, ER membrane-bound chaperone that acts as an upstream modulator of ER stress and thus a candidate host protein for host-based repurposing approaches to treat COVID-19 patients. Sig-1R ligands are frequently identified in in vitro drug repurposing screens aiming to identify antiviral compounds against CoVs, including severe acute respiratory syndrome CoV-2 (SARS-CoV-2). Sig-1R regulates key mechanisms of the adaptive host cell stress response and takes part in early steps of viral replication. It is enriched in lipid rafts and detergent-resistant ER membranes, where it colocalizes with viral replicase proteins. Indeed, the non-structural SARS-CoV-2 protein Nsp6 interacts with Sig-1R. The activity of Sig-1R ligands against COVID-19 remains to be specifically assessed in clinical trials. This review provides a rationale for targeting Sig-1R as a host-based drug repurposing approach to treat COVID-19 patients. Evidence gained using Sig-1R ligands in unbiased in vitro antiviral drug screens and the potential mechanisms underlying the modulatory effect of Sig-1R on the host cell response are discussed. Targeting Sig-1R is not expected to reduce dramatically established viral replication, but it might interfere with early steps of virus-induced host cell reprogramming, aid to slow down the course of infection, prevent the aggravation of the disease and/or allow a time window to mature a protective immune response. Sig-1R-based medicines could provide benefit not only as early intervention, preventive but also as adjuvant therapy.

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SIGMAR1/Sigma-1 receptor ablation impairs autophagosome clearance

Cited by 62 publications

References 68 publications

The mitochondria‐targeted anti‐oxidant MitoQ protects against intervertebral disc degeneration by ameliorating mitochondrial dysfunction and redox imbalance

The mitochondria‐targeted anti‐oxidant MitoQ protects against intervertebral disc degeneration by ameliorating mitochondrial dysfunction and redox imbalance

Stimulation of Sigma‐1 Receptor Protects against Cardiac Fibrosis by Alleviating IRE1 Pathway and Autophagy Impairment

Repurposing Sigma-1 Receptor Ligands for COVID-19 Therapy?

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