STIM2 knockdown protects against ischemia/reperfusion injury through reducing mitochondrial calcium overload and preserving mitochondrial function

Tu, Chenchen; Wan, Baoyan; Zeng, Yong

doi:10.1016/j.lfs.2019.116560

Cited by 23 publications

(14 citation statements)

References 47 publications

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“…Despite the lack of expected premature neurodegeneration in the STIM2/ORAI1 mice, our novel model can be a useful tool for further studies of the role of SOCE proteins in neurons. This is especially relevant in the context of conflicting evidence of STIM2 actions in neuronal pathophysiology [10,31,33,[48][49][50][51][52], the involvement of ORAI1 in neurotransmission [53] and the growing body of evidence that links Ca 2+ homeostasis to AD-related neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Transgenic Mice Overexpressing Human STIM2 and ORAI1 in Neurons Exhibit Changes in Behavior and Calcium Homeostasis but Show No Signs of Neurodegeneration

Majewski

Maciąg

Boguszewski

et al. 2020

IJMS

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The maintenance of proper cytosolic Ca2+ level is crucial for neuronal survival, and dysregulation of Ca2+ homeostasis is found in a variety of neurological disorders, including Alzheimer’s disease. According to the “Ca2+ hypothesis of aging”, Ca2+ disturbances precede the onset of AD symptoms and lead to neurodegeneration. STIM and ORAI proteins are involved in neuronal physiological and pathological processes as essential components of the store-operated Ca2+ entry. Our previous data suggested that overexpression of STIM2 and ORAI1 might increase basal neuronal cytosolic Ca2+ level. We generated double transgenic mice overexpressing these two genes in neurons, expecting that the increased basal Ca2+ concentration will lead to premature neurodegeneration. We observed changes in Ca2+ homeostasis and electrophysiological properties in acute brain slices of STIM2/ORAI1 neurons. However, we did not observe any augmentation of neurodegenerative processes, as tested by Fluoro-Jade® C staining and assessment of amyloidogenesis. The battery of behavioral tests did not show any signs of accelerated aging. We conclude that changes of calcium homeostasis induced by overexpression of STIM2 and ORAI1 had no substantial adverse effects on neurons and did not lead to early neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Transgenic Mice Overexpressing Human STIM2 and ORAI1 in Neurons Exhibit Changes in Behavior and Calcium Homeostasis but Show No Signs of Neurodegeneration

Majewski

Maciąg

Boguszewski

et al. 2020

IJMS

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“…In mice, STIM1 expression dominates over STIM2 expression. One exception is in the brain, mostly in the hippocampus and cortex, where higher amounts of STIM2 mRNA and protein expression have been observed [5][6][7]. In the human brain, the expression of both STIM1 and STIM2 was highest in the cortex, caudate, and hippocampus [6].…”

Section: Introductionmentioning

confidence: 99%

stim2b Knockout Induces Hyperactivity and Susceptibility to Seizures in Zebrafish Larvae

Wasilewska¹,

Gupta²,

Wojtaś³

et al. 2020

Cells

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In neurons, stromal interaction molecule (STIM) proteins regulate store-operated Ca2+ entry (SOCE) and are involved in calcium signaling pathways. However, STIM activity in neurological diseases is unclear and should be clarified by studies that are performed in vivo rather than in cultured cells in vitro. The present study investigated the role of neuronal Stim2b protein in zebrafish. We generated stim2b knockout zebrafish, which were fertile and had a regular lifespan. Using various behavioral tests, we found that stim2b−/− zebrafish larvae were hyperactive compared with wild-type fish. The mutants exhibited increases in mobility and thigmotaxis and disruptions of phototaxis. They were also more sensitive to pentylenetetrazol and glutamate treatments. Using lightsheet microscopy, a higher average oscillation frequency and higher average amplitude of neuronal Ca2+ oscillations were observed in stim2b−/− larvae. RNA sequencing detected upregulation of the annexin 3a and gpr39 genes and downregulation of the rrm2, neuroguidin, and homer2 genes. The latter gene encodes a protein that is involved in several processes that are involved in Ca2+ homeostasis in neurons, including metabotropic glutamate receptors. We propose that Stim2b deficiency in neurons dysregulates SOCE and triggers changes in gene expression, thereby causing abnormal behavior, such as hyperactivity and susceptibility to seizures.

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“…They also showed that in normal mucosal cells STIM2 knockdown increased resistance to apoptosis ( Sobradillo et al, 2014 ). Tu et al showed in cultured cardiomyocytes that STIM2 expression was significantly increased following I/R injury; whereas knockdown of STIM2 preserved mitochondrial function and attenuated the activation of apoptotic signaling in response to I/R ( Tu et al, 2020 ). There is also evidence for Orai3 mediated regulation of apoptosis, primarily in cancer cells.…”

Section: Stim and Orai In Cell Survivalmentioning

confidence: 99%

STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases

2022

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Tight spatiotemporal regulation of intracellular Ca2+ plays a critical role in regulating diverse cellular functions including cell survival, metabolism, and transcription. As a result, eukaryotic cells have developed a wide variety of mechanisms for controlling Ca2+ influx and efflux across the plasma membrane as well as Ca2+ release and uptake from intracellular stores. The STIM and Orai protein families comprising of STIM1, STIM2, Orai1, Orai2, and Orai3, are evolutionarily highly conserved proteins that are core components of all mammalian Ca2+ signaling systems. STIM1 and Orai1 are considered key players in the regulation of Store Operated Calcium Entry (SOCE), where release of Ca2+ from intracellular stores such as the Endoplasmic/Sarcoplasmic reticulum (ER/SR) triggers Ca2+ influx across the plasma membrane. SOCE, which has been widely characterized in non-excitable cells, plays a central role in Ca2+-dependent transcriptional regulation. In addition to their role in Ca2+ signaling, STIM1 and Orai1 have been shown to contribute to the regulation of metabolism and mitochondrial function. STIM and Orai proteins are also subject to redox modifications, which influence their activities. Considering their ubiquitous expression, there has been increasing interest in the roles of STIM and Orai proteins in excitable cells such as neurons and myocytes. While controversy remains as to the importance of SOCE in excitable cells, STIM1 and Orai1 are essential for cellular homeostasis and their disruption is linked to various diseases associated with aging such as cardiovascular disease and neurodegeneration. The recent identification of splice variants for most STIM and Orai isoforms while complicating our understanding of their function, may also provide insight into some of the current contradictions on their roles. Therefore, the goal of this review is to describe our current understanding of the molecular regulation of STIM and Orai proteins and their roles in normal physiology and diseases of aging, with a particular focus on heart disease and neurodegeneration.

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STIM2 knockdown protects against ischemia/reperfusion injury through reducing mitochondrial calcium overload and preserving mitochondrial function

Cited by 23 publications

References 47 publications

Transgenic Mice Overexpressing Human STIM2 and ORAI1 in Neurons Exhibit Changes in Behavior and Calcium Homeostasis but Show No Signs of Neurodegeneration

Transgenic Mice Overexpressing Human STIM2 and ORAI1 in Neurons Exhibit Changes in Behavior and Calcium Homeostasis but Show No Signs of Neurodegeneration

stim2b Knockout Induces Hyperactivity and Susceptibility to Seizures in Zebrafish Larvae

STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases

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