Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases

Zhemkov, Vladimir; Geva, Michal; Hayden, Michael R.; Bezprozvanny, Ilya

doi:10.3390/ijms22084082

Cited by 28 publications

(23 citation statements)

References 141 publications

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“…Induction of the ER stress using TUNI can lead to calcium deletion inside the ER that disrupts calcium communication between the ER and mitochondria [ 60 ]. Modulation of calcium communication between ER and mitochondria using sigma-1 receptor activators improves mitochondrial function [ 61 , 62 ]. Thus, TUNI treatment may impair mitochondrial function through interruption of calcium signaling between ER and mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Tunicamycin-Induced Endoplasmic Reticulum Stress Damages Complex I in Cardiac Mitochondria

Chen¹,

Thompson²,

Hu³

et al. 2022

Life

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Background: Induction of acute ER (endoplasmic reticulum) stress using thapsigargin contributes to complex I damage in mouse hearts. Thapsigargin impairs complex I by increasing mitochondrial calcium through inhibition of Ca2+-ATPase in the ER. Tunicamycin (TUNI) is used to induce ER stress by inhibiting protein folding. We asked if TUNI-induced ER stress led to complex I damage. Methods: TUNI (0.4 mg/kg) was used to induce ER stress in C57BL/6 mice. Cardiac mitochondria were isolated after 24 or 72 h following TUNI treatment for mitochondrial functional analysis. Results: ER stress was only increased in mice following 72 h of TUNI treatment. TUNI treatment decreased oxidative phosphorylation with complex I substrates compared to vehicle with a decrease in complex I activity. The contents of complex I subunits including NBUPL and NDUFS7 were decreased in TUNI-treated mice. TUNI treatment activated both cytosolic and mitochondrial calpain 1. Our results indicate that TUNI-induced ER stress damages complex I through degradation of its subunits including NDUFS7. Conclusion: Induction of the ER stress using TUNI contributes to complex I damage by activating calpain 1.

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Section: Discussionmentioning

confidence: 99%

Tunicamycin-Induced Endoplasmic Reticulum Stress Damages Complex I in Cardiac Mitochondria

Chen¹,

Thompson²,

Hu³

et al. 2022

Life

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“…Knockout of Sig-1R in hippocampal neurons results in shorter and smaller mitochondria and also causes a decrease in MtMP and release of cytochrome c, which leads to disruption of cytoskeletal networks loss of mature dendritic spines, and formation of immature dendritic spines [63,64]. Genetic deletion of σ-1R also impairs MAM stability and leads to a decreased number of MERC [65]. A reduced amount of σ-1R has been observed postmortem in the hippocampi of AD patients, and certain σ-1R gene polymorphisms coexist with the well-known risk factor Alzheimer's disease apolipoprotein ε4 (APOE ε4) [66].…”

Section: Er-mitochondria Interactionsmentioning

confidence: 99%

Mitochondria-Endoplasmic Reticulum Interaction in Central Neurons

Kushnireva¹,

Korkotian²

2023

Updates on Endoplasmic Reticulum

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The proteins presenilin-1/2 play a key role in the interactions between mitochondria and the endoplasmic reticulum at synaptic contacts of central neurons. Several novel observations suggest that mutations in presenilin-1 lead to an abnormal energy state, an early sign of neurodegeneration and Alzheimer’s disease. Recent studies suggest that in the postsynaptic region, calcium stores are widely represented in the spine apparatus, which is located in a strategically important compartment - the neck of mature mushroom-shaped dendritic spines. Moreover, in the dendritic shaft area, at the base of the spines, one finds oblong mitochondrial clusters supplying the postsynaptic area and the local protein synthesis with ATP. Calcium signals, generated by the postsynaptic membranes, affect both calcium release from local stores through ryanodine channels and the uptake based on store-operated calcium entry. The entire complex of nanoscale signaling most likely determines the production of ATP. Violation of the functional relationship between mitochondria and reticular calcium depots can lead to disruption of signaling pathways that stimulate ATP production at the stages of increased activity of individual synapses. In this chapter, we will present the signaling mechanisms of interaction between mitochondria, spine clusters, and calcium nano-stores in postsynaptic area.

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“…S1R associates with cholesterol through an intracellular domain. Vladimir Zhemkov et al found recently that the association of S1R with cholesterol induces the formation of cholesterol-enriched microdomains in the ER membrane that could retain secreted and signaling proteins [84]. Zhemkov et al proposed that S1R agonists allow the disassembly of cholesterol-enriched microdomains and the release of accumulated proteins such as ion channels, signaling receptors, and ER-trophic factors [85,86].…”

Section: The Chaperone Sigma1r Is a Key Regulator In Tdp43 Proteinopathymentioning

confidence: 99%

P53 Protein Modulates Muscle Metabolism and Generates a Non-Genetic Risk Environment that Contributes to Triggering Amyotrophic Lateral Sclerosis

Espina-Zambrano¹

2022

Preprint

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Amyotrophic lateral sclerosis (ALS) is also called "motor neuron disease”. In this review, we propose that ALS is not just a neuromotor disorder, but begins as a disorder of P53-modulated skeletal muscle metabolism, leading to failures at the energy state of the cells, incorrect redox states, motor denervation, and a loss of muscle fibers. Motoneurons die as a consequence of the lack of muscular feedback, and the oligomeric TDP43 aggregates progressively and relentlessly lead to mistakes in peripheral immune self-tolerance sustained over time. An effective treatment has not been found for this devastating pathology, as for 152 years the target has not been accurately defined. Scientists and doctors should consider new knowledge regarding ALS and consider immunomodulatory therapies that, based on genetic analysis and symptoms, can be combined with compounds that regulate metabolism and promote the elimination of useless organelles and cells. What if ALS could be cured as a result of seeing motor neuron disease differently? This review aims to develop that goal and change the paradigm of our understanding of ALS.

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Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases

Cited by 28 publications

References 141 publications

Tunicamycin-Induced Endoplasmic Reticulum Stress Damages Complex I in Cardiac Mitochondria

Tunicamycin-Induced Endoplasmic Reticulum Stress Damages Complex I in Cardiac Mitochondria

Mitochondria-Endoplasmic Reticulum Interaction in Central Neurons

P53 Protein Modulates Muscle Metabolism and Generates a Non-Genetic Risk Environment that Contributes to Triggering Amyotrophic Lateral Sclerosis

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