scholarly journals Calcium channel ITPR2 and mitochondria–ER contacts promote cellular senescence and aging

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Dorian V. Ziegler ◽  
David Vindrieux ◽  
Delphine Goehrig ◽  
Sara Jaber ◽  
Guillaume Collin ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Calcium Release ◽  
Liver Steatosis ◽  
Metabolic Stress ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Age Related ◽  
Trisphosphate Receptor

AbstractCellular senescence is induced by stresses and results in a stable proliferation arrest accompanied by a pro-inflammatory secretome. Senescent cells accumulate during aging, promoting various age-related pathologies and limiting lifespan. The endoplasmic reticulum (ER) inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) calcium-release channel and calcium fluxes from the ER to the mitochondria are drivers of senescence in human cells. Here we show that Itpr2 knockout (KO) mice display improved aging such as increased lifespan, a better response to metabolic stress, less immunosenescence, as well as less liver steatosis and fibrosis. Cellular senescence, which is known to promote these alterations, is decreased in Itpr2 KO mice and Itpr2 KO embryo-derived cells. Interestingly, ablation of ITPR2 in vivo and in vitro decreases the number of contacts between the mitochondria and the ER and their forced contacts induce premature senescence. These findings shed light on the role of contacts and facilitated exchanges between the ER and the mitochondria through ITPR2 in regulating senescence and aging.

Effects of the halothane-sensitivity gene on sarcoplasmic reticulum function

1989 ◽  
Vol 257 (4) ◽  
pp. C787-C794 ◽  
Author(s):  
J. R. Mickelson ◽  
E. M. Gallant ◽  
W. E. Rempel ◽  
K. M. Johnson ◽  
L. A. Litterer ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Calcium Release ◽  
Protein Product ◽  
Receptor Protein ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Sr Calcium Release ◽  
Sensitivity Gene

Pigs heterozygous for the halothane-sensitivity gene exhibit a distinct phenotype with regard to both in vivo and in vitro muscle responses to halothane (E. M. Gallant, J. R. Mickelson, B. D. Roggow, S. K. Donaldson, C. F. Louis, and W. E. Rempel. Am. J. Physiol. 257 (Cell Physiol. 26): C781-C786, 1989). In this paper heavy sarcoplasmic reticulum (SR) preparations were isolated from the muscles of pigs of all three genotypes. The rate of calcium release from SR of pigs homozygous for the halothane-sensitivity gene was approximately twice that of SR from pigs homozygous for the normal allele. Furthermore, in the presence of 6 microM Ca2+, the binding of [3H]ryanodine to SR isolated from the homozygous halothane-sensitive pigs was of a higher affinity than was the binding to SR isolated from the homozygous normal pigs (Kd = 70-90 vs. 265 nM, respectively). The SR from pigs heterozygous for the halothane-sensitivity gene, however, demonstrated intermediate values for the rate of calcium release and the affinity for [3H]ryanodine (Kd = 192 nM). Thus the alterations in heavy SR calcium release and [3H]ryanodine binding in the pigs containing one copy of the halothane-sensitivity gene demonstrate a distinct heterozygote phenotype. These data also suggest that the protein product of this gene is closely associated with, and perhaps identical to, the SR calcium release channel-ryanodine receptor protein.

scholarly journals Met125 is essential for maintaining the structural integrity of calmodulin’s C-terminal domain

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sarah E. D. Nelson ◽  
Daniel K. Weber ◽  
Robyn T. Rebbeck ◽  
Razvan L. Cornea ◽  
Gianluigi Veglia ◽  
...  
Keyword(s):  
Calcium Release ◽  
Structural Integrity ◽  
Regulatory Protein ◽  
Methionine Oxidation ◽  
Muscle Degeneration ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Protein Targets ◽  
Age Related ◽  
Ef Hand

AbstractWe have used NMR and circular dichroism spectroscopy to investigate the structural and dynamic effects of oxidation on calmodulin (CaM), using peroxide and the Met to Gln oximimetic mutations. CaM is a Ca2+-sensitive regulatory protein that interacts with numerous targets. Due to its high methionine content, CaM is highly susceptible to oxidation by reactive oxygen species under conditions of cell stress and age-related muscle degeneration. CaM oxidation alters regulation of a host of CaM’s protein targets, emphasizing the importance of understanding the mechanism of CaM oxidation in muscle degeneration and overall physiology. It has been shown that the M125Q CaM mutant can mimic the functional effects of methionine oxidation on CaM’s regulation of the calcium release channel, ryanodine receptor (RyR). We report here that the M125Q mutation causes a localized unfolding of the C-terminal lobe of CaM, preventing the formation of a hydrophobic cluster of residues near the EF-hand Ca2+ binding sites. NMR analysis of CaM oxidation by peroxide offers further insights into the susceptibility of CaM’s Met residues to oxidation and the resulting structural effects. These results further resolve oxidation-driven structural perturbation of CaM, with implications for RyR regulation and the decay of muscle function in aging.

scholarly journals Release of acidic store calcium is required for effective priming of the NLRP3 inflammasome

2022 ◽  
Author(s):  
Nick Platt ◽  
Dawn Shepherd ◽  
Yuzhe Weng ◽  
Grant Charles Churchill ◽  
Antony Galione ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Calcium Release ◽  
Inflammatory Responses ◽  
Lysosomal Storage ◽  
Release Channel ◽  
Type C ◽  
Niemann Pick ◽  
Lysosomal Protein

The lysosome is a dynamic signaling organelle that is critical for cell functioning. It is a regulated calcium store that can contribute to Ca2+-regulated processes via both local calcium release and more globally by influencing ER Ca2+release. Here, we provide evidence from studies of an authentic mouse model of the lysosomal storage disease Niemann-Pick Type C (NPC) that has reduced lysosomal Ca2+ levels, and genetically modified mice in which the two-pore lysosomal Ca2+ release channel family are deleted that lysosomal Ca2+ signaling is required for normal pro-inflammatory responses. We demonstrate that production of the pro-inflammatory cytokine IL-1beta via the NLRP3 inflammasome is significantly reduced in murine Niemann-Pick Type C, the inhibition is selective because secretion of TNF alpha is not diminished, and it is a consequence of inefficient inflammasome priming. Synthesis of precursor ProIL-1 beta is significantly reduced in macrophages genetically deficient in the lysosomal protein Npc1, which is mutated in most clinical cases of NPC, and in wild type cells in which Npc1 activity is pharmacologically inhibited. Comparable reductions in ProIL-1 beta generation were measured in vitro and in vivo by macrophages genetically altered to lack expression of the two-pore lysosomal Ca2+ release channels Tpcn1 or Tpcn2. These data demonstrate a requirement for lysosome-dependent Ca2+ signaling in the generation of specific pro-inflammatory responses.

scholarly journals Angptl2 is a Marker of Cellular Senescence: The Physiological and Pathophysiological Impact of Angptl2-Related Senescence

2021 ◽  
Vol 22 (22) ◽  
pp. 12232
Author(s):  
Nathalie Thorin-Trescases ◽  
Pauline Labbé ◽  
Pauline Mury ◽  
Mélanie Lambert ◽  
Eric Thorin
Keyword(s):  
Cell Fate ◽  
Cellular Senescence ◽  
Cellular Response ◽  
Inflammatory Diseases ◽  
Age Related ◽  
A Cell ◽  
Future Work ◽  
The Impact

Cellular senescence is a cell fate primarily induced by DNA damage, characterized by irreversible growth arrest in an attempt to stop the damage. Senescence is a cellular response to a stressor and is observed with aging, but also during wound healing and in embryogenic developmental processes. Senescent cells are metabolically active and secrete a multitude of molecules gathered in the senescence-associated secretory phenotype (SASP). The SASP includes inflammatory cytokines, chemokines, growth factors and metalloproteinases, with autocrine and paracrine activities. Among hundreds of molecules, angiopoietin-like 2 (angptl2) is an interesting, although understudied, SASP member identified in various types of senescent cells. Angptl2 is a circulatory protein, and plasma angptl2 levels increase with age and with various chronic inflammatory diseases such as cancer, atherosclerosis, diabetes, heart failure and a multitude of age-related diseases. In this review, we will examine in which context angptl2 was identified as a SASP factor, describe the experimental evidence showing that angptl2 is a marker of senescence in vitro and in vivo, and discuss the impact of angptl2-related senescence in both physiological and pathological conditions. Future work is needed to demonstrate whether the senescence marker angptl2 is a potential clinical biomarker of age-related diseases.

scholarly journals Senescent Cell-Secreted Netrin-1 Modulates Aging-Related Disorders by Recruiting Sympathetic Fibers

2020 ◽  
Vol 12 ◽  
Author(s):  
Ai Qing Yu ◽  
Jie Wang ◽  
Xiao Jia Zhou ◽  
Ke Yu Chen ◽  
You De Cao ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Molecular Mechanisms ◽  
Human Colon ◽  
Senescent Cell ◽  
Aged Mouse ◽  
Age Related ◽  
Mouse Tissues ◽  
6 Hydroxydopamine

Cellular senescence is implicated in several lines of aging-related disorders. However, the potential molecular mechanisms by which cellular senescence modulates age-related pathologies remain largely unexplored. Herein, we report that the density of sympathetic fibers (SFs) is significantly elevated in naturally aged mouse tissues and human colon adenoma tissues compared to the SFs densities in the corresponding young mouse tissues and human non-lesion colon tissues. A dorsal root ganglion (DRG)-human diploid fibroblast coculture assay revealed that senescent cells promote the outgrowth of SFs, indicating that the senescent cells induce recruitment of SFs in vitro. Additionally, subcutaneous transplantation of 2BS fibroblasts in nude mice shows that transplanted senescent 2BS fibroblasts promote SFs infiltration. Intra-articular senolytic molecular injection can reduce SFs density and inhibit SFs infiltration caused by senescent cells in osteoarthritis (OA), suggesting senescent cells promote the infiltration of SFs in vivo in aged tissues. Notably, the elevated level of SFs contributes to impaired cognitive function in naturally aged mice, which can be reversed by treatment with propranolol hydrochloride, a non-selective β receptor blocker that inhibits sympathetic nerve activity (SNA) by blocking non-selective β receptors. Additionally, 6-hydroxydopamine (6-OHDA)-induced sympathectomy improved hepatic sympathetic overactivity mediated hepatic steatosis in high fat diet (HFD)-fed APOE knockout mice (APOE−/− mice) by reducing hepatic SNA. Taken together, this study concludes that senescent cell-secreted netrin-1 mediated SFs outgrowth and infiltration, which contributes to aging-related disorders, suggesting that clearing senescent cells or inhibiting SNA is a promising therapeutic strategy for improving sympathetic nervous system (SNS) hyperactivity-induced aging-related pathologies.

scholarly journals Cardiac Type 2 Inositol 1,4,5-Trisphosphate Receptor

2005 ◽  
Vol 280 (16) ◽  
pp. 15912-15920 ◽  
Author(s):  
Dan J. Bare ◽  
Claudia S. Kettlun ◽  
Mei Liang ◽  
Donald M. Bers ◽  
Gregory A. Mignery
Keyword(s):  
Lipid Bilayers ◽  
Calcium Release ◽  
Ventricular Myocytes ◽  
Calcium Release Channel ◽  
Open Probability ◽  
Release Channel ◽  
Amino Terminal ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor

The type 2 inositol 1,4,5-trisphosphate receptor (InsP3R2) was identified previously as the predominant isoform in cardiac ventricular myocytes. Here we reported the subcellular localization of InsP3R2 to the cardiomyocyte nuclear envelope (NE). The other major known endo/sarcoplasmic reticulum calcium-release channel (ryanodine receptor) was not localized to the NE, indicating functional segregation of these channels and possibly a unique role for InsP3R2 in regulating nuclear calcium dynamics. Immunoprecipitation experiments revealed that the NE InsP3R2 associates with Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ), the major isoform expressed in cardiac myocytes. Recombinant InsP3R2 and CaMKIIδBalso co-immunoprecipitated after co-expression in COS-1 cells. Additionally, the amino-terminal 1078 amino acids of the InsP3R2 were sufficient for interaction with CaMKIIδBand associated upon mixing following separate expression. CaMKII can also phosphorylate InsP3R2, as demonstrated by32P labeling. Incorporation of CaMKII-treated InsP3R2 into planar lipid bilayers revealed that InsP3-mediated channel open probability is significantly reduced (∼11 times) by phosphorylation via CaMKII. We concluded that the InsP3R2 and CaMKIIδ likely represent two central components of a multiprotein signaling complex, and this raises the possibility that calcium release via InsP3R2 in the myocyte NE may activate local CaMKII signaling, which may feedback on InsP3R2 function.

scholarly journals T cells deficient in inositol 1,4,5-trisphosphate receptor are resistant to apoptosis.

1997 ◽  
Vol 17 (6) ◽  
pp. 3005-3012 ◽  
Author(s):  
T Jayaraman ◽  
A R Marks
Keyword(s):  
T Cells ◽  
Intracellular Calcium ◽  
Calcium Release ◽  
Calcium Influx ◽  
Cell Receptor ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Inositol 1,4,5 Trisphosphate ◽  
Intracellular Calcium Release ◽  
Trisphosphate Receptor

The type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) calcium release channel is present on the endoplasmic reticulum of most cell types. T lymphocytes which have been made deficient in IP3R1 lack detectable IP3-induced intracellular calcium release and exhibit defective signaling via the T-cell receptor (TCR) (T. Jayaraman, E. Ondriasova, K. Ondrias, D. Harnick, and A. R. Marks, Proc. Natl. Acad. Sci. USA 92:6007-6011, 1995). We now show that IP3R1-deficient T cells are resistant to apoptosis induced by dexamethasone, TCR stimulation, ionizing radiation, and Fas. Resistance to TCR-mediated apoptosis in IP3R1-deficient cells is reversed by pharmacologically raising cytoplasmic calcium levels. TCR-mediated apoptosis can be induced in calcium-free media, indicating that extracellular calcium influx is not required. These findings suggest that intracellular calcium release via the IP3R1 is a critical mediator of apoptosis.

Drosophila Calmodulin Mutants With Specific Defects in the Musculature or in the Nervous System

Genetics ◽  
2003 ◽  
Vol 165 (3) ◽  
pp. 1255-1268
Author(s):  
Bo Wang ◽  
Kathleen M C Sullivan ◽  
Kathy Beckingham
Keyword(s):  
Nervous System ◽  
Calcium Binding ◽  
Calcium Release ◽  
Genetic Interaction ◽  
Larval Instar ◽  
Single Amino Acid ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Single Amino Acid Change

Abstract We have studied lethal mutations in the single calmodulin gene (Cam) of Drosophila to gain insight into the in vivo functions of this important calcium sensor. As a result of maternal calmodulin (CaM) in the mature egg, lethality is delayed until the postembryonic stages. Prior to death in the first larval instar, Cam nulls show a striking behavioral abnormality (spontaneous backward movement) whereas a mutation, Cam7, that results in a single amino acid change (V91G) produces a very different phenotype: short indented pupal cases and pupal death with head eversion defects. We show here that the null behavioral phenotype originates in the nervous system and involves a CaM function that requires calcium binding to all four sites of the protein. Further, backward movement can be induced in hypomorphic mutants by exposure to high light levels. In contrast, the V91G mutation specifically affects the musculature and causes abnormal calcium release in response to depolarization of the muscles. Genetic interaction studies suggest that failed regulation of the muscle calcium release channel, the ryanodine receptor, is the major defect underlying the Cam7 phenotype.

Autosomal Dominant Canine Malignant Hyperthermia Is Caused by a Mutation in the Gene Encoding the Skeletal Muscle Calcium Release Channel (RYR1 )

2001 ◽  
Vol 95 (3) ◽  
pp. 716-725 ◽  
Author(s):  
Monica C. Roberts ◽  
James R. Mickelson ◽  
Edward E. Patterson ◽  
Thomas E. Nelson ◽  
P. Jane Armstrong ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Calcium Release ◽  
Autosomal Dominant ◽  
Calcium Release Channel ◽  
Gene Encoding ◽  
Release Channel ◽  
In Vitro Contracture Test ◽  
Mixed Breed ◽  
Muscle Calcium

Background Malignant hyperthermia (MH) is an inherited disorder of skeletal muscle characterized by hypercarbia, rhabdomyolysis, generalized skeletal muscle contracture, cardiac dysrhythmia, and renal failure, that develops on exposure to succinylcholine or volatile anesthetic agents. All swine and up to 50% of human MH events are thought to be associated with mutations in the calcium release channel of the sarcoplasmic reticulum, also known as the ryanodine receptor (RYR1). Events resembling MH have been reported in other species, but none have undergone genetic investigation to date. Methods To determine the molecular basis of canine MH, a breeding colony was established with a male, mixed-breed, MH-susceptible (MHS) dog that survived an in vivo halothane-succinylcholine challenge. He was mated to three unaffected females to produce four litters and back-crossed to an affected daughter to produce one litter. One of his MHS sons was mated to an unaffected female to produce an additional litter. Forty-seven dogs were phenotyped with an in vitro contracture test and diagnosed as MHS or MH normal based on the North American in vitro contracture test protocol. Nine microsatellite markers in the vicinity of RYR1 on canine chromosome 1 (CFA01) were tested for linkage to the MHS phenotype. Mutational analysis in two MHS and two MH-normal dogs was performed with direct sequencing of polymerase chain reaction products and of cloned fragments that represent frequently mutated human RYR1 regions. A restriction fragment length polymorphism was chosen to detect the candidate mutation in the pedigree at large. Results Pedigree inspection revealed that MHS in this colony is transmitted as an autosomal dominant trait. FH2294, the marker closest to RYR1, is linked to MHS at a theta = 0.03 with a LOD score of 9.24. A T1640C mutation gives rise to an alanine for valine substitution of amino acid 547 in the RYR1 protein, generating a maximum LOD score of 12.29 at theta = 0.00. All dogs diagnosed as MHS by in vitro contracture test were heterozygous for the mutation, and all MH-normal dogs were homozygous for the T1640 allele. Conclusions These results indicate that autosomal dominant canine MH is caused by a mutation in the gene encoding the skeletal muscle calcium release channel and that the MHS trait in this pedigree of mixed-breed dogs is in perfect cosegregation with the RYR1 V547A mutation.

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