scholarly journals ER–Mitochondria contact sites: A new regulator of cellular calcium flux comes into play

2016 ◽  
Vol 214 (4) ◽  
pp. 367-370 ◽  
Author(s):  
Michiel Krols ◽  
Geert Bultynck ◽  
Sophie Janssens
Keyword(s):  
Endoplasmic Reticulum ◽  
Calcium Signaling ◽  
Calcium Pump ◽  
Calcium Flux ◽  
Mitochondrial Calcium ◽  
Mitochondrial Bioenergetics ◽  
Cellular Calcium ◽  
Contact Sites ◽  
Cell Biol ◽  
Membrane Contacts

Endoplasmic reticulum (ER)–mitochondria membrane contacts are hotspots for calcium signaling. In this issue, Raturi et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201512077) show that the thioredoxin TMX1 inhibits the calcium pump SERCA2b at ER–mitochondria contact sites, thereby affecting ER–mitochondrial calcium transfer and mitochondrial bioenergetics.

scholarly journals Astroglial calcium transfer from endoplasmic reticulum to mitochondria determines synaptic integration

2020 ◽  
Author(s):  
Roman Serrat ◽  
Ana Covelo ◽  
Vladimir Kouskoff ◽  
Sebastien Delcasso ◽  
Andrea Ruiz ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Calcium Signaling ◽  
Intracellular Calcium ◽  
Hippocampal Slices ◽  
Cytosolic Calcium ◽  
Brain Network ◽  
Synaptic Integration ◽  
Mitochondrial Calcium ◽  
Intracellular Calcium Signaling ◽  
Electrophysiological Recordings

SummaryIntracellular calcium signaling underlies the astroglial control of synaptic transmission and plasticity. Mitochondria-endoplasmic reticulum contacts (MERCs) are key determinants of calcium dynamics, but their functional impact on astroglial regulation of brain information processing is currently unexplored. We found that the activation of astrocyte mitochondrial-associated CB1 receptors (mtCB1) determines MERCs-dependent intracellular calcium signaling and synaptic integration. The stimulation of mtCB1 receptors promotes calcium transfer from the endoplasmic reticulum to mitochondria through specific mechanisms regulating the activity of the mitochondrial calcium uniporter (MCU) channel. Physiologically, mtCB1-dependent mitochondrial calcium uptake determines the precise dynamics of cytosolic calcium events in astrocytes upon endocannabinoid mobilization. Accordingly, electrophysiological recordings in hippocampal slices showed that genetic exclusion of mtCB1 receptors or specific astroglial MCU inhibition blocks lateral synaptic potentiation, a key example of astrocyte-dependent integration of distant synapses activity. Altogether, these data reveal an unforeseen link between astroglial MERCs and the regulation of brain network functions.

Abstract P467: Cardiac-specific Deletion Of Voltage Dependent Anion Channel 2 Leads To Dilated Cardiomyopathy By Altering Calcium Homeostasis

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Thirupura S Shankar ◽  
Dinesh Kumar Anandamurugan Ramadurai ◽  
Kira Steinhorst ◽  
Salah Sommakia ◽  
Rachit Badolia ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Calcium Signaling ◽  
Calcium Homeostasis ◽  
Calcium Uptake ◽  
Mitochondrial Calcium ◽  
Voltage Dependent Anion Channel ◽  
Knock Out ◽  
Cellular Calcium ◽  
Mitochondrial Calcium Uptake

Voltage dependent anion channel 2 (VDAC2) is a mitochondrial outer membrane porin known to play a significant role in apoptosis and calcium signaling. Abnormalities in cellular calcium homeostasis often leads to electrical and contractile dysfunction and can cause dilated cardiomyopathy and heart failure. Previous literature suggests that improving mitochondrial calcium uptake via VDAC2 rescues arrhythmia phenotypes in genetic models of impaired cellular calcium signaling. However, the direct role of VDAC2 in intracellular calcium signaling and cardiac function is not well understood. To elucidate the role of VDAC2 in calcium homeostasis, we generated a cardiac-specific deletion of Vdac2 in mice. Our results indicate that loss of VDAC2 in the myocardium during development causes severe impairment in excitation-contraction coupling by reducing mitochondrial calcium uptake (n=3, p<0.05) and thereby impairing intracellular calcium signaling. VDAC2 knock-out mice showed a significant reduction in RYR-mediated calcium release (F/F 0 ) and rate of calcium uptake by SERCA2a [tau(msec)] compared to control mice (N=3, WT=54, KO=38, p<0.0001 (F/F 0 ) and p<0.05 (tau)). We also observed adverse cardiac remodeling which progressed to severe dilated cardiomyopathy and death (N=6, p<0.0001). Reintroducing VDAC2 in 6-week-old knock-out mice partially rescued the cardiomyopathy phenotype evident from improvement in ejection fraction and fractional shortening (n=3, p<0.05). Improving mitochondrial calcium uptake via VDAC2 using a VDAC2 agonist efsevin, increased cardiac contractile force in a mouse model of pressure-overload induced heart failure (N=8, n=22, p<0.05). In conclusion, our findings demonstrate that VDAC2 plays a crucial role in cardiac function by influencing mitochondrial and cellular calcium signaling. Through this role in cellular calcium dynamics and excitation-contraction coupling VDAC2 emerges as a plausible therapeutic target for heart failure.

scholarly journals ORP5 Transfers Phosphatidylserine To Mitochondria And Regulates Mitochondrial Calcium Uptake At Endoplasmic Reticulum - Mitochondria Contact Sites

2019 ◽  
Author(s):  
Leila Rochin ◽  
Cécile Sauvanet ◽  
Eeva Jääskeläinen ◽  
Audrey Houcine ◽  
Amita Arora ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Mammalian Cells ◽  
Calcium Uptake ◽  
Vesicular Transport ◽  
Mitochondrial Calcium ◽  
Mitochondrial Membranes ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact ◽  
Mitochondrial Calcium Uptake

SUMMARYMitochondria are dynamic organelles essential for cell survival whose structural and functional integrity rely on selective and regulated transport of lipids from/to the endoplasmic reticulum (ER) and across the two mitochondrial membranes. As they are not connected by vesicular transport, the exchange of lipids between ER and mitochondria occurs at sites of close organelle apposition called membrane contact sites. However, the mechanisms and proteins involved in these processes are only beginning to emerge. Here, we show that ORP5/8 mediate non-vesicular transport of Phosphatidylserine (PS) from the ER to mitochondria in mammalian cells. We also show that ER-mitochondria contacts where ORP5/8 reside are physically and functionally linked to the MIB/MICOS complexes that bridge the mitochondrial membranes, cooperating with them to facilitate PS transfer from the ER to the mitochondria. Finally, we show that ORP5 but not ORP8, additionally regulates import of calcium to mitochondria and consequently cell senescence.

MCU-complex-mediated mitochondrial calcium signaling is impaired in Barth syndrome

2021 ◽  
Author(s):  
Sagnika Ghosh ◽  
Mohammad Zulkifli ◽  
Alaumy Joshi ◽  
Manigandan Venkatesan ◽  
Allen Cristel ◽  
...  
Keyword(s):  
Calcium Signaling ◽  
Cardiac Tissue ◽  
Barth Syndrome ◽  
Regulatory Subunit ◽  
Mitochondrial Calcium ◽  
Mitochondrial Bioenergetics ◽  
Mouse Muscle ◽  
Calcium Dependent ◽  
The Stability ◽  
Mitochondrial Calcium Uptake

Abstract Calcium signaling via mitochondrial calcium uniporter (MCU) complex coordinates mitochondrial bioenergetics with cellular energy demands. Emerging studies show that the stability and activity of the pore-forming subunit of the complex, MCU, is dependent on the mitochondrial phospholipid, cardiolipin (CL), but how this impacts calcium-dependent mitochondrial bioenergetics in CL-deficiency disorder like Barth syndrome (BTHS) is not known. Here we utilized multiple models of BTHS including yeast, mouse muscle cell line, as well as BTHS patient cells and cardiac tissue to show that CL is required for the abundance and stability of the MCU-complex regulatory subunit MICU1. Interestingly, the reduction in MICU1 abundance in BTHS mitochondria is independent of MCU. Unlike MCU and MICU1/MICU2, other subunit and associated factor of the uniporter complex, EMRE and MCUR1, respectively, are not affected in BTHS models. Consistent with the decrease in MICU1 levels, we show that the kinetics of MICU1-dependent mitochondrial calcium uptake is perturbed and acute stimulation of mitochondrial calcium signaling in BTHS myoblasts fails to activate pyruvate dehydrogenase, which in turn impairs the generation of reducing equivalents and blunts mitochondrial bioenergetics. Taken together, our findings suggest that defects in mitochondrial calcium signaling could contribute to cardiac and skeletal muscle pathologies observed in BTHS patients.

scholarly journals Getting a handle on lipid droplets: Insights into ER–lipid droplet tethering

2019 ◽  
Vol 218 (4) ◽  
pp. 1089-1091 ◽  
Author(s):  
Truc B. Nguyen ◽  
James A. Olzmann
Keyword(s):  
Endoplasmic Reticulum ◽  
Lipid Metabolism ◽  
Lipid Droplet ◽  
Lipid Droplets ◽  
Human Cells ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Cell Biol ◽  
Membrane Contact

Lipid droplets (LDs) are hubs for lipid metabolism that form membrane contact sites with multiple organelles. In this issue, Hariri et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201808119) reveal the functions of Mdm1-mediated endoplasmic reticulum (ER)–LD tethering in yeast and Datta et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201808133) identify a role for the Mdm1 orthologue, Snx14, as an ER–LD tether that regulates lipid metabolism in human cells.

scholarly journals Re-evaluation of the Role of Calcium Homeostasis Endoplasmic Reticulum Protein (CHERP) in Cellular Calcium Signaling

2012 ◽  
Vol 288 (1) ◽  
pp. 355-367 ◽  
Author(s):  
Yaping Lin-Moshier ◽  
Peter J. Sebastian ◽  
LeeAnn Higgins ◽  
Natalie D. Sampson ◽  
Jane E. Hewitt ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Calcium Signaling ◽  
Calcium Homeostasis ◽  
Cellular Calcium ◽  
Endoplasmic Reticulum Protein

scholarly journals ER-mitochondria contacts underline cannabinoid regulation of calcium signaling in astrocytes

2021 ◽  
Author(s):  
Roman Serrat ◽  
Ana Covelo ◽  
Vladimir Kouskoff ◽  
Sebastien Delcasso ◽  
Andrea Ruiz-Calvo ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Calcium Signaling ◽  
Intracellular Calcium ◽  
Hippocampal Slices ◽  
Dominant Negative ◽  
Calcium Handling ◽  
Mitochondrial Calcium ◽  
Brain Functions ◽  
Intracellular Calcium Signaling

Abstract Intracellular calcium signaling underlies the astroglial control of brain functions. However, the cellular mechanisms regulating calcium handling by astrocytes are far from being understood. Mitochondria-endoplasmic reticulum contacts (MERCs) are key determinants of calcium dynamics, but their functional impact on astroglial regulation of brain information processing is currently unexplored. Here we show that the activation of astrocyte mitochondrial-associated CB1 receptors (mtCB1) regulates MERCs-dependent intracellular calcium signaling, thereby determining the synaptic functions of these cells. In vitro and in vivo stimulation of mtCB1 receptors promotes calcium transfer from the endoplasmic reticulum to mitochondria through a specific molecular cascade, involving AKT signaling, IPR3 receptors and different components of the mitochondrial calcium uniporter complex (MCU). Physiologically, mtCB1-dependent mitochondrial calcium uptake determines the dynamics of cytosolic calcium events in astrocytes upon endocannabinoid mobilization. Accordingly, electrophysiological recordings in hippocampal slices showed that astrocyte-specific mtCB1 receptors exclusion or dominant negative MCU expression blocks lateral synaptic potentiation, through which astrocytes integrate the activity of distant synapses. Altogether, these data reveal a cellular endocannabinoid link between astroglial MERCs and the regulation of brain network functions.

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