Membrane associated complexes : new approach to calcium dynamics modelling (original) (raw)
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A Computational Model of Cytosolic and Mitochondrial [Ca2+] in Paced Rat Ventricular Myocytes
The Korean Journal of Physiology and Pharmacology, 2011
W e carried out a series of experiment demonstrating the role of mitochondria in the cytosolic and mitochondrial Ca 2＋ transients and compared the results with those from computer simulation. In rat ventricular myocytes, increasing the rate of stimulation (1∼ 3 Hz) made both the diastolic and systolic [Ca 2＋ ] bigger in mitochondria as well as in cytosol. As L-type Ca 2＋ channel has key influence on the amplitude of Ca 2＋-induced Ca 2＋ release, the relation between stimulus frequency and the amplitude of Ca 2＋ transients was examined under the low density (1/10 of control) of L-type Ca 2＋ channel in model simulation, where the relation was reversed. In experiment, block of Ca 2＋ uniporter on mitochondrial inner membrane significantly reduced the amplitude of mitochondrial Ca 2＋ transients, while it failed to affect the cytosolic Ca 2＋ transients. In computer simulation, the amplitude of cytosolic Ca 2＋ transients was not affected by removal of Ca 2＋ uniporter. The application of carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) known as a protonophore on mitochondrial membrane to rat ventricular myocytes gradually increased the diastolic [Ca 2＋ ] in cytosol and eventually abolished the Ca 2＋ transients, which was similarly reproduced in computer simulation. The model study suggests that the relative contribution of L-type Ca 2＋ channel to total transsarcolemmal Ca 2＋ flux could determine whether the cytosolic Ca 2＋ transients become bigger or smaller with higher stimulus frequency. The present study also suggests that cytosolic Ca 2＋ affects mitochondrial Ca 2＋ in a beat-to-beat manner, however, removal of Ca 2＋ influx mechanism into mitochondria does not affect the amplitude of cytosolic Ca 2＋ transients.
Journal of Biological Chemistry, 2003
To better understand the functional role of the mitochondrial network in shaping the Ca 2؉ signals in living cells, we took advantage both of the newest genetically engineered green fluorescent protein-based Ca 2؉ sensors ("Cameleons," "Camgaroos," and "Pericams") and of the classical Ca 2؉ -sensitive photoprotein aequorin, all targeted to the mitochondrial matrix. The properties of the green fluorescent protein-based probes in terms of subcellular localization, photosensitivity, and Ca 2؉ affinity have been analyzed in detail. It is concluded that the ratiometric pericam is, at present, the most reliable mitochondrial Ca 2؉ probe for single cell studies, although this probe too is not devoid of problems. The results obtained with ratiometric pericam in single cells, combined with those obtained at the population level with aequorin, provide strong evidence demonstrating that the close vicinity of mitochondria to the Ca 2؉ release channels (and thus responsible for the fast uptake of Ca 2؉ by mitochondria upon receptor activation) are highly stable in time, suggesting the existence of specific interactions between mitochondria and the endoplasmic reticulum.
Interplay Between Intracellular Ca2+ Oscillations and Ca2+-stimulated Mitochondrial Metabolism
Scientific Reports, 2016
Oscillations of cytosolic Ca 2+ concentration are a widespread mode of signalling. Oscillatory spikes rely on repetitive exchanges of Ca 2+ between the endoplasmic reticulum (ER) and the cytosol, due to the regulation of inositol 1,4,5-trisphosphate receptors. Mitochondria also sequester and release Ca 2+ , thus affecting Ca 2+ signalling. Mitochondrial Ca 2+ activates key enzymes involved in ATP synthesis. We propose a new integrative model for Ca 2+ signalling and mitochondrial metabolism in electrically nonexcitable cells. The model accounts for (1) the phase relationship of the Ca 2+ changes in the cytosol, the ER and mitochondria, (2) the dynamics of mitochondrial metabolites in response to cytosolic Ca 2+ changes, and (3) the impacts of cytosol/mitochondria Ca 2+ exchanges and of mitochondrial metabolism on Ca 2+ oscillations. Simulations predict that as expected, oscillations are slowed down by decreasing the rate of Ca 2+ efflux from mitochondria, but also by decreasing the rate of Ca 2+ influx through the mitochondrial Ca 2+ uniporter (MCU). These predictions were experimentally validated by inhibiting MCU expression. Despite the highly non-linear character of Ca 2+ dynamics and mitochondrial metabolism, bioenergetics were found to be robust with respect to changes in frequency and amplitude of Ca 2+ oscillations. In most organisms, mitochondria play an important role in ATP production and act as Ca 2+ stores, both functions of these organelles being tightly connected. Mitochondria sequester and release Ca 2+ , thereby affecting the shape, the frequency and the amplitude of the Ca 2+ spikes in the cytosol 1-3. In turn, increased mitochondrial Ca 2+ ([Ca 2+ ] m) linked to the transfer of Ca 2+ from the cytosol to mitochondria during [Ca 2+ ] c signals stimulates mitochondrial metabolism and allows the coupling of ATP supply with energy demand 4-7. At rest, [Ca 2+ ] m and [Ca 2+ ] c are similar, in the 100 nM range 8. Upon cell stimulation by an agonist, inositol 1,4,5-trisphosphate (IP 3) is produced and triggers cytosolic Ca 2+ oscillations 9. In non-excitable cells, these oscillations are due to a cyclical exchange of Ca 2+ between the cytosol and the endoplasmic reticulum (ER), through the biphasic regulation of the IP 3 receptor (IP 3 R) by cytosolic Ca 2+. Fast activation and slow inhibition of the opening of the IP 3 R by Ca 2+ indeed suffice to generate either Ca 2+ oscillations in classical deterministic models or repetitive spiking, if noise is considered to play a predominant role in cellular Ca 2+ dynamics 10-12. Ca 2+ entry into mitochondria occurs through a multistep mechanism. By extruding protons out of mitochondria, the respiratory chain creates a large inside-negative potential difference across the inner mitochondrial membrane. This Δ Ψ , which is harnessed by the ATP synthase for the production of ATP, allows the Mitochondrial Calcium Uniporter (MCU) to transport Ca 2+ inside mitochondria 13,14. Ca 2+ entry then depolarizes the mitochondria, thus reducing its own driving force. When [Ca 2+ ] c returns to its basal value, extrusion of Ca 2+ out of mitochondria occurs through both a Na +-Ca 2+ exchanger (NCX) and a H +-Ca 2+ exchanger, possibly identified as LETM1, although the contribution of this channel to mitochondrial Ca 2+ transport is not yet firmly established 15-17. Uptake by mitochondria of pyruvate, the end product of cytosolic glycolysis, is at the onset of the oxidative phosphorylation cascade. A pyruvate dehydrogenase transforms substrates into acetyl-CoA which enters the Krebs cycle, also called the acid citric cycle or tricarboxylic acid cycle (TCA). This 9-step cycle converts the
A membrane model for cytosolic calcium oscillations. A study using Xenopus oocytes
Biophysical Journal, 1992
Cytosolic calcium oscillations occur in a wide variety of cells and are involved in different cellular functions. We describe these calcium oscillations by a mathematical model based on the putative electrophysiological properties of the endoplasmic reticulum (ER) membrane. The salient features of our membrane model are calcium-dependent calcium channels and calcium pumps in the ER membrane, constant entry of calcium into the cytosol, calcium dependent removal from the cytosol, and buffering by cytoplasmic calcium binding proteins. Numerical integration of the model allows us to study the fluctuations in the cytosolic calcium concentration, the ER membrane potential, and the concentration of free calcium binding sites on a calcium binding protein. The model demonstrates the physiological features necessary for calcium oscillations and suggests that the level of calcium flux into the cytosol controls the frequency and amplitude of oscillations. The model also suggests that the level of buffering affects the frequency and amplitude of the oscillations. The model is supported by experiments indirectly measuring cytosolic calcium by calcium-induced chloride currents in Xenopus oocytes as well as cytosolic calcium oscillations observed in other preparations.
Calcium signaling around Mitochondria Associated Membranes (MAMs)
Cell Communication and Signaling, 2011
Calcium (Ca 2+ ) homeostasis is fundamental for cell metabolism, proliferation, differentiation, and cell death. Elevation in intracellular Ca 2+ concentration is dependent either on Ca 2+ influx from the extracellular space through the plasma membrane, or on Ca 2+ release from intracellular Ca 2+ stores, such as the endoplasmic/sarcoplasmic reticulum (ER/SR). Mitochondria are also major components of calcium signalling, capable of modulating both the amplitude and the spatio-temporal patterns of Ca 2+ signals. Recent studies revealed zones of close contact between the ER and mitochondria called MAMs (Mitochondria Associated Membranes) crucial for a correct communication between the two organelles, including the selective transmission of physiological and pathological Ca 2+ signals from the ER to mitochondria. In this review, we summarize the most up-to-date findings on the modulation of intracellular Ca 2+ release and Ca 2+ uptake mechanisms. We also explore the tight interplay between ER-and mitochondria-mediated Ca 2+ signalling, covering the structural and molecular properties of the zones of close contact between these two networks.
Mathematical model of mitochondrial ionic homeostasis: Three modes of Ca2+ transport
Journal of Theoretical Biology, 2006
Mitochondria play an important role in regulation of Ca 2+ homeostasis in a cell. Here we present a mathematical model of mitochondrial ion transport and use this model to analyse different modes of Ca 2+ uptake by mitochondria. The model includes transport of H + , Ca 2+ , K + , inorganic phosphate and oxidative substrates across the inner mitochondrial membrane harboring permeability transition pore (PTP). The detailed description of ion fluxes is based on the experimental ion kinetics in isolated mitochondria. Using the model we show that the kinetics of Ca 2+ uptake by mitochondria is regulated by the total amount of Ca 2+ in the system and the rate of Ca 2+ infusion. Varying these parameters we find three different modes of ion transport. When the total amount of Ca 2+ is below 140 nmol Ca 2+ /mg protein, all available Ca 2+ is accumulated in the matrix without activation of the PTP. Between 140 and 160 nmol Ca 2+ /mg protein, accumulation of Ca 2+ generates periodic opening and closure of the PTP and oscillations of ion fluxes. Higher levels of Ca 2+ (4160 nmol Ca 2+ /mg protein) result in a permanently open PTP, membrane depolarization and loss of small ions from the matrix. We show that in the intermediate range of Ca 2+ concentrations the rate of Ca 2+ infusion regulates the PTP state, so that slow Ca 2+ infusion does not lead to PTP opening, while fast Ca 2+ infusion results in an oscillatory state. r J uni -the rate of Ca 2+ flux via a mitochondrial Ca 2+ uniporter; J CaH -the rate of Ca 2+ and/or H + fluxes via an electroneutral Ca/2H exchanger; J H,res -the rate of H + flux via the respiratory chain, supported by NADH oxidation; J H,leak -the rate of back-flow of H + ions via ''leakage'' of the mitochondrial membrane; J K -the rate of K + flux via the mitochondrial K + uniporter; J KH -the rate of K + and/or H + fluxes via an electroneutral K/H exchanger; J POH -the rate of inorganic phosphate flux via a mitochondrial P/OH exchanger; J dic -the rate of P 2À and A 2À fluxes via a mitochondrial dicarboxylic acid exchanger; J NADH -the rate of NADH recovery from NAD by matrix dehydrogenases; L Ca , L CaÀP , L CaÀA , L A , L K , L P À , L P 2À , L H -the rates of corresponding ion fluxes via PTP.
Annals of the New York Academy of Sciences, 2005
The goal of this study is to examine whether there is a difference in the regulation of Ca 2+ between mitochondria near the cell surface and mitochondria in the cytosol. Total internal reflection fluorescence and epifluorescence microscopy were used to monitor changes in the mitochondrial Ca 2+ ([Ca 2+ ] mt ) between the mitochondria near the plasma membrane and those in the cytosol. The results show that [Ca 2+ ] mt near the plasma membrane increased earlier and decayed slower after high K + stimulation than average mitochondria in the cytosol. In addition, the changes in [Ca 2+ ] mt in the mitochondria near the cell surface after a second stimulation were larger than those induced by the first stimulation. The results provide direct evidence to support the hypothesis that mitochondria in different subcellular localization show differential responses to the influx of extracellular Ca 2+ .
Identification and modeling of calcium dynamics in cardiac myocytes
Simulation Practice and Theory, 2000
Calcium plays an essential role as a messenger and as a factor in cardiac contraction. In the present study, a model for Ca2+ handling in cardiac cells is presented. After the identification of the sarcoplasmic reticulum (SR) parameters, the SERCA pump and ryanodine channels activities, a comparison is made between experimental and calculated responses. The model's parameters were identified using optimization methods. This identification is based on the response of the digitonin permeabilized cells. The model deals with the dynamics of the calcium exchange between the different compartments of the cell. Cell compartments involved are the SR, the cytosol and the extra-cellular medium. The different components of the mathematical models are discussed and compared. The modeling and simulation are run within Ψlab,1 a freeware for modeling and simulation of dynamic systems.
Modulation of Calcium Entry by Mitochondria
Advances in experimental medicine and biology, 2016
The role of mitochondria in intracellular Ca(2+) signaling relies mainly in its capacity to take up Ca(2+) from the cytosol and thus modulate the cytosolic [Ca(2+)]. Because of the low Ca(2+)-affinity of the mitochondrial Ca(2+)-uptake system, this organelle appears specially adapted to take up Ca(2+) from local high-Ca(2+) microdomains and not from the bulk cytosol. Mitochondria would then act as local Ca(2+) buffers in cellular regions where high-Ca(2+) microdomains form, that is, mainly close to the cytosolic mouth of Ca(2+) channels, both in the plasma membrane and in the endoplasmic reticulum (ER). One of the first targets proposed already in the 1990s to be regulated in this way by mitochondria were the store-operated Ca(2+) channels (SOCE). Mitochondria, by taking up Ca(2+) from the region around the cytosolic mouth of the SOCE channels, would prevent its slow Ca(2+)-dependent inactivation, thus keeping them active for longer. Since then, evidence for this mechanism has accum...