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1
Wang, Guang Jian, and Stanley A. Thayer. "NMDA-Induced Calcium Loads Recycle Across the Mitochondrial Inner Membrane of Hippocampal Neurons in Culture." Journal of Neurophysiology 87, no. 2 (February 1, 2002): 740–49. http://dx.doi.org/10.1152/jn.00345.2001.
Повний текст джерелаАнотація:
Mitochondria sequester N-methyl-d-aspartate (NMDA)-induced Ca2+ loads and regulate the shape of intracellular Ca2+ concentration ([Ca2+]i) responses in neurons. When isolated mitochondria are exposed to high [Ca2+],Ca2+ enters the matrix via the uniporter and returns to the cytosol by Na+/Ca2+ exchange. Released Ca2+ may re-enter the mitochondrion recycling across the inner membrane dissipating respiratory energy. Ca2+ recycling, the continuous uptake and release of Ca2+ by mitochondria, has not been described in intact neurons. Here we used single-cell microfluorimetry to measure [Ca2+]i and mitochondrially targeted aequorin to measure matrix Ca2+ concentration ([Ca2+]mt) to determine whether Ca2+ recycles across the mitochondrial inner membrane in intact neurons following treatment with NMDA. We used ruthenium red and CGP 37157 to block uptake via the uniporter and release via Na+/Ca2+exchange, respectively. As predicted by the Ca2+recycling hypothesis, blocking the uniporter immediately following challenge with 200 μM NMDA produced a rapid and transient increase in cytosolic Ca2+ without a corresponding increase in matrix Ca2+. Blocking mitochondrial Ca2+ release produced the opposite effect, depressing cytosolic Ca2+ levels and prolonging the time for matrix Ca2+ levels to recover. The Ca2+ recycling hypothesis uniquely predicts these reciprocal changes in the Ca2+ levels between the two compartments. Ca2+ recycling was not detected following treatment with 20 μM NMDA. Thus Ca2+recycling across the inner membrane was more pronounced following treatment with a high relative to a low concentration of NMDA, consistent with a role in Ca2+-dependent neurotoxicity.
2
Dubinin, Mikhail V., Eugeny Yu Talanov, Kirill S. Tenkov, Vlada S. Starinets, Natalia V. Belosludtseva, and Konstantin N. Belosludtsev. "The Effect of Deflazacort Treatment on the Functioning of Skeletal Muscle Mitochondria in Duchenne Muscular Dystrophy." International Journal of Molecular Sciences 21, no. 22 (November 19, 2020): 8763. http://dx.doi.org/10.3390/ijms21228763.
Повний текст джерелаАнотація:
Duchenne muscular dystrophy (DMD) is a severe hereditary disease caused by a lack of dystrophin, a protein essential for myocyte integrity. Mitochondrial dysfunction is reportedly responsible for DMD. This study examines the effect of glucocorticoid deflazacort on the functioning of the skeletal-muscle mitochondria of dystrophin-deficient mdx mice and WT animals. Deflazacort administration was found to improve mitochondrial respiration of mdx mice due to an increase in the level of ETC complexes (complexes III and IV and ATP synthase), which may contribute to the normalization of ATP levels in the skeletal muscle of mdx animals. Deflazacort treatment improved the rate of Ca2+ uniport in the skeletal muscle mitochondria of mdx mice, presumably by affecting the subunit composition of the calcium uniporter of organelles. At the same time, deflazacort was found to reduce the resistance of skeletal mitochondria to MPT pore opening, which may be associated with a change in the level of ANT2 and CypD. In this case, deflazacort also affected the mitochondria of WT mice. The paper discusses the mechanisms underlying the effect of deflazacort on the functioning of mitochondria and contributing to the improvement of the muscular function of mdx mice.
3
Rimessi, Alessandro, Chiara Pozzato, Lorenzo Carparelli, Alice Rossi, Serena Ranucci, Ida De Fino, Cristina Cigana, et al. "Pharmacological modulation of mitochondrial calcium uniporter controls lung inflammation in cystic fibrosis." Science Advances 6, no. 19 (May 2020): eaax9093. http://dx.doi.org/10.1126/sciadv.aax9093.
Повний текст джерелаАнотація:
Mitochondria physically associate with the endoplasmic reticulum to coordinate interorganelle calcium transfer and regulate fundamental cellular processes, including inflammation. Deregulated endoplasmic reticulum–mitochondria cross-talk can occur in cystic fibrosis, contributing to hyperinflammation and disease progression. We demonstrate that Pseudomonas aeruginosa infection increases endoplasmic reticulum–mitochondria associations in cystic fibrosis bronchial cells by stabilizing VAPB-PTPIP51 (vesicle-associated membrane protein–associated protein B–protein tyrosine phosphatase interacting protein 51) tethers, affecting autophagy. Impaired autophagy induced mitochondrial unfolding protein response and NLRP3 inflammasome activation, contributing to hyperinflammation. The mechanism by which VAPB-PTPIP51 tethers regulate autophagy in cystic fibrosis involves calcium transfer via mitochondrial calcium uniporter. Mitochondrial calcium uniporter inhibition rectified autophagy and alleviated the inflammatory response in vitro and in vivo, resulting in a valid therapeutic strategy for cystic fibrosis pulmonary disease.
4
Naon, Deborah, Marta Zaninello, Marta Giacomello, Tatiana Varanita, Francesca Grespi, Sowmya Lakshminaranayan, Annalisa Serafini, et al. "Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum–mitochondria tether." Proceedings of the National Academy of Sciences 113, no. 40 (September 19, 2016): 11249–54. http://dx.doi.org/10.1073/pnas.1606786113.
Повний текст джерелаАнотація:
The discovery of the multiple roles of mitochondria–endoplasmic reticulum (ER) juxtaposition in cell biology often relied upon the exploitation of Mitofusin (Mfn) 2 as an ER–mitochondria tether. However, this established Mfn2 function was recently questioned, calling for a critical re-evaluation of Mfn2’s role in ER–mitochondria cross-talk. Electron microscopy and fluorescence-based probes of organelle proximity confirmed that ER–mitochondria juxtaposition was reduced by constitutive or acute Mfn2 deletion. Functionally, mitochondrial uptake of Ca2+ released from the ER was reduced following acute Mfn2 ablation, as well as in Mfn2−/− cells overexpressing the mitochondrial calcium uniporter. Mitochondrial Ca2+ uptake rate and extent were normal in isolated Mfn2−/− liver mitochondria, consistent with the finding that acute or chronic Mfn2 ablation or overexpression did not alter mitochondrial calcium uniporter complex component levels. Hence, Mfn2 stands as a bona fide ER–mitochondria tether whose ablation decreases interorganellar juxtaposition and communication.
5
Tedesco, Scattolini, Albiero, Bortolozzi, Avogaro, Cignarella, and Fadini. "Mitochondrial Calcium Uptake Is Instrumental to Alternative Macrophage Polarization and Phagocytic Activity." International Journal of Molecular Sciences 20, no. 19 (October 8, 2019): 4966. http://dx.doi.org/10.3390/ijms20194966.
Повний текст джерелаАнотація:
Macrophages are highly plastic and dynamic cells that exert much of their function through phagocytosis. Phagocytosis depends on a coordinated, finely tuned, and compartmentalized regulation of calcium concentrations. We examined the role of mitochondrial calcium uptake and mitochondrial calcium uniporter (MCU) in macrophage polarization and function. In primary cultures of human monocyte-derived macrophages, calcium uptake in mitochondria was instrumental for alternative (M2) macrophage polarization. Mitochondrial calcium uniporter inhibition with KB-R7943 or MCU knockdown, which prevented mitochondrial calcium uptake, reduced M2 polarization, while not affecting classical (M1) polarization. Challenging macrophages with E. coli fragments induced spikes of mitochondrial calcium concentrations, which were prevented by MCU inhibition or silencing. In addition, mitochondria remodelled in M2 macrophages during phagocytosis, especially close to sites of E. coli internalization. Remarkably, inhibition or knockdown of MCU significantly reduced the phagocytic capacity of M2 macrophages. KB-R7943, which also inhibits the membrane sodium/calcium exchanger and Complex I, reduced mitochondria energization and cellular ATP levels, but such effects were not observed with MCU silencing. Therefore, phagocytosis inhibition by MCU knockdown depended on the impaired mitochondrial calcium buffering rather than changes in mitochondrial and cellular energy status. These data uncover a new role for MCU in alternative macrophage polarization and phagocytic activity.
6
Zhang, Linlin, Jingyi Qi, Xu Zhang, Xiya Zhao, Peng An, Yongting Luo, and Junjie Luo. "The Regulatory Roles of Mitochondrial Calcium and the Mitochondrial Calcium Uniporter in Tumor Cells." International Journal of Molecular Sciences 23, no. 12 (June 15, 2022): 6667. http://dx.doi.org/10.3390/ijms23126667.
Повний текст джерелаАнотація:
Mitochondria, as the main site of cellular energy metabolism and the generation of oxygen free radicals, are the key switch for mitochondria-mediated endogenous apoptosis. Ca2+ is not only an important messenger for cell proliferation, but it is also an indispensable signal for cell death. Ca2+ participates in and plays a crucial role in the energy metabolism, physiology, and pathology of mitochondria. Mitochondria control the uptake and release of Ca2+ through channels/transporters, such as the mitochondrial calcium uniporter (MCU), and influence the concentration of Ca2+ in both mitochondria and cytoplasm, thereby regulating cellular Ca2+ homeostasis. Mitochondrial Ca2+ transport-related processes are involved in important biological processes of tumor cells including proliferation, metabolism, and apoptosis. In particular, MCU and its regulatory proteins represent a new era in the study of MCU-mediated mitochondrial Ca2+ homeostasis in tumors. Through an in-depth analysis of the close correlation between mitochondrial Ca2+ and energy metabolism, autophagy, and apoptosis of tumor cells, we can provide a valuable reference for further understanding of how mitochondrial Ca2+ regulation helps diagnosis and therapy.
7
MONTERO, Mayte, Carmen D. LOBATÓN, Esther HERNÁNDEZ-SANMIGUEL, Jaime SANTODOMINGO, Laura VAY, Alfredo MORENO, and Javier ALVAREZ. "Direct activation of the mitochondrial calcium uniporter by natural plant flavonoids." Biochemical Journal 384, no. 1 (November 9, 2004): 19–24. http://dx.doi.org/10.1042/bj20040990.
Повний текст джерелаАнотація:
During cell activation, mitochondria play an important role in Ca2+ homoeostasis due to the presence of a fast and specific Ca2+ channel in its inner membrane, the mitochondrial Ca2+ uniporter. This channel allows mitochondria to buffer local cytosolic [Ca2+] changes and controls the intramitochondrial Ca2+ levels, thus modulating a variety of phenomena from respiratory rate to apoptosis. We have described recently that SB202190, an inhibitor of p38 MAPK (mitogen-activated protein kinase), strongly activated the uniporter. We show in the present study that a series of natural plant flavonoids, widely distributed in foods, produced also a strong stimulation of the mitochondrial Ca2+ uniporter. This effect was of the same magnitude as that induced by SB202190 (an approx. 20-fold increase in the mitochondrial Ca2+ uptake rate), developed without measurable delay and was rapidly reversible. In intact cells, the mitochondrial Ca2+ peak induced by histamine was also largely increased by the flavonoids. Stimulation of the uniporter by either flavonoids or SB202190 did not require ATP, suggesting a direct effect on the uniporter or an associated protein which is not mediated by protein phosphorylation. The most active compound, kaempferol, increased the rate of mitochondrial Ca2+ uptake by 85±15% (mean±S.E.M., n=4) and the histamine-induced mitochondrial Ca2+ peak by 139±19% (mean±S.E.M., n=5) at a concentration of 1 μM. Given that flavonoids can reach this concentration range in plasma after ingestion of flavonoid-rich food, these compounds could be modulating the uniporter under physiological conditions.
8
Satrústegui, Jorgina, Beatriz Pardo, and Araceli del Arco. "Mitochondrial Transporters as Novel Targets for Intracellular Calcium Signaling." Physiological Reviews 87, no. 1 (January 2007): 29–67. http://dx.doi.org/10.1152/physrev.00005.2006.
Повний текст джерелаАнотація:
Ca2+signaling in mitochondria is important to tune mitochondrial function to a variety of extracellular stimuli. The main mechanism is Ca2+entry in mitochondria via the Ca2+uniporter followed by Ca2+activation of three dehydrogenases in the mitochondrial matrix. This results in increases in mitochondrial NADH/NAD ratios and ATP levels and increased substrate uptake by mitochondria. We review evidence gathered more than 20 years ago and recent work indicating that substrate uptake, mitochondrial NADH/NAD ratios, and ATP levels may be also activated in response to cytosolic Ca2+signals via a mechanism that does not require the entry of Ca2+in mitochondria, a mechanism depending on the activity of Ca2+-dependent mitochondrial carriers (CaMC). CaMCs fall into two groups, the aspartate-glutamate carriers (AGC) and the ATP-Mg/Picarriers, also named SCaMC (for short CaMC). The two mammalian AGCs, aralar and citrin, are members of the malate-aspartate NADH shuttle, and citrin, the liver AGC, is also a member of the urea cycle. Both types of CaMCs are activated by Ca2+in the intermembrane space and function together with the Ca2+uniporter in decoding the Ca2+signal into a mitochondrial response.
9
Tsai, Chen-Wei, Yujiao Wu, Ping-Chieh Pao, Charles B. Phillips, Carole Williams, Christopher Miller, Matthew Ranaghan, and Ming-Feng Tsai. "Proteolytic control of the mitochondrial calcium uniporter complex." Proceedings of the National Academy of Sciences 114, no. 17 (April 10, 2017): 4388–93. http://dx.doi.org/10.1073/pnas.1702938114.
Повний текст джерелаАнотація:
The mitochondrial calcium uniporter is a Ca2+-activated Ca2+ channel complex mediating mitochondrial Ca2+ uptake, a process crucial for Ca2+ signaling, bioenergetics, and cell death. The uniporter is composed of the pore-forming MCU protein, the gatekeeping MICU1 and MICU2 subunits, and EMRE, a single-pass membrane protein that links MCU and MICU1 together. As a bridging subunit required for channel function, EMRE could paradoxically inhibit uniporter complex formation if expressed in excess. Here, we show that mitochondrial mAAA proteases AFG3L2 and SPG7 rapidly degrade unassembled EMRE using the energy of ATP hydrolysis. Once EMRE is incorporated into the complex, its turnover is inhibited >15-fold. Protease-resistant EMRE mutants produce uniporter subcomplexes that induce constitutive Ca2+ leakage into mitochondria, a condition linked to debilitating neuromuscular disorders in humans. The results highlight the dynamic nature of uniporter subunit assembly, which must be tightly regulated to ensure proper mitochondrial responses to intracellular Ca2+ signals.
10
Zavodnik, I. B. "Mitochondria, calcium homeostasis and calcium signaling." Biomeditsinskaya Khimiya 62, no. 3 (2016): 311–17. http://dx.doi.org/10.18097/pbmc20166203311.
Повний текст джерелаАнотація:
Са2+ is a very important and versatile intracellular signal which controls numerous biochemical and physiological (pathophysiological) processes in the cell. Good evidence exists that mitochondria are sensors, decoders and regulators of calcium signaling. Precise regulation of calcium signaling in the cell involves numerous molecular targets, which induce and decode changes of Са2+ concentrations in the cell (pumps, channels, Са2+-binding proteins, Са2+-dependent enzymes, localized in the cytoplasm and organelles). Mitochondrial Са2+ uniporter accumulates excess of Са2+ in mitochondria, while Na+/Са2+- and H+/Са2+-antiporters extrude Са2+ in the cytoplasm. Mitochondrial Са2+ overloading results in formation of mitochondria permeability transition pores which play an important role in cell death under many pathological conditions. Mitochondria regulate Са2+ homeostasis and control important cellular functions such as metabolism, proliferation, survival. Identification of cellular and mitochondrial Ca2+ transporters and understanding their functional mechanisms open up new prospects for their using as therapeutic targets
11
Peng, Wesley, Yvette C. Wong, and Dimitri Krainc. "Mitochondria-lysosome contacts regulate mitochondrial Ca2+dynamics via lysosomal TRPML1." Proceedings of the National Academy of Sciences 117, no. 32 (July 23, 2020): 19266–75. http://dx.doi.org/10.1073/pnas.2003236117.
Повний текст джерелаАнотація:
Mitochondria and lysosomes are critical for cellular homeostasis, and dysfunction of both organelles has been implicated in numerous diseases. Recently, interorganelle contacts between mitochondria and lysosomes were identified and found to regulate mitochondrial dynamics. However, whether mitochondria–lysosome contacts serve additional functions by facilitating the direct transfer of metabolites or ions between the two organelles has not been elucidated. Here, using high spatial and temporal resolution live-cell microscopy, we identified a role for mitochondria–lysosome contacts in regulating mitochondrial calcium dynamics through the lysosomal calcium efflux channel, transient receptor potential mucolipin 1 (TRPML1). Lysosomal calcium release by TRPML1 promotes calcium transfer to mitochondria, which was mediated by tethering of mitochondria–lysosome contact sites. Moreover, mitochondrial calcium uptake at mitochondria–lysosome contact sites was modulated by the outer and inner mitochondrial membrane channels, voltage-dependent anion channel 1 and the mitochondrial calcium uniporter, respectively. Since loss of TRPML1 function results in the lysosomal storage disorder mucolipidosis type IV (MLIV), we examined MLIV patient fibroblasts and found both altered mitochondria–lysosome contact dynamics and defective contact-dependent mitochondrial calcium uptake. Thus, our work highlights mitochondria–lysosome contacts as key contributors to interorganelle calcium dynamics and their potential role in the pathophysiology of disorders characterized by dysfunctional mitochondria or lysosomes.
12
Gavin, C. E., K. K. Gunter, and T. E. Gunter. "Manganese and calcium efflux kinetics in brain mitochondria. Relevance to manganese toxicity." Biochemical Journal 266, no. 2 (March 1, 1990): 329–34. http://dx.doi.org/10.1042/bj2660329.
Повний текст джерелаАнотація:
Manganese shares the uniport mechanism of mitochondrial calcium influx, accumulates in mitochondria and is cleared only very slowly from brain. Using dual-label isotope techniques, we have investigated both Mn2+ and Ca2+ mitochondrial efflux kinetics. We report that (1) there is no significant Na(+)-dependent Mn2+ efflux from brain mitochondria; (2) Mn2+ inhibits both Na(+)-dependent and Na(+)-independent Ca2+ efflux in brain, in a mode that appears to be primarily competitive and with apparent Ki values of 5.1 and 7.9 nmol/mg respectively; and (3) Ca2+ does not appear to inhibit Mn2+ efflux from brain mitochondria. Findings (1) and (2) suggest the possibility of mitochondrial accumulation of both Mn2+ and Ca2+ in Mn2(+)-intoxicated brain.
13
Duchen, Michael R., Anne Leyssens, and Martin Crompton. "Transient Mitochondrial Depolarizations Reflect Focal Sarcoplasmic Reticular Calcium Release in Single Rat Cardiomyocytes." Journal of Cell Biology 142, no. 4 (August 24, 1998): 975–88. http://dx.doi.org/10.1083/jcb.142.4.975.
Повний текст джерелаАнотація:
Digital imaging of mitochondrial potential in single rat cardiomyocytes revealed transient depolarizations of mitochondria discretely localized within the cell, a phenomenon that we shall call “flicker.” These events were usually highly localized and could be restricted to single mitochondria, but they could also be more widely distributed within the cell. Contractile waves, either spontaneous or in response to depolarization with 50 mM K+, were associated with propagating waves of mitochondrial depolarization, suggesting that propagating calcium waves are associated with mitochondrial calcium uptake and consequent depolarization. Here we demonstrate that the mitochondrial flicker was directly related to the focal release of calcium from sarcoplasmic reticular (SR) calcium stores and consequent uptake of calcium by local mitochondria. Thus, the events were dramatically reduced by (a) depletion of SR calcium stores after long-term incubation in EGTA or thapsigargin (500 nM); (b) buffering intracellular calcium using BAPTA-AM loading; (c) blockade of SR calcium release with ryanodine (30 μM); and (d) blockade of mitochondrial calcium uptake by microinjection of diaminopentane pentammine cobalt (DAPPAC), a novel inhibitor of the mitochondrial calcium uniporter. These observations demonstrate that focal SR calcium release results in calcium microdomains sufficient to promote local mitochondrial calcium uptake, suggesting a tight coupling of calcium signaling between SR release sites and nearby mitochondria.
14
Lee, Andy K., and Amy Tse. "Dominant Role of Mitochondria in Calcium Homeostasis of Single Rat Pituitary Corticotropes." Endocrinology 146, no. 11 (November 1, 2005): 4985–93. http://dx.doi.org/10.1210/en.2005-0358.
Повний текст джерелаАнотація:
The rise in cytosolic free Ca2+ concentration ([Ca2+]i) is the major trigger for secretion of ACTH from pituitary corticotropes. To better understand the shaping of the Ca2+ signal in corticotropes, we investigated the mechanisms regulating the depolarization-triggered Ca2+ signal using patch-clamp techniques and indo-1 fluorometry. The rate of cytosolic Ca2+ clearance was unaffected by inhibitors of Na+/Ca2+ exchanger or plasma membrane Ca2+-ATPase (PMCA), slightly slowed by sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor, but dramatically slowed by mitochondrial uncouplers or inhibitor of mitochondrial uniporter. Measurements with rhod-2 revealed that depolarization-triggered increase in mitochondrial Ca2+ concentration. Thus, mitochondria have a dominant role in cytosolic Ca2+ clearance. Using the Mn2+ quench technique, we found the presence of a continuous basal Ca2+ influx in corticotropes. This basal Ca2+ influx was balanced by the combined actions of mitochondrial uniporter and PMCA and SERCA pumps. Inhibition of the mitochondrial uniporter or PMCA or SERCA pumps elevated basal [Ca2+]i. Using membrane capacitance measurement, we found that the change in the shape of the depolarization-triggered Ca2+ signal after mitochondrial inhibition was associated with enhancement of the exocytotic response. Thus, mitochondria have a dominant role in the regulation of Ca2+ signal and exocytosis in corticotropes.
15
Zavodnik, I. B., T. A. Kovalenia, A. G. Veiko, E. A. Lapshina, T. V. Ilyich, R. I. Kravchuk, L. B. Zavodnik, and I. I. Klimovich. "Structural and functional changes in rat liver mitochondria under calcium ion loading in the absence and presence of flavonoids." Biomeditsinskaya Khimiya 68, no. 4 (2022): 237–49. http://dx.doi.org/10.18097/pbmc20226804237.
Повний текст джерелаАнотація:
The aim of the present work was to elucidate the mechanisms of calcium ion-induced impairments of the ultrastructure and functional activity of isolated rat liver mitochondria in the absence and presence of a number of flavonoids in vitro. In the presence of exogenous Ca2+ (20-60 μM), mitochondrial heterogeneity in size and electron density markedly increased: most organelles demonstrated a swollen electron-light matrix, bigger size, elongated cristae and a reduced their number, a damaged native structure of the inner membrane up to its detachment, and some mitochondria showed a more electron-dense matrix (condensed mitochondria). The calcium-induced opening of the mitochondrial permeability transition pores (MPTP) resulted in the ultrastructural disturbances and in the effective inhibition of the respiratory activity of rat liver mitochondria. The flavonoids (10-25 μM) naringenin and catechin, dose-dependently inhibited the respiratory activity of mitochondria and stimulated the MPTP opening in the presence of Ca2+ ions. Since Ruthenium red, an inhibitor of the mitochondrial Ca2+ uniporter, effectively prevented Ca2+-induced MPTP opening both in the absence and presence of flavonoids, we hypothesized that the effect of flavonoids on the MPTP opening could be mediated by stimulation of the Ca2+ uniporter.
16
Zhang, Ruobing. "Mitochondrial proteins that connected with calcium: do their pathways changes in PAH?" BIO Web of Conferences 55 (2022): 01018. http://dx.doi.org/10.1051/bioconf/20225501018.
Повний текст джерелаАнотація:
Calcium can be regulated by mitochondria and also plays a significant role in mitochondrial pathways. Recent study showed mitochondrial protein changes in the right ventricle in pulmonary arterial hypertension, which affects calcium network at the same time. The specific objective of this study is to assess the pathway of calcium transport by permeable pore in mitochondria and investigate the regulation of mitochondrial proteins in order to find the connection between mitochondrial proteins and right ventricular dysfunction in PAH (pulmonary arterial hypertension). This literature-based review came out by searching articles in Pubmed and Science Direct. And the related flow chart is expressed by the form of PRISMA. There is a network between mitochondria and calcium through the transport chain called mitochondria permeability transition pore (MPTP) as well as different kinds of proteins that are located in the mitochondria. MPTP is a kind of mitochondria pore and can have conformational changes after protein phosphorylation or reaction between mitochondrial proteins to activate the apoptosis capase cascade process in cell death. In addition, MPTP can be activated by other mitochondrial protein like signal transducer activator of transcription3 (STAT3) to activate cytochrome c in pro-apoptosis to initiate cell death at the same time. The most obvious finding from this study is the role of calcium regulation in therapeutic treatment in PAH patients, which suggest an imaginable role for calcium transporter like mitochondria calcium uniporter (MCU) promoting bio-markers in cardiovascular disease resulting from mitochondrial dysfunction. In addition, right ventricle is a target of PAH in which mitochondria in RV would play an essential role in pathways such as ATP production via mitochondria metabolism.
17
Sanganahalli, Basavaraju G., Peter Herman, Fahmeed Hyder, and Sridhar S. Kannurpatti. "Mitochondrial Calcium Uptake Capacity Modulates Neocortical Excitability." Journal of Cerebral Blood Flow & Metabolism 33, no. 7 (April 17, 2013): 1115–26. http://dx.doi.org/10.1038/jcbfm.2013.61.
Повний текст джерелаАнотація:
Local calcium (Ca2 +) changes regulate central nervous system metabolism and communication integrated by subcellular processes including mitochondrial Ca2 + uptake. Mitochondria take up Ca2 + through the calcium uniporter (mCU) aided by cytoplasmic microdomains of high Ca2 +. Known only in vitro, the in vivo impact of mCU activity may reveal Ca2 + -mediated roles of mitochondria in brain signaling and metabolism. From in vitro studies of mitochondrial Ca2 + sequestration and cycling in various cell types of the central nervous system, we evaluated ranges of spontaneous and activity-induced Ca2 + distributions in multiple subcellular compartments in vivo. We hypothesized that inhibiting (or enhancing) mCU activity would attenuate (or augment) cortical neuronal activity as well as activity-induced hemodynamic responses in an overall cytoplasmic and mitochondrial Ca2 + -dependent manner. Spontaneous and sensory-evoked cortical activities were measured by extracellular electrophysiology complemented with dynamic mapping of blood oxygen level dependence and cerebral blood flow. Calcium uniporter activity was inhibited and enhanced pharmacologically, and its impact on the multimodal measures were analyzed in an integrated manner. Ru360, an mCU inhibitor, reduced all stimulus-evoked responses, whereas Kaempferol, an mCU enhancer, augmented all evoked responses. Collectively, the results confirm aforementioned hypotheses and support the Ca2 + uptake-mediated integrative role of in vivo mitochondria on neocortical activity.
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Kannurpatti, Sridhar S. "Mitochondrial calcium homeostasis: Implications for neurovascular and neurometabolic coupling." Journal of Cerebral Blood Flow & Metabolism 37, no. 2 (November 24, 2016): 381–95. http://dx.doi.org/10.1177/0271678x16680637.
Повний текст джерелаАнотація:
Mitochondrial function is critical to maintain high rates of oxidative metabolism supporting energy demands of both spontaneous and evoked neuronal activity in the brain. Mitochondria not only regulate energy metabolism, but also influence neuronal signaling. Regulation of “energy metabolism” and “neuronal signaling” (i.e. neurometabolic coupling), which are coupled rather than independent can be understood through mitochondria’s integrative functions of calcium ion (Ca2+) uptake and cycling. While mitochondrial Ca2+ do not affect hemodynamics directly, neuronal activity changes are mechanistically linked to functional hyperemic responses (i.e. neurovascular coupling). Early in vitro studies lay the foundation of mitochondrial Ca2+ homeostasis and its functional roles within cells. However, recent in vivo approaches indicate mitochondrial Ca2+ homeostasis as maintained by the role of mitochondrial Ca2+ uniporter (mCU) influences system-level brain activity as measured by a variety of techniques. Based on earlier evidence of subcellular cytoplasmic Ca2+ microdomains and cellular bioenergetic states, a mechanistic model of Ca2+ mobilization is presented to understand systems-level neurovascular and neurometabolic coupling. This integrated view from molecular and cellular to the systems level, where mCU plays a major role in mitochondrial and cellular Ca2+ homeostasis, may explain the wide range of activation-induced coupling across neuronal activity, hemodynamic, and metabolic responses.
19
Zhang, Xinyi, Shuhu Liu, Yanshan Su, Ling Zhang, Ting Guo, and Xuemin Wang. "Sirtuin-1 Regulates Mitochondrial Calcium Uptake Through Mitochondrial Calcium Uptake 1 (MICU1)." Life 15, no. 2 (January 25, 2025): 174. https://doi.org/10.3390/life15020174.
Повний текст джерелаАнотація:
Mitochondria play a central role in cell biological processes, functioning not only as producers of ATP but also as regulators of Ca2+ signaling. Mitochondrial calcium uptake occurs primarily through the mitochondrial calcium uniporter channel (mtCU), with the mitochondrial calcium uptake subunits 1, 2, and 3 (MICU1, MICU2, and MICU3) serving as the main regulatory components. Dysregulated mitochondrial calcium uptake is a hallmark of cellular degeneration. Sirtuin 1 (SIRT1), a key regulator of cellular metabolism, plays a critical role in aging and various neurodegenerative conditions. By blocking SIRT1 using EX527 or shSIRT1, we observed mitochondrial structural fragmentation as well as intensified and prolonged mitochondrial calcium overload. Our study revealed a direct interaction between SIRT1 and MICU1. Notably, SIRT1 inhibition resulted in reduced MICU1 expression, hence led to mitochondrial calcium overload, illustrating the unconventional role of SIRT1 in governing mitochondrial function.
20
D’Angelo, Donato, and Rosario Rizzuto. "The Mitochondrial Calcium Uniporter (MCU): Molecular Identity and Role in Human Diseases." Biomolecules 13, no. 9 (August 25, 2023): 1304. http://dx.doi.org/10.3390/biom13091304.
Повний текст джерелаАнотація:
Calcium (Ca2+) ions act as a second messenger, regulating several cell functions. Mitochondria are critical organelles for the regulation of intracellular Ca2+. Mitochondrial calcium (mtCa2+) uptake is ensured by the presence in the inner mitochondrial membrane (IMM) of the mitochondrial calcium uniporter (MCU) complex, a macromolecular structure composed of pore-forming and regulatory subunits. MtCa2+ uptake plays a crucial role in the regulation of oxidative metabolism and cell death. A lot of evidence demonstrates that the dysregulation of mtCa2+ homeostasis can have serious pathological outcomes. In this review, we briefly discuss the molecular structure and the function of the MCU complex and then we focus our attention on human diseases in which a dysfunction in mtCa2+ has been shown.
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Granatiero, Veronica, Marco Pacifici, Anna Raffaello, Diego De Stefani, and Rosario Rizzuto. "Overexpression of Mitochondrial Calcium Uniporter Causes Neuronal Death." Oxidative Medicine and Cellular Longevity 2019 (October 16, 2019): 1–15. http://dx.doi.org/10.1155/2019/1681254.
Повний текст джерелаАнотація:
Neurodegenerative diseases are a large and heterogeneous group of disorders characterized by selective and progressive death of specific neuronal subtypes. In most of the cases, the pathophysiology is still poorly understood, although a number of hypotheses have been proposed. Among these, dysregulation of Ca2+ homeostasis and mitochondrial dysfunction represent two broadly recognized early events associated with neurodegeneration. However, a direct link between these two hypotheses can be drawn. Mitochondria actively participate to global Ca2+ signaling, and increases of [Ca2+] inside organelle matrix are known to sustain energy production to modulate apoptosis and remodel cytosolic Ca2+ waves. Most importantly, while mitochondrial Ca2+ overload has been proposed as the no-return signal, triggering apoptotic or necrotic neuronal death, until now direct evidences supporting this hypothesis, especially in vivo, are limited. Here, we took advantage of the identification of the mitochondrial Ca2+ uniporter (MCU) and tested whether mitochondrial Ca2+ signaling controls neuronal cell fate. We overexpressed MCU both in vitro, in mouse primary cortical neurons, and in vivo, through stereotaxic injection of MCU-coding adenoviral particles in the brain cortex. We first measured mitochondrial Ca2+ uptake using quantitative genetically encoded Ca2+ probes, and we observed that the overexpression of MCU causes a dramatic increase of mitochondrial Ca2+ uptake both at resting and after membrane depolarization. MCU-mediated mitochondrial Ca2+ overload causes alteration of organelle morphology and dysregulation of global Ca2+ homeostasis. Most importantly, MCU overexpression in vivo is sufficient to trigger gliosis and neuronal loss. Overall, we demonstrated that mitochondrial Ca2+ overload is per se sufficient to cause neuronal cell death both in vitro and in vivo, thus highlighting a potential key step in neurodegeneration.
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Wen, Haitao, Tianliang Li, Xinghui Li, Yu Lei, and Douglas R. Green. "Mitochondrial Calcium Signaling Facilitates Bacterial Survival by Restraining LC3-associated Phagocytosis." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 227.1. http://dx.doi.org/10.4049/jimmunol.204.supp.227.1.
Повний текст джерелаАнотація:
Abstract Mitochondria in eukaryotic cells are believed to have originated from proteobacteria through endosymbiosis 2.5 billion years ago. Accumulating evidence suggests essential roles of mitochondria in host defense response against invading pathogens. Whether intracellular bacteria can hijack mitochondria to promote their survival remains elusive. Here, we demonstrate a previously unappreciated pro-survival strategy employed by intracellular bacteria Listeria monocytogenesthat involves the suppression of LC3-associated phagocytosis (LAP) by mitochondrial Ca2+ signaling. Invasion of macrophages by L. monocytogenes caused a robust mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU), leading to elevated acetyl-coenzyme A (acetyl-CoA) production via the pyruvate dehydrogenase (PDH). Acetylation of LAP effector Rubicon with the use of acetyl-CoA antagonized LAP formation. Genetic ablation of Mcuimproved bacterial killing due to elevated LAP formation. Our study indicates that modulation of mitochondrial Ca2+ signaling is a beneficial strategy for bacterial survival and highlights the importance of mitochondrial metabolism in host-microbial interaction.
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Pallafacchina, Giorgia, Sofia Zanin, and Rosario Rizzuto. "From the Identification to the Dissection of the Physiological Role of the Mitochondrial Calcium Uniporter: An Ongoing Story." Biomolecules 11, no. 6 (May 23, 2021): 786. http://dx.doi.org/10.3390/biom11060786.
Повний текст джерелаАнотація:
The notion of mitochondria being involved in the decoding and shaping of intracellular Ca2+ signals has been circulating since the end of the 19th century. Despite that, the molecular identity of the channel that mediates Ca2+ ion transport into mitochondria remained elusive for several years. Only in the last decade, the genes and pathways responsible for the mitochondrial uptake of Ca2+ began to be cloned and characterized. The gene coding for the pore-forming unit of the mitochondrial channel was discovered exactly 10 years ago, and its product was called mitochondrial Ca2+ uniporter or MCU. Before that, only one of its regulators, the mitochondria Ca2+ uptake regulator 1, MICU1, has been described in 2010. However, in the following years, the scientific interest in mitochondrial Ca2+ signaling regulation and physiological role has increased. This shortly led to the identification of many of its components, to the description of their 3D structure, and the characterization of the uniporter contribution to tissue physiology and pathology. In this review, we will summarize the most relevant achievements in the history of mitochondrial Ca2+ studies, presenting a chronological overview of the most relevant and landmarking discoveries. Finally, we will explore the impact of mitochondrial Ca2+ signaling in the context of muscle physiology, highlighting the recent advances in understanding the role of the MCU complex in the control of muscle trophism and metabolism.
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Chakrabarti, Rajarshi, Wei-Ke Ji, Radu V. Stan, Jaime de Juan Sanz, Timothy A. Ryan, and Henry N. Higgs. "INF2-mediated actin polymerization at the ER stimulates mitochondrial calcium uptake, inner membrane constriction, and division." Journal of Cell Biology 217, no. 1 (November 15, 2017): 251–68. http://dx.doi.org/10.1083/jcb.201709111.
Повний текст джерелаАнотація:
Mitochondrial division requires division of both the inner and outer mitochondrial membranes (IMM and OMM, respectively). Interaction with endoplasmic reticulum (ER) promotes OMM division by recruitment of the dynamin Drp1, but effects on IMM division are not well characterized. We previously showed that actin polymerization through ER-bound inverted formin 2 (INF2) stimulates Drp1 recruitment in mammalian cells. Here, we show that INF2-mediated actin polymerization stimulates a second mitochondrial response independent of Drp1: a rise in mitochondrial matrix calcium through the mitochondrial calcium uniporter. ER stores supply the increased mitochondrial calcium, and the role of actin is to increase ER–mitochondria contact. Myosin IIA is also required for this mitochondrial calcium increase. Elevated mitochondrial calcium in turn activates IMM constriction in a Drp1-independent manner. IMM constriction requires electron transport chain activity. IMM division precedes OMM division. These results demonstrate that actin polymerization independently stimulates the dynamics of both membranes during mitochondrial division: IMM through increased matrix calcium, and OMM through Drp1 recruitment.
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Ajanel Gomez, Abigail, Frederik Denorme, Irina Portier, Mia Kowalczyk, Sradha Rameshbhatt, Yasuhiro Kosaka, and Robert A. Campbell. "Platelet Mitochondria Calcium Uniporter Regulates ITAM-Dependent Platelet Activation and Signaling." Blood 142, Supplement 1 (November 28, 2023): 1187. http://dx.doi.org/10.1182/blood-2023-189538.
Повний текст джерелаАнотація:
Introduction: The ability of platelets to multitask is critical to arrest bleeding after injury and for the development of arterial thrombosis, which underlies myocardial infarction and stroke. Platelet activation relies heavily on changes in cytoplasmic calcium flux. However, little is known on the role mitochondrial calcium flux directly plays in platelet activation. In other cells, release of calcium from intracellular stores results in calcium entry into channels located in the outer mitochondrial membrane. Once calcium enters the intermembrane space, entry into the mitochondrial matrix is regulated by a multimeric complex, composed of channel-forming subunits and regulatory elements called the mitochondrial calcium uniporter (MCU). MCU has been extensively studied in cardiac tissue where calcium flux through MCU is critical for regulating bioenergetics, ROS formation, and cytoplasmic calcium levels. As these processes are important for platelet activation, these studies would indicate mitochondrial calcium flux may regulate platelet activation. However, the role of MCU in platelet function and activation is poorly understood. Aim: The goals of the current study are 1) to examine the role of MCU and mitochondrial calcium flux in platelet function and 2) to establish if mitochondrial calcium regulates thrombosis. Methods: We generated a platelet-specific MCU-deficient mouse (MCU fl/fl-PF4-cre, KO) and compared them to littermate wild-type controls (MCU fl/fl, WT). Platelet function including activation, aggregation, and mitochondrial calcium flux in response to PAR4 activating peptide (PAR) and ADP (P2Y12), both GPCRs or to collagen (GPVI) and rhodocytin (CLEC-2), both ITAMs, were examined. In addition, we examined ex vivo platelet adhesion under arterial and venous shear to collagen and in vivo thrombosis using a ferric chloride carotid artery model. Results: Mice deficient inplatelet MCU were viable and fertile. In addition, platelet-specific MCU deletion did not alter platelet counts, mean platelet volume, or platelet half-life. MCU KO platelets had significantly reduced (p<0.05) GPVI and CLEC-2-dependent aIIbb3 activation and P-selectin expression while platelet activation in response to P2Y12 and PAR4 stimulation was unchanged. Consistent with our activation results, platelet aggregation was significantly reduced in response to collagen and rhodocytin (p<0.05) in MCU KO platelets, but not thrombin or ADP. MCU KO platelets adhered significantly less (p=0.0012) to collagen compared to MCU WT platelets under arterial and venous shear conditions. In vivo, MCU KO mice had longer occlusion time compared to the WT (p=0.0044). Mechanistically, mitochondrial calcium flux was significantly reduced (p<0.05) in MCU KO platelets compared to WT platelets after GPVI stimulation, but not PAR4 activation. Furthermore, mitochondrial reactive oxygen species (ROS) generation was significantly reduced in MCU KO platelets compared to WT platelets (p=0.0097) after GPVI-dependent activation while PAR4 activation induced no change in mitochondrial ROS. Mitochondrial ROS is known to regulate signaling in other cells. Consistent with this hypothesis, we observed a significant reduction in the ITAM signaling molecules pSyK (p=0.0084) and pPLCγ2 (p=0.012) in MCU KO platelets after GPVI stimulation. Furthermore, inhibiting mitochondrial ROS using MitoTempo, a specific mitochondrial ROS inhibitor, decreased aggregation (p=0.0004) as well as downstream signaling, including pSyk (p=0.0046) and pPLCγ2 (p=0.0493) in WT platelets when treated with a GPVI agonist. In parallel, treating MCU KO platelets with H 2O 2 to induce ROS production increased platelet aggregation (p=0.0036) after GPVI activation. Conclusion(s): Platelet MCU mediates platelet activation and thrombosis in an ITAM-dependent manner by regulating mitochondrial calcium flux and ROS generation as well as downstream ITAM signaling through GPVI and CLEC-2. Our data support a novel role for mitochondria and mitochondria calcium flux in regulating ITAM-dependent platelet activation and demonstrate platelet MCU as a novel anti-platelet target to reduce thrombosis
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Brisac, Cynthia, François Téoulé, Arnaud Autret, Isabelle Pelletier, Florence Colbère-Garapin, Catherine Brenner, Christophe Lemaire, and Bruno Blondel. "Calcium Flux between the Endoplasmic Reticulum and Mitochondrion Contributes to Poliovirus-Induced Apoptosis." Journal of Virology 84, no. 23 (September 22, 2010): 12226–35. http://dx.doi.org/10.1128/jvi.00994-10.
Повний текст джерелаАнотація:
ABSTRACT We show that poliovirus (PV) infection induces an increase in cytosolic calcium (Ca2+) concentration in neuroblastoma IMR5 cells, at least partly through Ca2+ release from the endoplasmic reticulum lumen via the inositol 1,4,5-triphosphate receptor (IP3R) and ryanodine receptor (RyR) channels. This leads to Ca2+ accumulation in mitochondria through the mitochondrial Ca2+ uniporter and the voltage-dependent anion channel (VDAC). This increase in mitochondrial Ca2+ concentration in PV-infected cells leads to mitochondrial dysfunction and apoptosis.
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Sun, Zhe, Zicheng Ma, Wandi Cao, Chenlong Jiang, Lei Guo, Kesen Liu, Yanni Gao, et al. "Calcium-mediated mitochondrial fission and mitophagy drive glycolysis to facilitate arterivirus proliferation." PLOS Pathogens 21, no. 1 (January 13, 2025): e1012872. https://doi.org/10.1371/journal.ppat.1012872.
Повний текст джерелаАнотація:
Mitochondria, recognized as the “powerhouse” of cells, play a vital role in generating cellular energy through dynamic processes such as fission and fusion. Viruses have evolved mechanisms to hijack mitochondrial function for their survival and proliferation. Here, we report that infection with the swine arterivirus porcine reproductive and respiratory syndrome virus (PRRSV), manipulates mitochondria calcium ions (Ca2+) to induce mitochondrial fission and mitophagy, thereby reprogramming cellular energy metabolism to facilitate its own replication. Mechanistically, PRRSV-induced mitochondrial fission is caused by elevated levels of mitochondria Ca2+, derived from the endoplasmic reticulum (ER) through inositol 1,4,5-triphosphate receptor (IP3R)—voltage-dependent anion channel 1 (VDAC1)—mitochondrial calcium uniporter (MCU) channels. This process is associated with increased mitochondria-associated membranes (MAMs), mediated by the upregulated expression of sigma non-opioid intracellular receptor 1 (SIGMAR1). Elevated mitochondria Ca2+ further activates the Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ)—AMP-activated protein kinase (AMPK)—dynamin-related protein 1 (DRP1) signaling pathway, which interacts with mitochondrial fission protein 1 (FIS1) and mitochondrial dynamics proteins of 49 kDa (MiD49) to promote mitochondrial fission. PRRSV infection, alongside mitochondrial fission, triggers mitophagy via the PTEN-induced putative kinase 1 (PINK1)-Parkin RBR E3 ubiquitin (Parkin) pathway, promoting cellular glycolysis and excessive lactate production to facilitate its own replication. This study reveals the mechanism by which mitochondrial Ca2+ regulates mitochondrial function during PRRSV infection, providing new insights into the interplay between the virus and host cell metabolism.
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Rolo, Anabela P., Paulo J. Oliveira, António J. M. Moreno, and Carlos M. Palmeira. "Chenodeoxycholate Is a Potent Inducer of the Permeability Transition Pore in Rat Liver Mitochondria." Bioscience Reports 21, no. 1 (February 1, 2001): 73–80. http://dx.doi.org/10.1023/a:1010438202519.
Повний текст джерелаАнотація:
Several reports support the concept that bile acids may be cytotoxic during cholestatic disease process by causing mitochondrial dysfunction. Here we report additional data and findings aimed at a better understanding of the involvement of the permeability transition pore (PTP) opening in bile acids toxicity. The mitochondrial PTP is implicated as a mediator of cell injury and death in many situations. In the presence of calcium and phosphate, chenodeoxycholic acid (CDCA) induced a permeability transition in freshly isolated rat liver mitochondria, characterized by membrane depolarization, release of matrix calcium, and osmotic swelling. All these events were blocked by cyclosporine A (CyA) and the calcium uniporter inhibitor ruthenium red (RR). The results suggest that CDCA increases the sensitivity of isolated mitochondria in vitro to the calcium-dependent induction of the PTP.
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Venugopal, Anila, Mahalaxmi Iyer, Venkatesh Balasubramanian, and Balachandar Vellingiri. "Mitochondrial calcium uniporter as a potential therapeutic strategy for Alzheimer’s disease." Acta Neuropsychiatrica 32, no. 2 (December 26, 2019): 65–71. http://dx.doi.org/10.1017/neu.2019.39.
Повний текст джерелаАнотація:
AbstractAlzheimer’s disease (AD), a neurodegenerative disorder, is the leading cause of dementia in the world whose aetiology is still unclear. AD was always related to ageing though there have been instances where people at an early age also succumb to this disease. With medical advancements, the mortality rate has significantly reduced which also makes people more prone to AD. AD is rare, yet the prominent disease has been widely studied with several hypotheses trying to understand the workings of its onset. The most recent and popular hypothesis in AD is the involvement of mitochondrial dysfunction and calcium homeostasis in the development of the disease though their exact roles are not known. With the sudden advent of the mitochondrial calcium uniporter (MCU), many previously known pathological hallmarks of AD may be better understood. Several studies have shown the effect of excess calcium in mitochondria and the influence of MCU complex in mitochondrial function. In this article, we discuss the possible involvement of MCU in AD by linking the uniporter to mitochondrial dysfunction, calcium homeostasis, reactive oxygen species, neurotransmitters and the hallmarks of AD – amyloid plaque formation and tau tangle formation.
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Weinberg, J. M., and H. D. Humes. "Calcium transport and inner mitochondrial membrane damage in renal cortical mitochondria." American Journal of Physiology-Renal Physiology 248, no. 6 (June 1, 1985): F876—F889. http://dx.doi.org/10.1152/ajprenal.1985.248.6.f876.
Повний текст джерелаАнотація:
Ca2+ uptake and efflux processes, as they are manifested during procedures used for isolation of renal cortical mitochondria, were characterized in order to provide a better basis for making inferences from isolated mitochondria about the in vivo state of mitochondrial Ca2+ homeostasis in both normal and injured tissues and to better define the mechanisms by which Ca2+ mediates injury to renal cortical mitochondria. Mitochondrial Ca2+ uptake predictably occurred when the capacity of the Ca2+ chelator added to the isolating medium to maintain free Ca2+ in the submicromolar range was exhausted unless ruthenium red was present to specifically inhibit the Ca2+ uniport. Ca2+ uptake during isolation ultimately led to loss of accumulated Ca2+ and intramitochondrial K+ as well as to deterioration of respiratory function. Extramitochondrial Ca2+ also evoked the latter two events in the absence of Ca2+ uptake but only at much higher medium Ca2+ levels than were required when Ca2+ uptake was allowed to occur. Studies using mitochondria loaded with known amounts of Ca2+ at 4 degrees C and then subjected to a reisolation procedure including all the steps of normal isolation demonstrated that phosphate markedly potentiated Ca2+-induced alterations of mitochondrial membrane permeability properties. Of several agents studied singly, fatty acid-free albumin was most effective in blocking Ca2+ + phosphate-induced alterations of mitochondrial membrane permeability. The protective effect of fatty acid-free albumin was further enhanced by combining it with Mg2+, dibucaine, or oligomycin + ADP. This study thus quantitatively defined conditions under which Ca2+ uptake can be expected to occur during mitochondrial isolation, demonstrated that the effects of this Ca2+ uptake on mitochondrial properties are similar to those previously elucidated in mitochondria studied at warmer temperatures, and defined methods suitable for blocking such Ca2+ movements and their deleterious effects.
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Lee, Sandra H., Hannah E. Duron, and Dipayan Chaudhuri. "Beyond the TCA cycle: new insights into mitochondrial calcium regulation of oxidative phosphorylation." Biochemical Society Transactions 51, no. 4 (August 29, 2023): 1661–73. http://dx.doi.org/10.1042/bst20230012.
Повний текст джерелаАнотація:
While mitochondria oxidative phosphorylation is broadly regulated, the impact of mitochondrial Ca2+ on substrate flux under both physiological and pathological conditions is increasingly being recognized. Under physiologic conditions, mitochondrial Ca2+ enters through the mitochondrial Ca2+ uniporter and boosts ATP production. However, maintaining Ca2+ homeostasis is crucial as too little Ca2+ inhibits adaptation to stress and Ca2+ overload can trigger cell death. In this review, we discuss new insights obtained over the past several years expanding the relationship between mitochondrial Ca2+ and oxidative phosphorylation, with most data obtained from heart, liver, or skeletal muscle. Two new themes are emerging. First, beyond boosting ATP synthesis, Ca2+ appears to be a critical determinant of fuel substrate choice between glucose and fatty acids. Second, Ca2+ exerts local effects on the electron transport chain indirectly, not via traditional allosteric mechanisms. These depend critically on the transporters involved, such as the uniporter or the Na+–Ca2+ exchanger. Alteration of these new relationships during disease can be either compensatory or harmful and suggest that targeting mitochondrial Ca2+ may be of therapeutic benefit during diseases featuring impairments in oxidative phosphorylation.
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Zhang, Dejiu, Fei Wang, Peifeng Li, and Yanyan Gao. "Mitochondrial Ca2+ Homeostasis: Emerging Roles and Clinical Significance in Cardiac Remodeling." International Journal of Molecular Sciences 23, no. 6 (March 11, 2022): 3025. http://dx.doi.org/10.3390/ijms23063025.
Повний текст джерелаАнотація:
Mitochondria are the sites of oxidative metabolism in eukaryotes where the metabolites of sugars, fats, and amino acids are oxidized to harvest energy. Notably, mitochondria store Ca2+ and work in synergy with organelles such as the endoplasmic reticulum and extracellular matrix to control the dynamic balance of Ca2+ concentration in cells. Mitochondria are the vital organelles in heart tissue. Mitochondrial Ca2+ homeostasis is particularly important for maintaining the physiological and pathological mechanisms of the heart. Mitochondrial Ca2+ homeostasis plays a key role in the regulation of cardiac energy metabolism, mechanisms of death, oxygen free radical production, and autophagy. The imbalance of mitochondrial Ca2+ balance is closely associated with cardiac remodeling. The mitochondrial Ca2+ uniporter (mtCU) protein complex is responsible for the uptake and release of mitochondrial Ca2+ and regulation of Ca2+ homeostasis in mitochondria and consequently, in cells. This review summarizes the mechanisms of mitochondrial Ca2+ homeostasis in physiological and pathological cardiac remodeling and the regulatory effects of the mitochondrial calcium regulatory complex on cardiac energy metabolism, cell death, and autophagy, and also provides the theoretical basis for mitochondrial Ca2+ as a novel target for the treatment of cardiovascular diseases.
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Gunter, T. E., and D. R. Pfeiffer. "Mechanisms by which mitochondria transport calcium." American Journal of Physiology-Cell Physiology 258, no. 5 (May 1, 1990): C755—C786. http://dx.doi.org/10.1152/ajpcell.1990.258.5.c755.
Повний текст джерелаАнотація:
It has been firmly established that the rapid uptake of Ca2+ by mitochondria from a wide range of sources is mediated by a uniporter which permits transport of the ion down its electrochemical gradient. Several mechanisms of Ca2+ efflux from mitochondria have also been extensively discussed in the literature. Energized mitochondria must expend a significant amount of energy to transport Ca2+ against its electrochemical gradient from the matrix space to the external space. Two separate mechanisms have been found to mediate this outward transport: a Ca2+/nNa+ exchanger and a Na(+)-independent efflux mechanism. These efflux mechanisms are considered from the perspective of available energy. In addition, a reversible Ca2(+)-induced increase in inner membrane permeability can also occur. The induction of this permeability transition is characterized by swelling of the mitochondria, leakiness to small ions such as K+, Mg2+, and Ca2+, and loss of the mitochondrial membrane potential. It has been suggested that the permeability transition and its reversal may also function as a mitochondrial Ca2+ efflux mechanism under some conditions. The characteristics of each of these mechanisms are discussed, as well as their possible physiological functions.
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Sander, Paulina, Thomas Gudermann, and Johann Schredelseker. "A Calcium Guard in the Outer Membrane: Is VDAC a Regulated Gatekeeper of Mitochondrial Calcium Uptake?" International Journal of Molecular Sciences 22, no. 2 (January 19, 2021): 946. http://dx.doi.org/10.3390/ijms22020946.
Повний текст джерелаАнотація:
Already in the early 1960s, researchers noted the potential of mitochondria to take up large amounts of Ca2+. However, the physiological role and the molecular identity of the mitochondrial Ca2+ uptake mechanisms remained elusive for a long time. The identification of the individual components of the mitochondrial calcium uniporter complex (MCUC) in the inner mitochondrial membrane in 2011 started a new era of research on mitochondrial Ca2+ uptake. Today, many studies investigate mitochondrial Ca2+ uptake with a strong focus on function, regulation, and localization of the MCUC. However, on its way into mitochondria Ca2+ has to pass two membranes, and the first barrier before even reaching the MCUC is the outer mitochondrial membrane (OMM). The common opinion is that the OMM is freely permeable to Ca2+. This idea is supported by the presence of a high density of voltage-dependent anion channels (VDACs) in the OMM, forming large Ca2+ permeable pores. However, several reports challenge this idea and describe VDAC as a regulated Ca2+ channel. In line with this idea is the notion that its Ca2+ selectivity depends on the open state of the channel, and its gating behavior can be modified by interaction with partner proteins, metabolites, or small synthetic molecules. Furthermore, mitochondrial Ca2+ uptake is controlled by the localization of VDAC through scaffolding proteins, which anchor VDAC to ER/SR calcium release channels. This review will discuss the possibility that VDAC serves as a physiological regulator of mitochondrial Ca2+ uptake in the OMM.
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Yun, Bogeon, HeeJung Lee, Moumita Ghosh, Benjamin F. Cravatt, Ku-Lung Hsu, Joseph V. Bonventre, Heather Ewing, Michael H. Gelb, and Christina C. Leslie. "Serine Hydrolase Inhibitors Block Necrotic Cell Death by Preventing Calcium Overload of the Mitochondria and Permeability Transition Pore Formation." Journal of Biological Chemistry 289, no. 3 (December 2, 2013): 1491–504. http://dx.doi.org/10.1074/jbc.m113.497651.
Повний текст джерелаАнотація:
Perturbation of calcium signaling that occurs during cell injury and disease, promotes cell death. In mouse lung fibroblasts A23187 triggered mitochondrial permeability transition pore (MPTP) formation, lactate dehydrogenase (LDH) release, and necrotic cell death that were blocked by cyclosporin A (CsA) and EGTA. LDH release temporally correlated with arachidonic acid release but did not involve cytosolic phospholipase A2α (cPLA2α) or calcium-independent PLA2. Surprisingly, release of arachidonic acid and LDH from cPLA2α-deficient fibroblasts was inhibited by the cPLA2α inhibitor pyrrophenone, and another serine hydrolase inhibitor KT195, by preventing mitochondrial calcium uptake. Inhibitors of calcium/calmodulin-dependent protein kinase II, a mitochondrial Ca2+ uniporter (MCU) regulator, also prevented MPTP formation and arachidonic acid release induced by A23187 and H2O2. Pyrrophenone blocked MCU-mediated mitochondrial calcium uptake in permeabilized fibroblasts but not in isolated mitochondria. Unlike pyrrophenone, the diacylglycerol analog 1-oleoyl-2-acetyl-sn-glycerol and CsA blocked cell death and arachidonic acid release not by preventing mitochondrial calcium uptake but by inhibiting MPTP formation. In fibroblasts stimulated with thapsigargin, which induces MPTP formation by a direct effect on mitochondria, LDH and arachidonic acid release were blocked by CsA and 1-oleoyl-2-acetyl-sn-glycerol but not by pyrrophenone or EGTA. Therefore serine hydrolase inhibitors prevent necrotic cell death by blocking mitochondrial calcium uptake but not the enzyme releasing fatty acids that occurs by a novel pathway during MPTP formation. This work reveals the potential for development of small molecule cell-permeable serine hydrolase inhibitors that block MCU-mediated mitochondrial calcium overload, MPTP formation, and necrotic cell death.
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Vlessis, A. A., and L. Mela-Riker. "Potential role of mitochondrial calcium metabolism during reperfusion injury." American Journal of Physiology-Cell Physiology 256, no. 6 (June 1, 1989): C1196—C1206. http://dx.doi.org/10.1152/ajpcell.1989.256.6.c1196.
Повний текст джерелаАнотація:
Ischemia-reperfusion injury has been associated with intracellular H2O2 and superoxide radical production from accumulated hypoxanthine (HX) and xanthine oxidase (XO). The effect of H2O2 and superoxide radical on mitochondrial Ca2+ efflux was characterized in isolated renal mitochondria using a HX-XO system. Mitochondria were suspended in buffered medium containing 200 microM HX. Extramitochondrial Ca2+ was monitored kinetically at 660-685 nm using the Ca2+ indicator arsenazo III. After preloading mitochondria with 18-25 nmol Ca2+/mg protein, addition of XO to the medium caused a rapid oxidation of mitochondrial NAD(P)H followed by Ca2+ release. Ca2+ efflux was attributed to mitochondrial metabolism of H2O2 because efflux could be prevented with catalase but not superoxide dismutase. The Ca2+ efflux rate (r = 0.995) and lag time to Ca2+ efflux (r = 0.987) both correlate well with the NAD(P)H oxidation rate. Exogenous ATP prevents Ca2+ efflux in a dose-dependent fashion (Km = 35 microM ATP) without affecting NAD(P)H oxidation; ATP plus oligomycin, however, had no effect. The protective effect of ATP on Ca2+ efflux was diminished by ruthenium red (RR). XO-induced Ca2+ efflux increased state 4 respiration 148% via a futile Ca2+ cycle involving the Ca2+ uniport. The increase in state 4 respiration could be reversed with RR (alpha less than 0.001) or ATP (alpha less than 0.01); ATP plus oligomycin, however, had no effect. The results are discussed in relation to the oxygen free radical theory of reperfusion injury.
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Weissenrieder, Jillian S., Jason Pitarresi, Natalie Weinmann, Rebecca Drager, Usha Paudel, Anil Rustgi, Ben Stanger, and J. Kevin Foskett. "Abstract C113: The mitochondrial calcium uniporter supports epithelial to mesenchymal transition of pancreatic ductal adenocarcinoma." Cancer Research 84, no. 2_Supplement (January 16, 2024): C113. http://dx.doi.org/10.1158/1538-7445.panca2023-c113.
Повний текст джерелаАнотація:
Abstract In spite of many new developments in cancer treatments and targeted therapies over the past few decades, outcomes for pancreatic ductal adenocarcinoma (PDAC) patients continue to be poor. Calcium signaling and mitochondrial function are known to contribute to cancer outcomes in many paradigms, yet much remains unknown in the context of PDAC. The mitochondrial Ca2+ uniporter, MCU, is the main route by which mitochondria can take up Ca2+ into the mitochondrial matrix, where it drives metabolic activity in the tricarboxylic acid cycle and promotes ATP synthesis by the electron transport chain. Our previous work suggests that Ca2+ flux from the endoplasmic reticulum (ER) into the mitochondria at mitochondria-associated membranes (MAMs) may be important to drive malignancy. Here, we show that MCU expression is associated with poor outcomes in PDAC patients and disease progression in murine organoid models of cancer development. Further, deletion of Mcu in murine KPC cells results in ablation of mitochondrial Ca2+ uptake, which reduces growth, proliferation, and clonogenicity. Tumor growth and metastatic colonization are also reduced in orthotopic implantation models, with some KPCY-McucKO models failing to develop primary lesions. This suggests that MCU, and thus mitochondrial Ca2+, play an important role in tumor growth. Critically, we here elucidate a heretofore unknown relationship between ER-to-mitochondrial Ca2+ flux through Mcu and epithelial to mesenchymal transition (EMT), an important process that contributes to poor outcomes in PDAC. To this end, McucKO associates with reduced basal Snail expression and reduced TGFβ secretion, and McucKO clones have a more epithelial morphology than their isogenic, Mcu-expressing counterparts. Both stable expression of Snail and treatment with TGFβ are able to rescue growth, mobility, and clonogenic deficits in McucKO cell lines to levels comparable to isogenic, Mcu-expressing cell lines. Uptake assays, metabolomics, isotope tracing, and mRNA-Seq have enabled us to elucidate metabolic and transcriptional rewiring induced by Snail and TGFβ treatment which may promote cell survival and proliferation despite the lack of Mcu. This work has important implications for potential targeting of Ca2+ signaling in the context of PDAC. Citation Format: Jillian S. Weissenrieder, Jason Pitarresi, Natalie Weinmann, Rebecca Drager, Usha Paudel, Anil Rustgi, Ben Stanger, J. Kevin Foskett. The mitochondrial calcium uniporter supports epithelial to mesenchymal transition of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C113.
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Apicco, Daniel J., Evgeny Shlevkov, Catherine L. Nezich, David T. Tran, Edward Guilmette, Justin W. Nicholatos, Collin M. Bantle та ін. "The Parkinson’s disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release". Proceedings of the National Academy of Sciences 118, № 1 (21 грудня 2020): e2006476118. http://dx.doi.org/10.1073/pnas.2006476118.
Повний текст джерелаАнотація:
Inositol-1,4,5-triphosphate (IP3) kinase B (ITPKB) is a ubiquitously expressed lipid kinase that inactivates IP3, a secondary messenger that stimulates calcium release from the endoplasmic reticulum (ER). Genome-wide association studies have identified common variants in the ITPKB gene locus associated with reduced risk of sporadic Parkinson’s disease (PD). Here, we investigate whether ITPKB activity or expression level impacts PD phenotypes in cellular and animal models. In primary neurons, knockdown or pharmacological inhibition of ITPKB increased levels of phosphorylated, insoluble α-synuclein pathology following treatment with α-synuclein preformed fibrils (PFFs). Conversely, ITPKB overexpression reduced PFF-induced α-synuclein aggregation. We also demonstrate that ITPKB inhibition or knockdown increases intracellular calcium levels in neurons, leading to an accumulation of calcium in mitochondria that increases respiration and inhibits the initiation of autophagy, suggesting that ITPKB regulates α-synuclein pathology by inhibiting ER-to-mitochondria calcium transport. Furthermore, the effects of ITPKB on mitochondrial calcium and respiration were prevented by pretreatment with pharmacological inhibitors of the mitochondrial calcium uniporter complex, which was also sufficient to reduce α-synuclein pathology in PFF-treated neurons. Taken together, these results identify ITPKB as a negative regulator of α-synuclein aggregation and highlight modulation of ER-to-mitochondria calcium flux as a therapeutic strategy for the treatment of sporadic PD.
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de la Fuente, Sergio, Rosalba I. Fonteriz, Pedro J. de la Cruz, Mayte Montero, and Javier Alvarez. "Mitochondrial free [Ca2+] dynamics measured with a novel low-Ca2+ affinity aequorin probe." Biochemical Journal 445, no. 3 (July 13, 2012): 371–76. http://dx.doi.org/10.1042/bj20120423.
Повний текст джерелаАнотація:
Mitochondria have a very large capacity to accumulate Ca2+ during cell stimulation driven by the mitochondrial membrane potential. Under these conditions, [Ca2+]M (mitochondrial [Ca2+]) may well reach millimolar levels in a few seconds. Measuring the dynamics of [Ca2+]M during prolonged stimulation has been previously precluded by the high Ca2+ affinity of the probes available. We have now developed a mitochondrially targeted double-mutated form of the photoprotein aequorin which is able to measure [Ca2+] in the millimolar range for long periods of time without problems derived from aequorin consumption. We show in the present study that addition of Ca2+ to permeabilized HeLa cells triggers an increase in [Ca2+]M up to an steady state of approximately 2–3 mM in the absence of phosphate and 0.5–1 mM in the presence of phosphate, suggesting buffering or precipitation of calcium phosphate when the free [Ca2+] reaches 0.5–1 mM. Mitochondrial pH acidification partially re-dissolved these complexes. These millimolar [Ca2+]M levels were stable for long periods of time provided the mitochondrial membrane potential was not collapsed. Silencing of the mitochondrial Ca2+ uniporter largely reduced the rate of [Ca2+]M increase, but the final steady-state [Ca2+]M reached was similar. In intact cells, the new probe allows monitoring of agonist-induced increases of [Ca2+]M without problems derived from aequorin consumption.
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Motloch, Lukas Jaroslaw, Robert Larbig, Tina Gebing, Sara Reda, Stephanie Weichselbaumer, Daniela Kokoschinegg, Astrid Schwaiger, Martin Wolny, and Uta C. Hoppe. "Ucp2 Modulates Mitochondrial Calcium Uniporter." Biophysical Journal 106, no. 2 (January 2014): 593a. http://dx.doi.org/10.1016/j.bpj.2013.11.3282.
Повний текст джерела
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Stoll, Shaunrick, Jing Xi, Ben Ma, Christiana Leimena, Erik J. Behringer, Gangjian Qin, and Hongyu Qiu. "The Valosin-Containing Protein Protects the Heart Against Pathological Ca2+ Overload by Modulating Ca2+ Uptake Proteins." Toxicological Sciences 171, no. 2 (July 31, 2019): 473–84. http://dx.doi.org/10.1093/toxsci/kfz164.
Повний текст джерелаАнотація:
Abstract Stress-induced mitochondrial calcium (Ca2+) overload is a key cellular toxic effectors and a trigger of cardiomyocyte death during cardiac ischemic injury through the opening of mitochondrial permeability transition pore (mPTP). We previously found that the valosin-containing protein (VCP), an ATPase-associated protein, protects cardiomyocytes against stress-induced death and also inhibits mPTP opening in vitro. However, the underlying molecular mechanisms are not fully understood. Here, we tested our hypothesis that VCP acts as a novel regulator of mitochondrial Ca2+ uptake proteins and resists cardiac mitochondrial Ca2+ overload by modulating mitochondrial Ca2+ homeostasis. By using a cardiac-specific transgenic (TG) mouse model in which VCP is overexpressed by 3.5 folds in the heart compared to the wild type (WT) mouse, we found that, under the pathological extra-mitochondrial Ca2+ overload, Ca2+ entry into cardiac mitochondria was reduced in VCP TG mice compared to their little-matched WT mice, subsequently preventing mPTP opening and ATP depletion under the Ca2+ challenge. Mechanistically, overexpression of VCP in the heart resulted in post-translational protein degradation of the mitochondrial Ca2+ uptake protein 1, an activator of the mitochondria Ca2+ uniporter that is responsible for mitochondrial calcium uptake. Together, our results reveal a new regulatory role of VCP in cardiac mitochondrial Ca2+ homeostasis and unlock the potential mechanism by which VCP confers its cardioprotection.
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Dedkova, Elena N., Xiang Ji, Stephen L. Lipsius, and Lothar A. Blatter. "Mitochondrial calcium uptake stimulates nitric oxide production in mitochondria of bovine vascular endothelial cells." American Journal of Physiology-Cell Physiology 286, no. 2 (February 2004): C406—C415. http://dx.doi.org/10.1152/ajpcell.00155.2003.
Повний текст джерелаАнотація:
Although nitric oxide (NO) is a known modulator of cell respiration in vascular endothelium, the presence of a mitochondria-specific nitric oxide synthase (mtNOS) in these cells is still a controversial issue. We have used laser scanning confocal microscopy in combination with the NO-sensitive fluorescent dye DAF-2 to monitor changes in NO production by mitochondria of calf vascular endothelial (CPAE) cells. Cells were loaded with the membrane-permeant NO-sensitive dye 4,5-diaminofluorescein (DAF-2) diacetate and subsequently permeabilized with digitonin to remove cytosolic DAF-2 to allow measurements of NO production in mitochondria ([NO]mt). Stimulation of mitochondrial Ca2+ uptake by exposure to different cytoplasmic Ca2+ concentrations (1, 2, and 5 μM) resulted in a dose-dependent increase of NO production by mitochondria. This increase of [NO]mt was sensitive to the NOS antagonist l- N5-(1-iminoethyl)ornithine and the calmodulin antagonist calmidazolium (R-24571), demonstrating the endogenous origin of NO synthesis and its calmodulin dependence. Collapsing the mitochondrial membrane potential with the protonophore FCCP or blocking the mitochondrial Ca2+ uniporter with ruthenium red, as well as blocking the respiratory chain with antimycin A in combination with oligomycin, inhibited mitochondrial NO production. Addition of the NO donor spermine NONOate caused a profound increase in DAF-2 fluorescence that was not affected by either of these treatments. The mitochondrial origin of the DAF-2 signals was confirmed by colocalization with the mitochondrial marker MitoTracker Red and by the observation that disruption of caveolae (where cytoplasmic NOS is localized) formation with methyl-β-cyclodextrin did not prevent the increase of DAF-2 fluorescence. The activation of mitochondrial calcium uptake stimulates mtNOS phosphorylation (at Ser-1177) which was prevented by FCCP. The data demonstrate that stimulation of mitochondrial Ca2+ uptake activates NO production in mitochondria of CPAE cells. This indicates the presence of a mitochondria-specific NOS that can provide a fast local modulatory effect of NO on cell respiration, membrane potential, and apoptosis.
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Tanzarella, Paola, Anna Ferretta, Simona Barile, Mariella Ancona, Domenico De Rasmo, Anna Signorile, Sergio Papa, Nazzareno Capitanio, Consiglia Pacelli, and Tiziana Cocco. "Increased Levels of cAMP by the Calcium-Dependent Activation of Soluble Adenylyl Cyclase in Parkin-Mutant Fibroblasts." Cells 8, no. 3 (March 15, 2019): 250. http://dx.doi.org/10.3390/cells8030250.
Повний текст джерелаАнотація:
Almost half of autosomal recessive early-onset parkinsonism has been associated with mutations in PARK2, coding for parkin, which plays an important role in mitochondria function and calcium homeostasis. Cyclic adenosine monophosphate (cAMP) is a major second messenger regulating mitochondrial metabolism, and it is strictly interlocked with calcium homeostasis. Parkin-mutant (Pt) fibroblasts, exhibiting defective mitochondrial respiratory/OxPhos activity, showed a significant higher value of basal intracellular level of cAMP, as compared with normal fibroblasts (CTRL). Specific pharmacological inhibition/activation of members of the adenylyl cyclase- and of the phosphodiesterase-families, respectively, as well as quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis, indicate that the higher level of cAMP observed in Pt fibroblasts can contribute to a higher level of activity/expression by soluble adenylyl cyclase (sAC) and to low activity/expression of the phosphodiesterase isoform 4 (PDE4). As Ca2+ regulates sAC, we performed quantitative calcium-fluorimetric analysis, showing a higher level of Ca2+ in the both cytosol and mitochondria of Pt fibroblasts as compared with CTRL. Most notably, inhibition of the mitochondrial Ca2+ uniporter decreased, specifically the cAMP level in PD fibroblasts. All together, these findings support the occurrence of an altered mitochondrial Ca2+-mediated cAMP homeostasis in fibroblasts with the parkin mutation.
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Dong, Hong, Bao Zhao, and Haitao Wen. "Mitochondrial calcium uniporter positively regulates phagocytosis-dependent activation of NLRP3 inflammasome." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 15.01. http://dx.doi.org/10.4049/jimmunol.206.supp.15.01.
Повний текст джерелаАнотація:
Abstract Mitochondria have been shown to play an essential role in the innate immune function and inflammatory response. Mitochondrial Ca2+ signaling, which is controlled by mitochondrial Ca2+ uniporter (MCU), is a fundamental mechanism regulating mitochondrial metabolism. Accumulative evidence suggests MCU-dependent mitochondrial Ca2+ signaling may bridge the metabolic reprogramming and regulation of immune cell function. However, the mechanism by which MCU regulates inflammation and its related disease remains elusive. Here we report a critical role of MCU in promoting phagocytosis-dependent activation of the NLRP3 inflammasome by dampening phagosome membrane repair. Myeloid deletion of MCU (McuΔmye) resulted in decreased caspase-1 cleavage and IL-1β maturation in response to the challenge with silica and alum, but not ATP and nigericin, in lipopolysaccharide (LPS)-primed macrophages. Stimulation with poly(dA:dT) or flagellin induced a similar IL-1β release between McuΔmye and wild-type (WT) macrophages. Mechanistically, we detected an enhanced phagosomal recruitment of ESCRT (endosomal sorting complex required for transport)-III complex in McuΔmye macrophages after silica or alum stimulation compared to similarly treated WT cells. ESCRT-III complex is known to be essential for repair of phagosomal membrane after damage, suggesting that deletion of MCU might lead to improved phagosomal membrane repair to limit NLRP3 inflammasome activation. Furthermore, McuΔmye mice showed attenuated inflammatory response and tissue damage in a chemically induced colitis model. In sum, our results identify a novel function and mechanism of MCU in regulating phagocytosis-dependent NLRP3 inflammatory response.
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Pandey, Vikas, Lai-Hua Xie, Zhilin Qu, and Zhen Song. "Mitochondrial depolarization promotes calcium alternans: Mechanistic insights from a ventricular myocyte model." PLOS Computational Biology 17, no. 1 (January 25, 2021): e1008624. http://dx.doi.org/10.1371/journal.pcbi.1008624.
Повний текст джерелаАнотація:
Mitochondria are vital organelles inside the cell and contribute to intracellular calcium (Ca2+) dynamics directly and indirectly via calcium exchange, ATP generation, and production of reactive oxygen species (ROS). Arrhythmogenic Ca2+ alternans in cardiac myocytes has been observed in experiments under abnormal mitochondrial depolarization. However, complex signaling pathways and Ca2+ cycling between mitochondria and cytosol make it difficult in experiments to reveal the underlying mechanisms of Ca2+ alternans under abnormal mitochondrial depolarization. In this study, we use a newly developed spatiotemporal ventricular myocyte computer model that integrates mitochondrial Ca2+ cycling and complex signaling pathways to investigate the mechanisms of Ca2+ alternans during mitochondrial depolarization. We find that elevation of ROS in response to mitochondrial depolarization plays a critical role in promoting Ca2+ alternans. Further examination reveals that the redox effect of ROS on ryanodine receptors and sarco/endoplasmic reticulum Ca2+-ATPase synergistically promote alternans. Upregulation of mitochondrial Ca2+ uniporter promotes Ca2+ alternans via Ca2+-dependent mitochondrial permeability transition pore opening. Due to their relatively slow kinetics, oxidized Ca2+/calmodulin-dependent protein kinase II activation and ATP do not play significant roles acutely in the genesis of Ca2+ alternans after mitochondrial depolarization, but their roles can be significant in the long term, mainly through their effects on sarco/endoplasmic reticulum Ca2+-ATPase activity. In conclusion, mitochondrial depolarization promotes Ca2+ alternans acutely via the redox effect of ROS and chronically by ATP reduction. It suppresses Ca2+ alternans chronically through oxidized Ca2+/calmodulin-dependent protein kinase II activation.
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Wang, Guoqiang, Elisabeth Mémin, Ishwarya Murali, and Lawrence D. Gaspers. "The effect of chronic alcohol consumption on mitochondrial calcium handling in hepatocytes." Biochemical Journal 473, no. 21 (October 27, 2016): 3903–21. http://dx.doi.org/10.1042/bcj20160255.
Повний текст джерелаАнотація:
The damage to liver mitochondria is universally observed in both humans and animal models after excessive alcohol consumption. Acute alcohol treatment has been shown to stimulate calcium (Ca2+) release from internal stores in hepatocytes. The resultant increase in cytosolic Ca2+ is expected to be accumulated by neighboring mitochondria, which could potentially lead to mitochondrial Ca2+ overload and injury. Our data indicate that total and free mitochondrial matrix Ca2+ levels are, indeed, elevated in hepatocytes isolated from alcohol-fed rats compared with their pair-fed control littermates. In permeabilized hepatocytes, the rates of mitochondrial Ca2+ uptake were substantially increased after chronic alcohol feeding, whereas those of mitochondrial Ca2+ efflux were decreased. The changes in mitochondrial Ca2+ handling could be explained by an up-regulation of the mitochondrial Ca2+ uniporter and loss of a cyclosporin A-sensitive Ca2+ transport pathway. In intact cells, hormone-induced increases in mitochondrial Ca2+ declined at slower rates leading to more prolonged elevations of matrix Ca2+ in the alcohol-fed group compared with controls. Moreover, treatment with submaximal concentrations of Ca2+-mobilizing hormones markedly increased the levels of mitochondrial reactive oxygen species (ROS) in hepatocytes from alcohol-fed rats, but did not affect ROS levels in controls. The changes in mitochondrial Ca2+ handling are expected to buffer and attenuate cytosolic Ca2+ increases induced by acute alcohol exposure or hormone stimulation. However, these alterations in mitochondrial Ca2+ handling may also lead to Ca2+ overload during cytosolic Ca2+ increases, which may stimulate the production of mitochondrial ROS, and thus contribute to alcohol-induced liver injury.
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Ghosh, Sagnika, Writoban Basu Ball, Travis R. Madaris, Subramanya Srikantan, Muniswamy Madesh, Vamsi K. Mootha, and Vishal M. Gohil. "An essential role for cardiolipin in the stability and function of the mitochondrial calcium uniporter." Proceedings of the National Academy of Sciences 117, no. 28 (June 29, 2020): 16383–90. http://dx.doi.org/10.1073/pnas.2000640117.
Повний текст джерелаАнотація:
Calcium uptake by the mitochondrial calcium uniporter coordinates cytosolic signaling events with mitochondrial bioenergetics. During the past decade all protein components of the mitochondrial calcium uniporter have been identified, including MCU, the pore-forming subunit. However, the specific lipid requirements, if any, for the function and formation of this channel complex are currently not known. Here we utilize yeast, which lacks the mitochondrial calcium uniporter, as a model system to address this problem. We use heterologous expression to functionally reconstitute human uniporter machinery both in wild-type yeast as well as in mutants defective in the biosynthesis of phosphatidylethanolamine, phosphatidylcholine, or cardiolipin (CL). We uncover a specific requirement of CL for in vivo reconstituted MCU stability and activity. The CL requirement of MCU is evolutionarily conserved with loss of CL triggering rapid turnover of MCU homologs and impaired calcium transport. Furthermore, we observe reduced abundance and activity of endogenous MCU in mammalian cellular models of Barth syndrome, which is characterized by a partial loss of CL. MCU abundance is also decreased in the cardiac tissue of Barth syndrome patients. Our work raises the hypothesis that impaired mitochondrial calcium transport contributes to the pathogenesis of Barth syndrome, and more generally, showcases the utility of yeast phospholipid mutants in dissecting the phospholipid requirements of ion channel complexes.
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Dikalov, Sergey I., Wei Li, Abdulrahman K. Doughan, Raul R. Blanco, and A. Maziar Zafari. "Mitochondrial reactive oxygen species and calcium uptake regulate activation of phagocytic NADPH oxidase." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 302, no. 10 (May 15, 2012): R1134—R1142. http://dx.doi.org/10.1152/ajpregu.00842.2010.
Повний текст джерелаАнотація:
Production of superoxide (O2·−) by NADPH oxidases contributes to the development of hypertension and atherosclerosis. Factors responsible for activation of NADPH oxidases are not well understood; interestingly, cardiovascular disease is associated with both altered NADPH oxidase activity and age-associated mitochondrial dysfunction. We hypothesized that mitochondrial dysfunction may contribute to activation of NADPH oxidase. The effect of mitochondrial inhibitors on phagocytic NADPH oxidase in human lymphoblasts and whole blood was measured at the basal state and upon PKC-dependent stimulation with PMA using extracellular 1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl-trimethylammonium or mitochondria-targeted 1-hydroxy-4-[2-triphenylphosphonio)-acetamido]-2,2,6,6-tetramethylpiperidine spin probes and electron spin resonance (ESR). Intracellular cytosolic calcium [Ca2+]iwas measured spectrofluorometrically using fura-2 AM. Incubation of lymphoblasts with the mitochondrial inhibitors rotenone, antimycin A, CCCP, or ruthenium red (an inhibitor of mitochondrial Ca2+uniporter) did not significantly change basal activity of NADPH oxidase. In contrast, preincubation with the mitochondrial inhibitors prior to PMA stimulation of lymphoblasts resulted in two- to three-fold increase of NADPH oxidase activity compared with stimulation with PMA alone. Most notably, the intracellular Ca2+-chelating agent BAPTA-AM abolished the effect of mitochondrial inhibitors on NADPH oxidase activity. Cytosolic Ca2+measurements with fura-2 AM showed that the mitochondrial inhibitors increased [Ca2+]i, while BAPTA-AM abolished the increase in [Ca2+]i. Furthermore, depletion of cellular Ca2+with thapsigargin attenuated CCCP- and antimycin A-mediated activation of NADPH oxidase in the presence of PMA by 42% and 31%, correspondingly. Our data suggest that mitochondria regulate PKC-dependent activation of phagocytic NADPH oxidase. In summary, increased mitochondrial O2·−and impaired buffering of cytosolic Ca2+by dysfunctional mitochondria result in enhanced NADPH oxidase activity, which may contribute to the development of cardiovascular diseases.
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Pallafacchina, Giorgia, Sofia Zanin, and Rosario Rizzuto. "Recent advances in the molecular mechanism of mitochondrial calcium uptake." F1000Research 7 (November 28, 2018): 1858. http://dx.doi.org/10.12688/f1000research.15723.1.
Повний текст джерелаАнотація:
In the last few decades, a large body of experimental evidence has highlighted the complex role for mitochondria in eukaryotic cells: they are not only the site of aerobic metabolism (thus providing most of the ATP supply for endergonic processes) but also a crucial checkpoint of cell death processes (both necrosis and apoptosis) and autophagy. For this purpose, mitochondria must receive and decode the wide variety of physiological and pathological stimuli impacting on the cell. The “old” notion that mitochondria possess a sophisticated machinery for accumulating and releasing Ca2+, the most common and versatile second messenger of eukaryotic cells, is thus no surprise. What may be surprising is that the identification of the molecules involved in mitochondrial Ca2+ transport occurred only in the last decade for both the influx (the mitochondrial Ca2+ uniporter, MCU) and the efflux (the sodium calcium exchanger, NCX) pathways. In this review, we will focus on the description of the amazing molecular complexity of the MCU complex, highlighting the numerous functional implications of the tissue-specific expression of the variants of the channel pore components (MCU/MCUb) and of the associated proteins (MICU 1, 2, and 3, EMRE, and MCUR1).
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Babcock, Donner F., James Herrington, Paul C. Goodwin, Young Bae Park, and Bertil Hille. "Mitochondrial Participation in the Intracellular Ca2+ Network." Journal of Cell Biology 136, no. 4 (February 24, 1997): 833–44. http://dx.doi.org/10.1083/jcb.136.4.833.
Повний текст джерелаАнотація:
Calcium can activate mitochondrial metabolism, and the possibility that mitochondrial Ca2+ uptake and extrusion modulate free cytosolic [Ca2+] (Cac) now has renewed interest. We use whole-cell and perforated patch clamp methods together with rapid local perfusion to introduce probes and inhibitors to rat chromaffin cells, to evoke Ca2+ entry, and to monitor Ca2+-activated currents that report near-surface [Ca2+]. We show that rapid recovery from elevations of Cac requires both the mitochondrial Ca2+ uniporter and the mitochondrial energization that drives Ca2+ uptake through it. Applying imaging and single-cell photometric methods, we find that the probe rhod-2 selectively localizes to mitochondria and uses its responses to quantify mitochondrial free [Ca2+] (Cam). The indicated resting Cam of 100–200 nM is similar to the resting Cac reported by the probes indo-1 and Calcium Green, or its dextran conjugate in the cytoplasm. Simultaneous monitoring of Cam and Cac at high temporal resolution shows that, although Cam increases less than Cac, mitochondrial sequestration of Ca2+ is fast and has high capacity. We find that mitochondrial Ca2+ uptake limits the rise and underlies the rapid decay of Cac excursions produced by Ca2+ entry or by mobilization of reticular stores. We also find that subsequent export of Ca2+ from mitochondria, seen as declining Cam, prolongs complete Cac recovery and that suppressing export of Ca2+, by inhibition of the mitochondrial Na+/ Ca2+ exchanger, reversibly hastens final recovery of Cac. We conclude that mitochondria are active participants in cellular Ca2+ signaling, whose unique role is determined by their ability to rapidly accumulate and then release large quantities of Ca2+.