Mitochondria in a variety of cell types respond to physiological Ca(2+) oscillations in the cytosol dynamically with Ca(2+) uptakes. In heart cells, mitochondrial Ca(2+) uptakes occur by a ruthenium red-sensitive Ca(2+) uniporter (CaUP), a rapid mode of Ca(2+) uptake (RaM) and a ryanodine receptor (RyR) localized in the inner mitochondrial membrane (IMM). Three subtypes of RyRs have been described and cloned, however, the subtype identity of the mitochondrial ryanodine receptor (mRyR) is unknown. Using subtype specific antibodies, we characterized the mRyR in the IMM from rat heart as RyR1. These results are substantiated by the absence of RyR protein in heart mitochondria from RyR1 knockout mice. The bell-shape Ca(2+)-dependent [(3)H]ryanodine binding curve and its modulation by caffeine and adenylylmethylenediphosphonate (AMPPCP) give further evidence that mRyR functions pharmacologically like RyR1. Ryanodine prevents mitochondrial Ca(2+) uptake induced by raising extramitochondrial Ca(2+) to 10 microM. Similarly, ryanodine inhibits oxidative phosphorylation stimulated by 10 microM extramitochondrial Ca(2+). In summary, our results show that the mRyR in cardiac muscle has similar biochemical and pharmacological properties to the RyR1 in the sarcoplasmic reticulum (SR) of skeletal muscle. These results could also suggest an efficient mechanism by which mitochondria sequesters Ca(2+) via mRyR during excitation-contraction coupling to stimulate oxidative phosphorylation for ATP production to meet metabolic demands. Thus, the mRyR functions as a transducer for excitation-metabolism coupling.
Intracellular Ca2+ is vital for cell physiology. Disruption of Ca2+ homeostasis contributes to human diseases such as heart failure, neuron-degeneration, and diabetes. To ensure an effective intracellular Ca2+ dynamics, various Ca2+ transport proteins localized in different cellular regions have to work in coordination. The central role of mitochondrial Ca2+ transport mechanisms in responding to physiological Ca2+ pulses in cytosol is to take up Ca2+ for regulating energy production and shaping the amplitude and duration of Ca2+ transients in various micro-domains. Since the discovery that isolated mitochondria can take up large quantities of Ca2+ approximately 5 decades ago, extensive studies have been focused on the functional characterization and implication of ion channels that dictate Ca2+ transport across the inner mitochondrial membrane. The mitochondrial Ca2+ uptake sensitive to non-specific inhibitors ruthenium red and Ru360 has long been considered as the activity of mitochondrial Ca2+ uniporter (MCU). The general consensus is that MCU is dominantly or exclusively responsible for the mitochondrial Ca2+ influx. Since multiple Ca2+ influx mechanisms (e.g. L-, T-, and N-type Ca2+ channel) have their unique functions in the plasma membrane, it is plausible that mitochondrial inner membrane has more than just MCU to decode complex intracellular Ca2+ signaling in various cell types. During the last decade, four molecular identities related to mitochondrial Ca2+ influx mechanisms have been identified. These are mitochondrial ryanodine receptor, mitochondrial uncoupling proteins, LETM1 (Ca2+/H+ exchanger), and MCU and its Ca2+ sensing regulatory subunit MICU1. Here, we briefly review recent progress in these and other reported mitochondrial Ca2+ influx pathways and their differences in kinetics, Ca2+ dependence, and pharmacological characteristics. Their potential physiological and pathological implications are also discussed.
Hydrogen peroxide (H2O2) is an endothelium-derived hyperpolarizing factor. Since opposing vasoactive effects have been reported for H2O2 depending on the vascular bed and experimental conditions, this study was performed to assess whether H2O2 acts as a vasodilator in the rat mesenteric artery and, if so, to determine the underlying mechanisms. H2O2 elicited concentration-dependent relaxation in mesenteric arteries precontracted with norepinephrine. The vasodilatory effect of H2O2 was reversed by treatment with dithiothreitol. H2O2-elicited vasodilation was significantly reduced by blocking 4-aminopyridine (4-AP)-sensitive Kv channels, but it was resistant to blockers of big-conductance Ca2+-activated K+ channels and inward rectifier K+ channels. A patch-clamp study in mesenteric arterial smooth muscle cells (MASMCs) showed that H2O2 increased Kv currents in a concentration-dependent manner. H2O2 speeded up Kv channel activation and shifted steady state activation to hyperpolarizing potentials. Similar channel activation was seen with oxidized glutathione (GSSG). The H2O2-mediated channel activation was prevented by glutathione reductase. Consistent with S-glutathionylation, streptavidin pull-down assays with biotinylated glutathione ethyl ester showed incorporation of glutathione (GSH) in the Kv channel proteins in the presence of H2O2. Interestingly, conditions of increased oxidative stress within MASMCs impaired the capacity of H2O2 to stimulate Kv channels. Not only was the H2O2 stimulatory effect much weaker, but the inhibitory effect of H2O2 was unmasked. These data suggest that H2O2 activates 4-AP-sensitive Kv channels, possibly through S-glutathionylation, which elicits smooth muscle relaxation in rat mesenteric arteries. Furthermore, our results support the idea that the basal redox status of MASMCs determines the response of Kv currents to H2O2.Electronic supplementary materialThe online version of this article (doi:10.1007/s00424-014-1513-3) contains supplementary material, which is available to authorized users.
We investigated the variation of current density–voltage (J–V) characteristics of an organic solar cell (OSC) in the dark and at 9 different light intensities ranging from 0.01 to 1 sun of the AM1.5G spectrum. All three conventional parameters, short-circuit currents (Jsc), open-circuit voltage (Voc), and Fill factor (FF), representing OSC performance evolved systematically in response to light intensity increase. Unlike Jsc that showed quasi-linear monotonic increase, Voc and FF showed distinctive non-monotonic variations. To elucidate the origin of such variations, we performed extensive simulation studies including Shockley–Read–Hall (SRH) recombination losses. Simulation results were sensitive to defect densities, and simultaneous agreement to 10 measured J–V curves was possible only with the defect density of $$5 \times 10^{12} {\text{ cm}}^{ - 3}$$ 5 × 10 12 cm - 3 . Based on analyses of simulation results, we were able to separate current losses into SRH- and bimolecular-recombination components and, moreover, identify that the competition between SRH- and bimolecular-loss currents were responsible for the aforementioned variations in Jsc, Voc, and FF. In particular, we verified that apparent demarcation in Voc, and FF variations, which seemed to appear at different light intensities, originated from the same mechanism of dominance switching between recombination losses.
We investigated operation of a planar MAPbI3 solar cell with respect to intensity variation ranging from 0.01 to 1 sun. Measured J-V curves consisted of space-charge-limited currents (SCLC) in a drift-dominant range and diode-like currents in a diffusion-dominant range. The variation of power-law exponent of SCLC showed that charge trapping by defects diminished as intensity increased, and that drift currents became eventually almost ohmic. Diode-like currents were analysed using a modified Shockley-equation model, the validity of which was confirmed by comparing measured and estimated open-circuit voltages. Intensity dependence of ideality factor led us to the conclusion that there were two other types of defects that contributed mostly as recombination centers. At low intensities, monomolecular recombination occurred due to one of these defects in addition to bimolecular recombination to result in the ideality factor of ~1.7. However, at high intensities, another type of defect not only took over monomolecular recombination, but also dominated bimolecular recombination to result in the ideality factor of ~2.0. These ideality-factor values were consistent with those representing the intensity dependence of loss-current ratio estimated by using a constant internal-quantum-efficiency approximation. The presence of multiple types of defects was corroborated by findings from equivalent-circuit analysis of impedance spectra.
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