scholarly journals Inorganic polyphosphate (polyP) is required for sustained free mitochondrial calcium elevation, following stimulated calcium uptake.

2018 ◽  
Author(s):  
Maria E Solesio ◽  
Luis C Garcia del Molino ◽  
Pia A Elustondo ◽  
Diao Catherine ◽  
Joshua C Chang ◽  
...  
Keyword(s):  
Calcium Uptake ◽  
Cellular Signaling ◽  
Living Cells ◽  
Free Calcium ◽  
Mitochondrial Calcium ◽  
Inorganic Polyphosphate ◽  
Physiological Conditions ◽  
Calcium Elevation

Mitochondrial free calcium is critically linked to the regulation of bioenergetics and cellular signaling. Free calcium concentrations within the organelle are regulated by two processes: flux across the mitochondrial inner membranes and buffering by phosphate. The key role of phosphate in the buffering of free calcium in mitochondria is well-established. Specifically, during stimulated calcium uptake, calcium is partially buffered by orthophosphate, allowing for elevated calcium concentrations, while preventing calcium toxicity. However, this buffering system is expected to lead to the irreversible formation of insoluble precipitates, which are not observed in living cells, under physiological conditions. Here, we demonstrate that the regulation of free mitochondrial calcium requires the presence of free inorganic polyphosphate (polyP) within the organelle. Specifically, we found that the verexpression of a mitochondrial targeted enzyme hydrolyzing polyP, leads to the loss of the cellular ability to maintain elevated calcium concentrations within the organelle, following stimulated cytoplasmic signal. We hypothesize that the presence of polyP prevents the formation of calciumphosphate insoluble clusters, allowing for the maintenance of elevated free calcium levels, during stimulated calcium uptake.

scholarly journals Inorganic polyphosphate is required for sustained free mitochondrial calcium elevation, following calcium uptake

Cell Calcium ◽  
2020 ◽  
Vol 86 ◽  
pp. 102127 ◽  
Author(s):  
Maria E. Solesio ◽  
Luis C. Garcia del Molino ◽  
Pia A. Elustondo ◽  
Catherine Diao ◽  
Joshua C. Chang ◽  
...  
Keyword(s):  
Calcium Uptake ◽  
Mitochondrial Calcium ◽  
Inorganic Polyphosphate ◽  
Calcium Elevation

Abstract 284: Loss of Micu3 Confers Cardioprotection Against Cardiac Injury

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Bao Puente ◽  
Junhui Sun ◽  
Maria Fergusson ◽  
Julia Liu ◽  
Anna Kosmach ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Calcium Uptake ◽  
Cardiac Injury ◽  
Mitochondrial Calcium ◽  
Wild Type ◽  
Ischemic Reperfusion ◽  
Mitochondrial Calcium Uptake

Background: Mitochondrial calcium flux and signaling is integral to cardiac function and contraction. However, during pathologic conditions such as ischemic/reperfusion injury, mitochondrial calcium overload can induce the opening of the mitochondrial permeability transitioning pore (PTP), resulting in the collapse of mitochondrial membrane potential, ATP depletion, and generation of reactive oxygen species, all together leading to cell death. Hence, modulation of mitochondrial calcium and inhibition of the PTP is a promising target for cardioprotection and prevention of cardiomyocyte death. The mitochondrial calcium uniporter (MCU) complex mediates rapid mitochondrial calcium uptake. MICU3 is a regulator of the MCU complex and has been shown to be a highly potent stimulator of MCU-dependent calcium uptake in neuronal cells. We found that MICU3 is expressed in hearts and we therefore investigated the role of MICU3 in the heart. We examined the role of MICU3 in the development of hypertrophy and in a separate study we examined the response to ischemic-reperfusion (I/R) injury. Given its role in regulating mitochondrial calcium uptake, we hypothesized that loss of MICU3 confers protection against cardiac injury. Methods: Mice with global deletion of Micu3 (Micu3 -/- ) were created utilizing CRISPR-Cas9 technology. Adult knockout and littermate wild type mice were treated with Isoproterenol (15mg/kg/day) for two weeks to induce hypertrophy. Echocardiograms were performed at baseline and after treatment to assess changes in left ventricular size and function. I/R injury was studied using Langendorff ex vivo perfused heart system, exposing knockout and wild type hearts to 20 minutes of ischemia and 90 minutes of reperfusion. Hemodynamic data and infarct size were collected and compared. Student t-test and 2-way ANOVA were used for statistical analysis. Result: Micu3 -/- mice had normal cardiac function at baseline. There was no sex difference in cardiac function. Micu3 -/- mice continued to show normal function after 2 weeks of treatment with Isoproterenol, whereas wild type mice exhibited depressed function (median FS 35% vs. 24% p = 0.0001, EF 64% vs. 50% p = 0.0001). Wild type mice developed LV dilation from baseline (median 4.15mm vs. 4.57mm, p = 0.0014), whereas LV dimension remained stable in Micu3 -/- mice (median 4.12mm vs. 4.18mm, p= 0.9892). Micu3 - /- mice were also protected from I/R injury. Compared to wild types, Micu3 -/- hearts demonstrated less contractile dysfunction at end reperfusion (median rate pressure product 62% vs. 41%, p = 0.002), and significantly smaller infarct size (median 33% vs. 53%, p = 0.0001). Conclusion: Loss of MICU3 confers cardioprotection against ischemic reperfusion injury and Isoproterenol induced cardiac dysfunction.

scholarly journals Role of mitochondrial calcium uptake homeostasis in resting state fMRI brain networks

2015 ◽  
Vol 28 (11) ◽  
pp. 1579-1588 ◽  
Author(s):  
Sridhar S. Kannurpatti ◽  
Basavaraju G. Sanganahalli ◽  
Peter Herman ◽  
Fahmeed Hyder
Keyword(s):  
Resting State ◽  
Calcium Uptake ◽  
Brain Networks ◽  
Resting State Fmri ◽  
Mitochondrial Calcium ◽  
Mitochondrial Calcium Uptake

Mechanisms of cytosolic calcium elevation in plants: the role of ion channels, calcium extrusion systems and NADPH oxidase-mediated 'ROS-Ca2+ Hub'

2018 ◽  
Vol 45 (2) ◽  
pp. 9 ◽  
Author(s):  
Vadim Demidchik ◽  
Sergey Shabala
Keyword(s):  
Calcium Influx ◽  
Gene Families ◽  
Cytosolic Calcium ◽  
Recent Experimental Data ◽  
Free Calcium ◽  
Cyclic Nucleotide Gated Channels ◽  
Physiological Reactions ◽  
Calcium Extrusion ◽  
Calcium Elevation

Elevation in the cytosolic free calcium is crucial for plant growth, development and adaptation. Calcium influx into plant cells is mediated by Ca2+ depolarisation-activated, hyperpolarisation-activated and voltage-independent Ca2+-permeable channels (DACCs, HACCs and VICCs respectively). These channels are encoded by the following gene families: (1) cyclic nucleotide-gated channels (CNGCs), (2) ionotropic glutamate receptors (GLRs), (3) annexins, (4) ‘mechanosensitive channels of small (MscS) conductance’-like channels (MSLs), (5) ‘mid1-complementing activity’ channels (MCAs), Piezo channels, and hyperosmolality-induced [Ca2+]cyt. channel 1 (OSCA1). Also, a ‘tandem-pore channel1’ (TPC1) catalyses Ca2+ efflux from the vacuole in response to the plasma membrane-mediated Ca2+ elevation. Recent experimental data demonstrated that Arabidopsis thaliana (L.) Heynh. CNGCs 2, 5–10, 14, 16 and 18, GLRs 1.2, 3.3, 3.4, 3.6 and 3.7, TPC1, ANNEXIN1, MSL9 and MSL10,MCA1 and MCA2, OSCA1, and some their homologues counterparts in other species, are responsible for Ca2+ currents and/or cytosolic Ca2+ elevation. Extrusion of Ca2+ from the cytosol is mediated by Ca2+-ATPases and Ca2+/H+ exchangers which were recently examined at the level of high resolution crystal structure. Calcium-activated NADPH oxidases and reactive oxygen species (ROS)-activated Ca2+ conductances form a self-amplifying ‘ROS-Ca2+hub’, enhancing and transducing Ca2+ and redox signals. The ROS-Ca2+ hub contributes to physiological reactions controlled by ROS and Ca2+, demonstrating synergism and unity of Ca2+ and ROS signalling mechanisms.

scholarly journals Structure of the MICU1–MICU2 heterodimer provides insights into the gatekeeping threshold shift

IUCrJ ◽  
2020 ◽  
Vol 7 (2) ◽  
pp. 355-365 ◽  
Author(s):  
Jongseo Park ◽  
Youngjin Lee ◽  
Taein Park ◽  
Jung Youn Kang ◽  
Sang A Mun ◽  
...  
Keyword(s):  
Calcium Uptake ◽  
Mitochondrial Calcium ◽  
Salt Bridges ◽  
Face To Face ◽  
Calcium Uniporter ◽  
Molecular Action ◽  
The Face ◽  
Mitochondrial Calcium Uptake ◽  
Apo State

Mitochondrial calcium uptake proteins 1 and 2 (MICU1 and MICU2) mediate mitochondrial Ca2+ influx via the mitochondrial calcium uniporter (MCU). Its molecular action for Ca2+ uptake is tightly controlled by the MICU1–MICU2 heterodimer, which comprises Ca2+ sensing proteins which act as gatekeepers at low [Ca2+] or facilitators at high [Ca2+]. However, the mechanism underlying the regulation of the Ca2+ gatekeeping threshold for mitochondrial Ca2+ uptake through the MCU by the MICU1–MICU2 heterodimer remains unclear. In this study, we determined the crystal structure of the apo form of the human MICU1–MICU2 heterodimer that functions as the MCU gatekeeper. MICU1 and MICU2 assemble in the face-to-face heterodimer with salt bridges and methionine knobs stabilizing the heterodimer in an apo state. Structural analysis suggests how the heterodimer sets a higher Ca2+ threshold than the MICU1 homodimer. The structure of the heterodimer in the apo state provides a framework for understanding the gatekeeping role of the MICU1–MICU2 heterodimer.

scholarly journals Increased mitochondrial calcium uniporter in adipocytes underlies mitochondrial alterations associated with insulin resistance

2017 ◽  
Vol 313 (6) ◽  
pp. E641-E650 ◽  
Author(s):  
Lauren E. Wright ◽  
Denis Vecellio Reane ◽  
Gabriella Milan ◽  
Anna Terrin ◽  
Giorgia Di Bello ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Calcium Uptake ◽  
Genetic Manipulation ◽  
Mitochondrial Calcium ◽  
Mitochondrial Calcium Uniporter ◽  
Insulin Resistant ◽  
Calcium Uniporter ◽  
Obesity And Diabetes ◽  
Mitochondrial Calcium Uptake

Intracellular calcium influences an array of pathways and affects cellular processes. With the rapidly progressing research investigating the molecular identity and the physiological roles of the mitochondrial calcium uniporter (MCU) complex, we now have the tools to understand the functions of mitochondrial Ca2+ in the regulation of pathophysiological processes. Herein, we describe the role of key MCU complex components in insulin resistance in mouse and human adipose tissue. Adipose tissue gene expression was analyzed from several models of obese and diabetic rodents and in 72 patients with obesity as well as in vitro insulin-resistant adipocytes. Genetic manipulation of MCU activity in 3T3-L1 adipocytes allowed the investigation of the role of mitochondrial calcium uptake. In insulin-resistant adipocytes, mitochondrial calcium uptake increased and several MCU components were upregulated. Similar results were observed in mouse and human visceral adipose tissue (VAT) during the progression of obesity and diabetes. Intriguingly, subcutaneous adipose tissue (SAT) was spared from overt MCU fluctuations. Furthermore, MCU expression returned to physiological levels in VAT of patients after weight loss by bariatric surgery. Genetic manipulation of mitochondrial calcium uptake in 3T3-L1 adipocytes demonstrated that changes in mitochondrial calcium concentration ([Ca2+]mt) can affect mitochondrial metabolism, including oxidative enzyme activity, mitochondrial respiration, membrane potential, and reactive oxygen species formation. Finally, our data suggest a strong relationship between [Ca2+]mt and the release of IL-6 and TNFα in adipocytes. Altered mitochondrial calcium flux in fat cells may play a role in obesity and diabetes and may be associated with the differential metabolic profiles of VAT and SAT.

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