Interplay between calcium and endoplasmic reticulum stress

Groenendyk, Jody; Michalak, Marek

doi:10.1016/j.ceca.2023.102753

Cited by 14 publications

(6 citation statements)

References 120 publications

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“…These observations suggest that TPP2 depletion-induced Ca 2+ dyshomeostasis and PC dysregulation are very tightly conjugated, and their synergistic effect causes ER stress. As known, ER is the main Ca 2+ storage organelle, and ER Ca 2+ not only provides a favorable environment for protein folding but also a source of Ca 2+ for cell signaling 147 , 158 . As such, it is conceivable that the ER Ca 2+ content must be tightly controlled and altered ER homeostasis can impact a myriad of cellular processes and therefore lead to ER stress.…”

Section: Discussionmentioning

confidence: 99%

Tripeptidyl peptidase II coordinates the homeostasis of calcium and lipids in the central nervous system and its depletion causes presenile dementia in female mice through calcium/lipid dyshomeostasis-induced autophagic degradation of CYP19A1

Zhao,

He,

Fan

et al. 2024

Theranostics

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Rationale: Tripeptidyl peptidase II (TPP2) has been proven to be related to human immune and neurological diseases. It is generally considered as a cytosolic protein which forms the largest known protease complex in eukaryotic cells to operate mostly downstream of proteasomes for degradation of longer peptides. However, this canonical function of TPP2 cannot explain its role in a wide variety of biological and pathogenic processes. The mechanistic interrelationships and hierarchical order of these processes have yet to be clarified. Methods: Animals, cells, plasmids, and viruses established and/or used in this study include: TPP2 knockout mouse line, TPP2 conditional knockout mouse lines (different neural cell type oriented), TRE-TPP2 knockin mouse line on the C57BL/6 background; 293T cells with depletion of TPP2, ATF6, IRE1, PERK, SYVN1, UCHL1, ATG5, CEPT1, or CCTα, respectively; 293T cells stably expressing TPP2, TPP2 S449A, TPP2 S449T, or CCTα-KDEL proteins on the TPP2-depleted background; Plasmids for eukaryotic transient expression of rat CYP19A1-Flag, CYP19A1 S118A-Flag, CYP19A1 S118D-Flag, Sac I ML GFP Strand 11 Long, OMMGFP 1-10, G-CEPIA1er, GCAMP2, CEPIA3mt, ACC-GFP, or SERCA1-GFP; AAV2 carrying the expression cassette of mouse CYP19A1-3 X Flag-T2A-ZsGreen. Techniques used in this study include: Flow cytometry, Immunofluorescence (IF) staining, Immunohistochemical (IHC) staining, Luxol fast blue (LFB) staining, β-galactosidase staining, Lipid droplet (LD) staining, Calcium (Ca 2+ ) staining, Stimulated emission depletion (STED) imaging, Transmission electron microscopic imaging, Two-photon imaging, Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end Labeling (TUNEL) assay, Bromodeoxyuridine (BrdU) assay, Enzymatic activity assay, Proximity ligation assay (PLA), In vivo electrophysiological recording, Long-term potentiation (LTP) recording, Split-GFP-based mitochondria-associated membrane (MAM) detection, Immunoprecipitation (IP), Cellular fractionation, In situ hybridization, Semi-quantitative RT-PCR, Immunoblot, Mass spectrometry-based lipidomics, metabolomics, proteomics, Primary hippocampal neuron culture and Morris water maze (MWM) test. Results: We found that TPP2, independent of its enzymatic activity, plays a crucial role in maintaining the homeostasis of intracellular Ca 2+ and phosphatidylcholine (PC) in the central nervous system (CNS) of mice. In consistence with the critical importance of Ca 2+ and PC in the CNS, TPP2 gene ablation causes presenile dementia in female mice, which is closely associated with Ca 2+ /PC dysregulation-induced endoplasmic reticulum (ER) stress, abnormal autophagic degradation of CYP19A1 (aromatase), and estrogen depletion. This work therefore uncovers a new role of TPP2 in lipogenesis and neurosteroidogenesis which is tightly related to cognitive function of adult female mice. Conclusion: ...

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Section: Discussionmentioning

confidence: 99%

Tripeptidyl peptidase II coordinates the homeostasis of calcium and lipids in the central nervous system and its depletion causes presenile dementia in female mice through calcium/lipid dyshomeostasis-induced autophagic degradation of CYP19A1

Zhao,

He,

Fan

et al. 2024

Theranostics

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“…The ER plays an important role in a variety of cellular functions that are essential for the healthy functioning of an organism, such as protein folding and Ca 2+ signaling [28] (Figure 1).…”

Section: The Er and The Uprmentioning

confidence: 99%

“…The ER is the major organelle for the storage of intracellular Ca 2+ and controls calcium dynamics [28]. This regulation is essential for creating a favorable environment for protein folding and for serving as a reservoir for the rapid and specific release of calcium [35].…”

Section: Ca 2+ Signalingmentioning

confidence: 99%

“…When the ER faces stress, such as ischemia, hypoxia, toxic substances, or increased protein production, the resulting accumulation of misfolded proteins activates the UPR [2]. The UPR restores normal cellular function by suppressing protein translation, promoting the degradation of misfolded proteins, and facilitating the production of molecular chaperones [2,28]. The UPR involves three main stress kinases: inositol-requiring enzyme 1α (IRE1α), protein kinase R (PKR)-like ER kinase (PERK), and activating transcription factor 6 (ATF6) [2].…”

Section: Uprmentioning

confidence: 99%

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Unraveling the Connection: Pain and Endoplasmic Reticulum Stress

Kawanaka,

Jin,

Aoe

2024

IJMS

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Pain is a complex and multifaceted experience. Recent research has increasingly focused on the role of endoplasmic reticulum (ER) stress in the induction and modulation of pain. The ER is an essential organelle for cells and plays a key role in protein folding and calcium dynamics. Various pathological conditions, such as ischemia, hypoxia, toxic substances, and increased protein production, may disturb protein folding, causing an increase in misfolding proteins in the ER. Such an overload of the folding process leads to ER stress and causes the unfolded protein response (UPR), which increases folding capacity in the ER. Uncompensated ER stress impairs intracellular signaling and cell function, resulting in various diseases, such as diabetes and degenerative neurological diseases. ER stress may be a critical universal mechanism underlying human diseases. Pain sensations involve the central as well as peripheral nervous systems. Several preclinical studies indicate that ER stress in the nervous system is enhanced in various painful states, especially in neuropathic pain conditions. The purpose of this narrative review is to uncover the intricate relationship between ER stress and pain, exploring molecular pathways, implications for various pain conditions, and potential therapeutic strategies.

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“…further articles highlight the role of different Ca 2+ -dependent processes in cell death, including store-operated Ca 2+ entry [14] and endoplasmic reticulum (ER)-mitochondrial Ca 2+ signaling [15]. Also, Ca 2+ signals and/or deranged organellar Ca 2+ homeostasis can intersect and direct different cell death processes in response to cell stress including ferroptosis [16], lysosomaldependent cell death [17] and the unfolded protein response (UPR), a pathway activated by ER stress [18]. While UPR triggers cell death in conditions of persistent or excessive ER stress, it can also act as an adaptive, coping response to restore ER homeostasis and thus sustain cell survival in conditions of transient or mild ER stress.…”

mentioning

confidence: 99%