The neuroprotective effects of targeting key factors of neuronal cell death in neurodegenerative diseases: The role of ER stress, oxidative stress, and neuroinflammation

Frontiers in Cellular Neuroscience, Год журнала: 2023, Номер 17

Опубликована: Март 6, 2023

Neuronal loss is one of the striking causes various central nervous system (CNS) disorders, including major neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s (PD), Huntington’s (HD), and Amyotrophic lateral sclerosis (ALS). Although these diseases have different features clinical manifestations, they share some common mechanisms pathology. Progressive regional neurons in patients responsible for motor, memory, cognitive dysfunctions, leading to disabilities death. cell death linked pathways conditions. Protein misfolding aggregation, mitochondrial dysfunction, generation reactive oxygen species (ROS), activation innate immune response are most critical hallmarks diseases. Thus, endoplasmic reticulum (ER) stress, oxidative neuroinflammation pathological factors neuronal Even though exact not fully discovered, notable role mentioned well known. On this basis, researchers been prompted investigate neuroprotective effects targeting underlying determine a promising therapeutic approach treatment. This review provides an overview ER death, mainly discussing or molecules involved factors.

Язык: Английский

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Endoplasmic reticulum stress—a key guardian in cancer

Cell Death Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Июль 30, 2024

Abstract Endoplasmic reticulum stress (ERS) is a cellular response characterized by excessive contraction of the endoplasmic (ER). It pathological hallmark many diseases, such as diabetes, obesity, and neurodegenerative diseases. In unique growth characteristic varied microenvironment cancer, high levels are necessary to maintain rapid proliferation metastasis tumor cells. This process closely related ERS, which enhances ability cells adapt unfavorable environments promotes malignant progression cancer. this paper, we review roles mechanisms ERS in cell proliferation, apoptosis, metastasis, angiogenesis, drug resistance, metabolism, immune response. We found that can modulate via unfolded protein (UPR) signaling IRE1, PERK, ATF6. Targeting may be new strategy attenuate protective effects on manuscript explores potential ERS-targeted therapies, detailing through influences cancer highlighting experimental clinical evidence supporting these strategies. Through review, aim deepen our understanding role ER development provide insights for therapy.

Язык: Английский

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PERK signaling promotes mitochondrial elongation by remodeling membrane phosphatidic acid

The EMBO Journal, Год журнала: 2023, Номер 42(15)

Опубликована: Июнь 12, 2023

Abstract Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are linked in the onset pathogenesis of numerous diseases. This has led to considerable interest defining mechanisms responsible for regulating mitochondria during ER stress. The PERK signaling arm unfolded protein response (UPR) emerged as a prominent stress‐responsive pathway that regulates diverse aspects biology. Here, we show activity promotes adaptive remodeling membrane phosphatidic acid (PA) induce protective elongation acute We find is required stress‐dependent increases both cellular PA YME1L‐dependent degradation intramitochondrial transporter PRELID1. These two processes lead accumulation on outer where it can by inhibiting fission. Our results establish new role phospholipids demonstrate PERK‐dependent regulation adapts organellar shape

Язык: Английский

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PERK recruits E-Syt1 at ER–mitochondria contacts for mitochondrial lipid transport and respiration

The Journal of Cell Biology, Год журнала: 2023, Номер 222(3)

Опубликована: Фев. 23, 2023

The integrity of ER–mitochondria appositions ensures transfer ions and phospholipids (PLs) between these organelles exerts crucial effects on mitochondrial bioenergetics. Malfunctions within the contacts altering lipid trafficking homeostasis manifest in diverse pathologies, but molecular effectors governing this process remain ill-defined. Here, we report that PERK promotes at contact sites (EMCS) through a non-conventional, unfolded protein response-independent, mechanism. operates as an adaptor for recruitment ER–plasma membrane tether (LTP) Extended-Synaptotagmin 1 (E-Syt1), EMCS. In resting cells, heterotypic E-Syt1-PERK interaction endorses PLs ER mitochondria. Weakening or removing SMP-domain E-Syt1, compromises respiration. Our findings unravel E-Syt1 interacting LTP component machinery EMCS, which critically maintains fitness.

Язык: Английский

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Esculin induces endoplasmic reticulum stress and drives apoptosis and ferroptosis in colorectal cancer via PERK regulating eIF2α/CHOP and Nrf2/HO-1 cascades

Journal of Ethnopharmacology, Год журнала: 2024, Номер 328, С. 118139 - 118139

Опубликована: Март 30, 2024

Язык: Английский

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Mammalian integrated stress responses in stressed organelles and their functions

Acta Pharmacologica Sinica, Год журнала: 2024, Номер 45(6), С. 1095 - 1114

Опубликована: Янв. 24, 2024

Язык: Английский

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Redox regulation of UPR signalling and mitochondrial ER contact sites

Cellular and Molecular Life Sciences, Год журнала: 2024, Номер 81(1)

Опубликована: Июнь 7, 2024

Mitochondria and the endoplasmic reticulum (ER) have a synergistic relationship are key regulatory hubs in maintaining cell homeostasis. Communication between these organelles is mediated by mitochondria ER contact sites (MERCS), allowing exchange of material information, modulating calcium homeostasis, redox signalling, lipid transfer regulation mitochondrial dynamics. MERCS dynamic structures that allow cells to respond changes intracellular environment under normal homeostatic conditions, while their assembly/disassembly affected pathophysiological conditions such as ageing disease. Disruption protein folding lumen can activate Unfolded Protein Response (UPR), promoting remodelling membranes formation. The UPR stress receptor kinases PERK IRE1, located at or close MERCS. signalling be adaptive maladaptive, depending on whether disruption transient sustained. Adaptive via increase import, metabolism dynamics, maladaptive result excessive import activation apoptotic pathways. Targeting assembly an attractive therapeutic approach for range age-related neurodegeneration sarcopenia. This review highlights emerging evidence related role orchestrating inter-organelle communication mitochondria, ultimately determination function fate.

Язык: Английский

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eIF2α Phosphorylation-ATF4 Axis-Mediated Transcriptional Reprogramming Mitigates Mitochondrial Impairment During ER Stress

Molecules and Cells, Год журнала: 2025, Номер unknown, С. 100176 - 100176

Опубликована: Янв. 1, 2025

Eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, which regulates all three unfolded protein response pathways, helps maintain cellular homeostasis and overcome endoplasmic reticulum (ER) stress through transcriptional translational reprogramming. However, regulation of mitochondrial by eIF2α phosphorylation during ER is not fully understood. Here, we report that the phosphorylation-activating transcription 4 (ATF4) axis required for expression multiple factors (TFs) including nuclear erythroid 2-related 2 (Nrf2) their target genes responsible stress. phosphorylation-deficient (A/A) cells displayed dysregulated dynamics DNA replication, decreased oxidative complex proteins, impaired functions ATF4 overexpression suppressed impairment in A/A promoting downstream TFs genes. Our findings underscore importance phosphorylation-ATF4 maintaining reprogramming

Язык: Английский

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NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson’s Disease

Cells, Год журнала: 2022, Номер 11(15), С. 2416 - 2416

Опубликована: Авг. 4, 2022

Dysfunctional mitochondrial quality control (MQC) is implicated in the pathogenesis of Parkinson’s disease (PD). The improper selection mitochondria for mitophagy increases reactive oxygen species (ROS) levels and lowers ATP levels. downstream effects include oxidative damage, failure to maintain proteostasis ion gradients, decreased NAD+ NADPH levels, resulting insufficient energy metabolism neurotransmitter synthesis. A ketosis-based metabolic therapy that (R)-3-hydroxybutyrate (BHB) may reverse dysfunctional MQC by partially replacing glucose as an source, stimulating mitophagy, decreasing inflammation. Fasting can potentially raise cytoplasmic increasing export ketone body-derived citrate flux through isocitrate dehydrogenase 1 (IDH1). essential cofactor nitric oxide synthase, synthesized diffuse into matrix react with electron transport chain-synthesized superoxide form peroxynitrite. Excessive peroxynitrite production cause opening permeability transition pore (mPTP) depolarize activate PINK1-dependent mitophagy. Both fasting exercise increase ketogenesis cellular NAD+/NADH ratio, both which are beneficial neuronal metabolism. In addition, engage adaptive stress response signaling pathways protect neurons against proteotoxic PD. Here, we discuss how intermittent from evening meal next-day lunch together morning exercise, when circadian most oxidized, NADP+/NADPH reduced, gene expression high, slow progression

Язык: Английский

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Non-canonical STING–PERK pathway dependent epigenetic regulation of vascular endothelial dysfunction via integrating IRF3 and NF-κB in inflammatory response

Acta Pharmaceutica Sinica B, Год журнала: 2023, Номер 13(12), С. 4765 - 4784

Опубликована: Авг. 17, 2023

Inflammation-driven endothelial dysfunction is the major initiating factor in atherosclerosis, while underlying mechanism remains elusive. Here, we report that non-canonical stimulator of interferon genes (STING)-PKR-like ER kinase (PERK) pathway was significantly activated both human and mice atherosclerotic arteries. Typically, STING activation leads to regulatory 3 (IRF3) nuclear factor-kappa B (NF-κB)/p65, thereby facilitating IFN signals inflammation. In contrast, our study reveals STING-PERK increases scaffold protein bromodomain 4 (BRD4) expression, which encourages formation super-enhancers on proximal promoter regions proinflammatory cytokines, enabling transactivation these cytokines by integrating IRF3 NF-κB via a condensation process. Endothelium-specific BRD4 deficiency decreased plaque area Mechanistically, this triggered leaked mitochondrial DNA (mtDNA) permeability transition pore (mPTP), formed voltage-dependent anion channel 1 (VDAC1) oligomer interaction with oxidized mtDNA upon cholesterol oxidation stimulation. Especially, compared macrophages, plays more pronounced role atherosclerosis. We propose pathway-dependent epigenetic paradigm atherosclerosis integrates IRF3, inflammatory responses, provides emerging therapeutic modalities for vascular dysfunction.

Язык: Английский

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