Cell Calcium
December 2024
The IP receptor (IPR) is a ubiquitously expressed Ca-release channel located in the endoplasmic reticulum (ER). Ca signals originating from the IPR initiate or regulate a plethora of cellular events, including cell life and death processes, e.g.
View Article and Find Full Text PDFBiochim Biophys Acta Mol Cell Res
January 2025
CISD2, a 2Fe2S cluster domain-containing protein, is implicated in Wolfram syndrome type 2, longevity and cancer. CISD2 is part of a ternary complex with IP receptors (IPRs) and anti-apoptotic BCL-2 proteins and enhances BCL-2's anti-autophagic function. Here, we examined how CISD2 impacted the function of BCL-2 in apoptosis and in controlling IPR-mediated Ca signaling.
View Article and Find Full Text PDFBiochim Biophys Acta Mol Cell Res
October 2024
Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme interacting with the inositol 1,4,5-trisphosphate receptor (IPR). This interaction suppresses IPR-mediated cytosolic [Ca] rises. As PKM2 exists in monomeric, dimeric and tetrameric forms displaying different properties including catalytic activity, we investigated the molecular determinants of PKM2 enabling its interaction with IPRs.
View Article and Find Full Text PDFThere have been in the last three decades repeated publications indicating that the inositol 1,4,5-trisphosphate receptor (IPR) is regulated not only by cytosolic Ca but also by intraluminal Ca. Although most studies indicated that a decreasing intraluminal Ca level led to an inhibition of the IPR, a number of publications reported exactly the opposite effect, i.e.
View Article and Find Full Text PDFPyruvate kinase M (PKM) 2 was described to interact with the inositol 1,4,5-trisphosphate (IP) receptor (IPR) and suppress its activity. To further investigate the physiological importance of the PKM2:IPR interaction, we developed and characterized HeLa PKM2 knockout (KO) cells. In the HeLa PKM2 KO cells, the release of Ca to the cytosol appears to be more sensitive to low agonist concentrations than in HeLa wild-type (WT) cells.
View Article and Find Full Text PDFMutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson's disease (PD), with growing importance also for Crohn's disease and cancer. LRRK2 is a large and complex protein possessing both GTPase and kinase activity. Moreover, LRRK2 activity and function can be influenced by its phosphorylation status.
View Article and Find Full Text PDFEndoplasmic reticulum (ER)-mitochondria contact sites are crucial to allow Ca flux between them and a plethora of proteins participate in tethering both organelles together. Inositol 1,4,5-trisphosphate receptors (IPRs) play a pivotal role at such contact sites, participating in both ER-mitochondria tethering and as Ca-transport system that delivers Ca from the ER towards mitochondria. At the ER-mitochondria contact sites, the IPRs function as a multi-protein complex linked to the voltage-dependent anion channel 1 (VDAC1) in the outer mitochondrial membrane, via the chaperone glucose-regulated protein 75 (GRP75).
View Article and Find Full Text PDFThe heterotrimeric Sec61 protein complex forms the functional core of the so-called translocon that forms an aqueous channel in the endoplasmic reticulum (ER). The primary role of the Sec61 complex is to allow protein import in the ER during translation. Surprisingly, a completely different function in intracellular Ca homeostasis has emerged for the Sec61 complex, and the latter is now accepted as one of the major Ca-leak pathways of the ER.
View Article and Find Full Text PDFBiochim Biophys Acta Rev Cancer
November 2022
Members of the Bcl-2-protein family are key controllers of apoptotic cell death. The family is divided into antiapoptotic (including Bcl-2 itself, Bcl-xL, Mcl-1, etc.) and proapoptotic members (Bax, Bak, Bim, Bim, Puma, Noxa, Bad, etc.
View Article and Find Full Text PDFIon fluxes across the inner mitochondrial membrane control mitochondrial volume, energy production, and apoptosis. TMBIM5, a highly conserved protein with homology to putative pH-dependent ion channels, is involved in the maintenance of mitochondrial cristae architecture, ATP production, and apoptosis. Here, we demonstrate that overexpressed TMBIM5 can mediate mitochondrial calcium uptake.
View Article and Find Full Text PDFAnti-apoptotic BCL-2 targets and inhibits IP receptors (IPRs), thereby preventing apoptosis by limiting ER-mitochondrial Ca flux. Recently, Dulloo et al. (2022), Nat.
View Article and Find Full Text PDFCellular senescence is implicated in a great number of diseases including cancer. Although alterations in mitochondrial metabolism were reported as senescence drivers, the underlying mechanisms remain elusive. We report the mechanism altering mitochondrial function and OXPHOS in stress-induced senescent fibroblasts.
View Article and Find Full Text PDFBiochim Biophys Acta Mol Cell Res
April 2022
Pyruvate kinase isoform M2 (PKM2) is a rate-limiting glycolytic enzyme that is widely expressed in embryonic tissues. The expression of PKM2 declines in some tissues following embryogenesis, while other pyruvate kinase isozymes are upregulated. However, PKM2 is highly expressed in cancer cells and is believed to play a role in supporting anabolic processes during tumour formation.
View Article and Find Full Text PDFBiochim Biophys Acta Mol Cell Res
February 2022
Anti-apoptotic Bcl-2-family members not only act at mitochondria but also at the endoplasmic reticulum, where they impact Ca dynamics by controlling IP receptor (IPR) function. Current models propose distinct roles for Bcl-2 vs. Bcl-xL, with Bcl-2 inhibiting IPRs and preventing pro-apoptotic Ca release and Bcl-xL sensitizing IPRs to low [IP] and promoting pro-survival Ca oscillations.
View Article and Find Full Text PDFMutations in (which encodes Wolframin, WFS1) and (which encodes CDGSH iron sulfur domain 2) result in Wolfram syndrome (WS), a rare genetic disorder that starts with juvenile diabetes and progresses to neurological dysfunction. WFS1 and CISD2 belong to different protein families with distinct properties. Despite differences between WFS1 and CISD2, loss-of-function mutations in these proteins result in similar disease phenotypes, suggesting that they have convergent roles.
View Article and Find Full Text PDFProg Mol Subcell Biol
August 2021
Biochim Biophys Acta Mol Cell Res
June 2021
Inside cells, the endoplasmic reticulum (ER) forms the largest Ca store. Ca is actively pumped by the SERCA pumps in the ER, where intraluminal Ca-binding proteins enable the accumulation of large amount of Ca. IP receptors and the ryanodine receptors mediate the release of Ca in a controlled way, thereby evoking complex spatio-temporal signals in the cell.
View Article and Find Full Text PDFOrganelles cooperate with each other to control cellular homeostasis and cell functions by forming close connections through membrane contact sites. Important contacts are present between the endoplasmic reticulum (ER), the main intracellular Ca-storage organelle, and the mitochondria, the organelle responsible not only for the majority of cellular ATP production but also for switching on cell death processes. Several Ca-transport systems focalize at these contact sites, thereby enabling the efficient transmission of Ca signals from the ER toward mitochondria.
View Article and Find Full Text PDFAnti-apoptotic Bcl-2 critically controls cell death by neutralizing pro-apoptotic Bcl-2-family members at the mitochondria. Bcl-2 proteins also act at the endoplasmic reticulum, the main intracellular Ca-storage organelle, where they inhibit IP receptors (IPR) and prevent pro-apoptotic Ca-signaling events. IPR channels are targeted by the BH4 domain of Bcl-2.
View Article and Find Full Text PDFThe store-operated calcium entry, better known as SOCE, forms the main Ca influx pathway in non-excitable cells, especially in leukocytes, where it is required for cell activation and the immune response. During the past decades, several inhibitors were developed, but they lack specificity or efficacy. From the non-specific SOCE inhibitor 2-aminoethyl diphenylborinate (2-APB), we synthetized 16 new analogues by replacing/modifying the phenyl groups.
View Article and Find Full Text PDFThe construction of a low affinity Ca-probe that locates to the cell cortex and cell surface wrinkles, is described called. EPIC3 (ezrin-protein indicator of Ca). The novel probe is a fusion of CEPIA3 with ezrin, and is used in combination with a Ca-insensitive probe, ezrin-mCherry, both of which locate at the cell cortex.
View Article and Find Full Text PDFThe Transmembrane Bax Inhibitor-1 motif (TMBIM)-containing protein family is evolutionarily conserved and has been implicated in cell death susceptibility. The only member with a mitochondrial localization is TMBIM5 (also known as GHITM or MICS1), which affects cristae organization and associates with the Parkinson's disease-associated protein CHCHD2 in the inner mitochondrial membrane. We here used CRISPR-Cas9-mediated knockout HAP1 cells to shed further light on the function of TMBIM5 in physiology and cell death susceptibility.
View Article and Find Full Text PDF