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Background: Sepsis is a systemic inflammatory response to a local severe infection that can lead to multiple organ failure and ultimately death. Studies have shown that 40%-50% of septic patients have diverse myocardial injuries, with mortality ranging from 70% to 90% in contrast to 20% in septic patients without myocardial injury. Therefore, uncovering the mechanism of myocardial injury induced by sepsis and finding a treatment for the corresponding target are immensely important.Methods: We employed cecal ligation and puncture (CLP) for inducing sepsis in mice, and detect the situation of myocardial injury and cardiac function through serological markers and echocardiography. The cardiomyocytes apoptosis and the ultrastructural of heart tissue detected by TUNEL and transmission electron microscope (TEM) respectively. The Fura-2 AM was used to monitored Ca2+ uptake and efflux of mitochondria. FQ-PCR and Western blot detected the expression of mitochondria Ca2+ distribution regulators and PINK1. JC-1 was used to detected the mitochondrial membrane potential (Δψm) of cardiomyocytes. Results: We found that the expression of PINK1 decreased in mouse hearts during sepsis, which caused cardiomyocyte mitochondrial calcium efflux disorder, mitochondrial calcium overload and cardiomyocyte injury. In contrast, we found that exosomes isolated from huMSCs (huMSCs-exo) carried Pink1 mRNA that could be transferred to recipient cardiomyocytes, increasing PINK1 expression. Then, the reduction in cardiomyocyte mitochondrial calcium efflux was reversed, and cardiomyocytes recovered from their injury. Furthermore, we confirmed the effect of the PINK1-PKA-NCLX axis on mitochondrial calcium homeostasis in cardiomyocytes during sepsis.Conclusion: The PINK1-PKA-NCLX axis play an important role in cardiomyocytes mitochondrial calcium efflux, therefore PINK1 could be a therapeutic target to protect cardiomyocyte mitochondria, and the application of huMSCs-exo is a promising strategy against heart dysfunction induced by sepsis.

Mitochondrial Ca2+ transport is essential for regulating cell bioenergetics, Ca2+ signaling and cell death. Mitochondria accumulate Ca2+ via the mitochondrial Ca2+ uniporter (MCU), whereas Ca2+ is extruded by the mitochondrial Na+/Ca2+ (mtNCX) and H+/Ca2+ exchangers. The balance between these processes is essential for preventing toxic mitochondrial Ca2+ overload. Recent work demonstrated that MCU activity varies significantly among tissues, likely reflecting tissue-specific Ca2+ signaling and energy needs. It is less clear whether this diversity in MCU activity is matched by tissue-specific diversity in mitochondrial Ca2+ extrusion. Here we compared properties of mitochondrial Ca2+ extrusion in three tissues with prominent mitochondria function: brain, heart and liver. At the transcript level, expression of the Na+/Ca2+/Li+ exchanger (NCLX), which has been proposed to mediate mtNCX transport, was significantly greater in liver than in brain or heart. At the functional level, Na+ robustly activated Ca2+ efflux from brain and heart mitochondria, but not from liver mitochondria. The mtNCX inhibitor CGP37157 blocked Ca2+ efflux from brain and heart mitochondria but had no effect in liver mitochondria. Replacement of Na+ with Li+ to test the involvement of NCLX, resulted in a slowing of mitochondrial Ca2+ efflux by ∼70 %. Collectively, our findings suggest that mtNCX is responsible for Ca2+ extrusion from the mitochondria of the brain and heart, but plays only a small, if any, role in mitochondria of the liver. They also reveal that Li+ is significantly less effective than Na+ in driving mitochondrial Ca2+ efflux.

Because of its outstanding thermochromic characteristics and metal-insulator transition (MIT) property, nano-vanadium dioxide (abbreviated as nano-VO2 or nVO2) has been applied widely in electrical/optical devices and design of intelligent window. However, the biological effect of nVO2 is not well understood, especially when affected by environmental factors or living organisms. For VO2 is an amphoteric oxide, we simulated pH's influence to nVO2’s physicochemical properties by exposure nVO2 in water of different pH values. We found that nVO2 transformed to a new product after exposure in acidic water for two weeks, as revealed by physicochemical characterization such as SEM, TEM, XRD, and DLS. This transformation product formed in acidic water was referred as (acidic) transformed nVO2). Both pristine/untransformed and transformed nVO2 displayed no obvious toxicity to common epithelial cells; however, the acidic transformed nVO2 rapidly induced macrophage cell death. Further investigation demonstrated that transformed nVO2 caused macrophage apoptosis by the induction of Ca2+ efflux and the following mitochondrial membrane permeabilization (MMP) process. And a more detailed time course study indicated that transformed nVO2 caused lysosomal membrane permeabilization (LMP) at the earlier stage, indicating LMP could be chosen as an earlier and sensitive end point for nanotoxicological study. We conclude that although nVO2 displays no acute toxicity, its acidic transformation product induces macrophage apoptosis by the induction of LMP and Ca2+ efflux. This report suggests that the interplay with environmental factors or living organisms can results in physicochemical transformation of nanomaterials and the ensuing distinctive biological effects.

In many non-excitable eukaryotic cells, including hepatocytes, Ca(2+) oscillations play a key role in intra- and intercellular signalling, thus regulating many cellular processes from fertilisation to death. Therefore, understanding the mechanisms underlying these oscillations, and consequently understanding how they may be regulated, is of great interest. In this paper, we study the influence of reduced Ca(2+) plasma membrane efflux on Ca(2+) oscillations in hepatocytes. Our previous experiments with carboxyeosin show that a reduced plasma membrane Ca(2+) efflux increases the frequency of Ca(2+) oscillations, but does not affect the duration of individual transients. This phenomenon can be best explained by taking into account not only the temporal, but also the spatial dynamics underlying the generation of Ca(2+) oscillations in the cell. Here we divide the cell into a grid of elements and treat the Ca(2+) dynamics as a spatio-temporal phenomenon. By converting an existing temporal model into a spatio-temporal one, we obtain theoretical predictions that are in much better agreement with the experimental observations.

The G protein-coupled estrogen receptor 1 (GPER) has been demonstrated to have a vast array of cardiovascular effects. Ca2+ extrusion via the plasma membrane Ca2+-ATPase (PMCA) plays important role...

The effects of Pion sarcoplasmic reticulum (SR) Ca2+regulation were studied in mechanically skinned rat skeletal muscle fibers. Brief application of caffeine was used to assess the SR Ca2+content, and changes in concentration of Ca2+([Ca2+]) within the cytosol were detected with fura 2 fluorescence. Introduction of Pi(1–40 mM) induced a concentration-dependent Ca2+efflux from the SR. In solutions lacking creatine phosphate (CP), the amplitude of the Pi-induced Ca2+transient approximately doubled. A similar potentiation of Pi-induced Ca2+release occurred after inhibition of creatine kinase (CK) with 2,4-dinitrofluorobenzene. In the presence of ruthenium red or ryanodine, caffeine-induced Ca2+release was almost abolished, whereas Pi-induced Ca2+release was unaffected. However, introduction of the SR Ca2+ATPase inhibitor cyclopiazonic acid effectively abolished Pi-induced Ca2+release. These data suggest that Piinduces Ca2+release from the SR by reversal of the SR Ca2+pump but not via the SR Ca2+channel under these conditions. If this occurs in intact skeletal muscle during fatigue, activation of a Ca2+efflux pathway by Pimay contribute to the reported decrease in net Ca2+uptake and increase in resting [Ca2+].

The effect of extracellular adenosine 5′-triphosphate (ATP) on Ca 2+ efflux from freshly isolated adult rat cardiomyocytes was examined. ATP stimulated the efflux of 45 Ca 2+ from the cells in a concentration-dependent manner (0.01–1 mM). The 45 Ca 2+ efflux from the cells was also stimulated by adenosine-5′-O-(3-thiotriphosphate) (ATP-γs) and α,β-methylene-ATP and adenosine 5′-diphosphate, but not by adenosine 5′-monophosphate and adenosine. The ATP-stimulated 45 Ca 2+ efflux was not affected by deprivation of the extracellular Ca 2+ , but was dependent on the presence of extracellular Na + . These results indicate that ATP stimulates extracellular Na + -dependent 45 Ca 2+ efflux from freshly isolated adult rat cardiomyocytes, probably through its stimulatory effect on the plasma membrane P 2 purinoceptors which may couple to Na + /Ca 2+ exchange.

Tetraphenylphosphonium (TPP + ) inhibits Na + -stimulated Ca 2+ efflux from brain mitochondria. Half inhibition is observed when 1·10 −8 M TPP + is present in the medium. Some other lipophylic cations show similar effect. TPP + must be used carefully for measuring transmembrane potential because of its effects on the system studied. TPP + will be a useful tool to study Ca-transport system in mitochondria.

Bongkrekic acid and atractyloside, inhibitors of adenine nucleotide translocase, do not inhibit Ca2+ uptake and H+ production by pig heart mitochondria. However, bongkrekic acid, but not atractyloside, inhibits dinitrophenol-induced Ca2+ efflux and H+ uptake. Conversely, ruthenium red blocks Ca2+ uptake and H+ production but does not prevent dinitrophenol-induced Ca2+ efflux and H+ uptake by mitochondria. These results suggest that mitochondrial Ca2+ uptake and release exist as two independent pathways. The efflux of Ca2+ from mitochondria is mediated by a bongkrekic acid sensitive component which is apparently not identical to the ruthenium red sensitive Ca2+ uptake carrier.

1. Two processes of Ruthenium Red-insensitive Ca2+ efflux exist in liver and in heart mitochondria: one Na+-independent, and another Na+-dependent. The processes attain maximal rates of 1.4 and 3.0 nmol of Ca2+.min-1.mg-1 for the Na+-dependent and 1.2 and 2.0 nmol of Ca2+.min-1.mg-1 for the Na+-independent, in liver and heart mitochondria, respectively. 2. The Na+-dependent pathway is inhibited, both in heart and in liver mitochondria, by the Ca2+ antagonist diltiazem with a Ki of 4 microM. The Na+-independent pathway is inhibited by diltiazem with a Ki of 250 microM in liver mitochondria, while it behaves as almost insensitive to diltiazem in heart mitochondria. 3. Stretching of the mitochondrial inner membrane in hypo-osmotic media results in activation of the Na+-independent pathway both in liver and in heart mitochondria. 4. Both in heart and liver mitochondria the Na+-independent pathway is insensitive to variations of medium pH around physiological values, while the Na+-dependent pathway is markedly stimulated parallel with acidification of the medium. The pH-activated, Na+-dependent pathway maintains the diltiazem sensitivity. 5. In heart mitochondria, the Na+-dependent pathway is non-competitively inhibited by Mg2+ with a Ki of 0.27 mM, while the Na+-independent pathway is less affected; similarly, in liver mitochondria Mg2+ inhibits the Na+-dependent pathway more than it does the Na+-independent pathway. In the presence of physiological concentrations of Na+, Ca2+ and Mg2+, the Na+-independent and the Na+-dependent pathways operate at rates, respectively, of 0.5 and 1.0 nmol of Ca2+.min-1.mg-1 in heart mitochondria and 0.9 and 0.2 nmol of Ca2+.min-1.mg-1 in liver mitochondria. It is concluded that both heart and liver mitochondria possess two independent pathways for Ca2+ efflux operating at comparable rates.