Calcium ions (Ca2+) are some of the most versatile signalling molecules, and they have many physiological functions, prominently including muscle contraction, neuronal excitability, cell migration and cell growth. By sequestering and releasing Ca2+, mitochondria serve as important regulators of cellular Ca2+. Mitochondrial Ca2+ also has other important functions, such as regulation of mitochondrial metabolism, ATP production and cell death. In recent years, identification of the molecular machinery regulating mitochondrial Ca2+ accumulation and efflux has expanded the number of (patho)physiological conditions that rely on mitochondrial Ca2+ homeostasis. Thus, expanding the understanding of the mechanisms of mitochondrial Ca2+ regulation and function in different cell types is an important task in biomedical research, which offers the possibility of targeting mitochondrial Ca2+ machinery for the treatment of several disorders.
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Berridge, M. J., Lipp, P. & Bootman, M. D. The versatility and universality of calcium signalling. Nat. Rev. Mol. Cell Biol. 1, 11–21 (2000).
Giorgi, C., Danese, A., Missiroli, S., Patergnani, S. & Pinton, P. Calcium dynamics as a machine for decoding signals. Trends Cell Biol. 28, 258–273 (2018).
Carafoli, E. Historical review: mitochondria and calcium: ups and downs of an unusual relationship. Trends Biochem. Sci. 28, 175–181 (2003).
Slater, E. C. & Cleland, K. W. The calcium content of isolated heart-muscle sarcosomes. Biochem J. 54, xxii (1953). This study provides the first historical evidence indicating Ca 2+ transport inside mitochondria.
Deluca, H. F. & Engstrom, G. W. Calcium uptake by rat kidney mitochondria. Proc. Natl Acad. Sci. USA 47, 1744–1750 (1961).
Vasington, F. D. & Murphy, J. V. Ca ion uptake by rat kidney mitochondria and its dependence on respiration and phosphorylation. J. Biol. Chem. 237, 2670–2677 (1962).
Prakriya, M. & Lewis, R. S. Store-operated calcium channels. Physiol. Rev. 95, 1383–1436 (2015).
Shoshan-Barmatz, V. & Mizrachi, D. VDAC1: from structure to cancer therapy. Front. Oncol. 2, 164 (2012).
Messina, A., Reina, S., Guarino, F. & De Pinto, V. VDAC isoforms in mammals. Biochim. Biophys. Acta 1818, 1466–1476 (2012).
Shoshan-Barmatz, V., Krelin, Y. & Shteinfer-Kuzmine, A. VDAC1 functions in Ca(2+) homeostasis and cell life and death in health and disease. Cell Calcium 69, 81–100 (2018).
Colombini, M. VDAC structure, selectivity, and dynamics. Biochim. Biophys. Acta 1818, 1457–1465 (2012).
Tan, W. & Colombini, M. VDAC closure increases calcium ion flux. Biochim. Biophys. Acta 1768, 2510–2515 (2007).
Adams, V., Bosch, W., Schlegel, J., Wallimann, T. & Brdiczka, D. Further characterization of contact sites from mitochondria of different tissues: topology of peripheral kinases. Biochim. Biophys. Acta 981, 213–225 (1989).
De Stefani, D. et al. VDAC1 selectively transfers apoptotic Ca2+ signals to mitochondria. Cell Death Differ. 19, 267–273 (2012).
Shimizu, H. et al. Mitochondrial Ca(2+) uptake by the voltage-dependent anion channel 2 regulates cardiac rhythmicity. Elife 4, e04801 (2015).
Baines, C. P., Kaiser, R. A., Sheiko, T., Craigen, W. J. & Molkentin, J. D. Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nat. Cell Biol. 9, 550–555 (2007).
Ryu, S. Y., Beutner, G., Dirksen, R. T., Kinnally, K. W. & Sheu, S. S. Mitochondrial ryanodine receptors and other mitochondrial Ca2+ permeable channels. FEBS Lett. 584, 1948–1955 (2010).
Feng, S. et al. Canonical transient receptor potential 3 channels regulate mitochondrial calcium uptake. Proc. Natl Acad. Sci. USA 110, 11011–11016 (2013).
Trenker, M., Malli, R., Fertschai, I., Levak-Frank, S. & Graier, W. F. Uncoupling proteins 2 and 3 are fundamental for mitochondrial Ca2+ uniport. Nat. Cell Biol. 9, 445–452 (2007).
Jiang, D., Zhao, L. & Clapham, D. E. Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter. Science 326, 144–147 (2009). This study indicates that the IMM protein LETM1 functions as the HCXs.
Kamer, K. J. & Mootha, V. K. The molecular era of the mitochondrial calcium uniporter. Nat. Rev. Mol. Cell Biol. 16, 545–553 (2015).
Marchi, S. & Pinton, P. The mitochondrial calcium uniporter complex: molecular components, structure and physiopathological implications. J. Physiol. 592, 829–839 (2014).
Foskett, J. K. & Philipson, B. The mitochondrial Ca(2+) uniporter complex. J. Mol. Cell. Cardiol. 78, 3–8 (2015).
Baughman, J. M. et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476, 341–345 (2011).
De Stefani, D., Raffaello, A., Teardo, E., Szabo, I. & Rizzuto, R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476, 336–340 (2011).
Raffaello, A. et al. The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit. EMBO J. 32, 2362–2376 (2013).
Perocchi, F. et al. MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake. Nature 467, 291–296 (2010). This study details the characterization of the first component of the mitochondrial uniporter complex, which paved the way for the identification of the other members, MCU (references 24 and 25), MCUb (reference 26), MICU2 (reference 28) and EMRE (reference 31).
Plovanich, M. et al. MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling. PLOS One 8, e55785 (2013).
Patron, M. et al. MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity. Mol. Cell 53, 726–737 (2014).
Petrungaro, C. et al. The Ca(2+)-dependent release of the Mia40-induced MICU1-MICU2 dimer from MCU regulates mitochondrial Ca(2+) uptake. Cell Metab. 22, 721–733 (2015).
Sancak, Y. et al. EMRE is an essential component of the mitochondrial calcium uniporter complex. Science 342, 1379–1382 (2013).
Vecellio Reane, D. et al. A MICU1 splice variant confers high sensitivity to the mitochondrial Ca2+ uptake machinery of skeletal muscle. Mol. Cell 64, 760–773 (2016).
Csordas, G. et al. MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca(2)(+) uniporter. Cell Metab. 17, 976–987 (2013).
Mallilankaraman, K. et al. MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca(2+) uptake that regulates cell survival. Cell 151, 630–644 (2012).
Liu, J. C. et al. MICU1 serves as a molecular gatekeeper to prevent in vivo mitochondrial calcium overload. Cell Rep. 16, 1561–1573 (2016).
Payne, R., Hoff, H., Roskowski, A. & Foskett, J. K. MICU2 restricts spatial crosstalk between InsP3R and MCU Channels by regulating threshold and gain of MICU1-mediated inhibition and activation of MCU. Cell Rep. 21, 3141–3154 (2017).
Kamer, K. J., Grabarek, Z. & Mootha, V. K. High-affinity cooperative Ca(2+) binding by MICU1-MICU2 serves as an on-off switch for the uniporter. EMBO Rep. 18, 1397–1411 (2017).
Matesanz-Isabel, J. et al. Functional roles of MICU1 and MICU2 in mitochondrial Ca(2+) uptake. Biochim. Biophys. Acta 1858, 1110–1117 (2016).
Oxenoid, K. et al. Architecture of the mitochondrial calcium uniporter. Nature 533, 269–273 (2016).
Yoo, J. et al. Cryo-EM structure of a mitochondrial calcium uniporter. Science 361, 506–511 (2018).
Nguyen, N. X. et al. Cryo-EM structure of a fungal mitochondrial calcium uniporter. Nature 559, 570–574 (2018).
Fan, C. et al. X-ray and cryo-EM structures of the mitochondrial calcium uniporter. Nature 559, 575–579 (2018).
Baradaran, R., Wang, C., Siliciano, A. F. & Long, S. B. Cryo-EM structures of fungal and metazoan mitochondrial calcium uniporters. Nature 559, 580–584 (2018).
Vais, H. et al. EMRE Is a matrix Ca(2+) sensor that governs gatekeeping of the mitochondrial Ca(2+) uniporter. Cell Rep. 14, 403–410 (2016).
Yamamoto, T. et al. Analysis of the structure and function of EMRE in a yeast expression system. Biochim. Biophys. Acta 1857, 831–839 (2016).
Tsai, M. F. et al. Dual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex. Elife 5, e15545 (2016).
Chiurillo, M. A. et al. Different roles of mitochondrial calcium uniporter complex subunits in growth and infectivity of Trypanosoma cruzi. MBio 8, e00574–17 (2017).
Kirichok, Y., Krapivinsky, G. & Clapham, D. E. The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427, 360–364 (2004).
Bragadin, M., Pozzan, T. & Azzone, G. F. Kinetics of Ca2+ carrier in rat liver mitochondria. Biochemistry 18, 5972–5978 (1979).
Babcock, D. F., Herrington, J., Goodwin, P. C., Park, Y. B. & Hille, B. Mitochondrial participation in the intracellular Ca2+ network. J. Cell Biol. 136, 833–844 (1997).
Friel, D. D. & Tsien, R. W. An FCCP-sensitive Ca2+ store in bullfrog sympathetic neurons and its participation in stimulus-evoked changes in [Ca2+]i. J. Neurosci. 14, 4007–4024 (1994).
Rizzuto, R. et al. Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science 280, 1763–1766 (1998). This study demonstrates the crucial role of ER–mitochondria contacts in rapid mitochondrial Ca 2+ accumulation.
Gaigg, B., Simbeni, R., Hrastnik, C., Paltauf, F. & Daum, G. Characterization of a microsomal subfraction associated with mitochondria of the yeast. Saccharomyces cerevisiae. Involvement in synthesis and import of phospholipids into mitochondria. Biochim. Biophys. Acta 1234, 214–220 (1995).
Willson, V. J. & Tipton, K. F. Purification and characterization of ox brain NAD+-dependent isocitrate dehydrogenase. J. Neurochem. 33, 1239–1247 (1979).
Giorgi, C. et al. Mitochondria-associated membranes: composition, molecular mechanisms, and physiopathological implications. Antioxid. Redox Signal. 22, 995–1019 (2015).
Giacomello, M. et al. Ca2+ hot spots on the mitochondrial surface are generated by Ca2+ mobilization from stores, but not by activation of store-operated Ca2+ channels. Mol. Cell 38, 280–290 (2010).
Suski, J. M. et al. Isolation of plasma membrane-associated membranes from rat liver. Nat. Protoc. 9, 312–322 (2014).
Jung, D. W., Baysal, K. & Brierley, G. P. The sodium-calcium antiport of heart mitochondria is not electroneutral. J. Biol. Chem. 270, 672–678 (1995).
Dash, R. K. & Beard, D. A. Analysis of cardiac mitochondrial Na+-Ca2+ exchanger kinetics with a biophysical model of mitochondrial Ca2+ handling suggests a 3:1 stoichiometry. J. Physiol. 586, 3267–3285 (2008).
Gunter, K. K., Zuscik, M. J. & Gunter, T. E. The Na(+)-independent Ca2+ efflux mechanism of liver mitochondria is not a passive Ca2+/2H+ exchanger. J. Biol. Chem. 266, 21640–21648 (1991).
Scorziello, A. et al. NCX3 regulates mitochondrial Ca(2+) handling through the AKAP121-anchored signaling complex and prevents hypoxia-induced neuronal death. J. Cell Sci. 126, 5566–5577 (2013).
Palty, R. et al. NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. Proc. Natl Acad. Sci. USA 107, 436–441 (2010). This study identifies NCLX as the mitochondrial NCX.
Crompton, M., Kunzi, M. & Carafoli, E. The calcium-induced and sodium-induced effluxes of calcium from heart mitochondria. Evidence for a sodium-calcium carrier. Eur. J. Biochem. 79, 549–558 (1977).
De Marchi, U. et al. NCLX protein, but not LETM1, mediates mitochondrial Ca2+ extrusion, thereby limiting Ca2+-induced NAD(P)H production and modulating matrix redox state. J. Biol. Chem. 289, 20377–20385 (2014).
Kim, B., Takeuchi, A., Hikida, M. & Matsuoka, S. Roles of the mitochondrial Na(+)-Ca(2+) exchanger, NCLX, in B lymphocyte chemotaxis. Sci. Rep. 6, 28378 (2016).
Luongo, T. S. et al. The mitochondrial Na(+)/Ca(2+) exchanger is essential for Ca(2+) homeostasis and viability. Nature 545, 93–97 (2017). This study shows that mitochondrial Ca 2+ efflux through NCLX is crucial for cardiac homeostasis.
Shao, J. et al. Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) forms a Ca2+/H+ antiporter. Sci. Rep. 6, 34174 (2016).
Nowikovsky, K., Pozzan, T., Rizzuto, R., Scorrano, L. & Bernardi, P. Perspectives on: SGP symposium on mitochondrial physiology and medicine: the pathophysiology of LETM1. J. Gen. Physiol. 139, 445–454 (2012).
Froschauer, E., Nowikovsky, K. & Schweyen, R. J. Electroneutral K+/H+ exchange in mitochondrial membrane vesicles involves Yol027/Letm1 proteins. Biochim. Biophys. Acta 1711, 41–48 (2005).
Nowikovsky, K. et al. The LETM1/YOL027 gene family encodes a factor of the mitochondrial K+ homeostasis with a potential role in the Wolf-Hirschhorn syndrome. J. Biol. Chem. 279, 30307–30315 (2004). In conflict with reference 20, this study shows that LETM1 mediates mitochondrial K + /H + exchange.
Hashimi, H., McDonald, L., Stribrna, E. & Lukes, J. Trypanosome Letm1 protein is essential for mitochondrial potassium homeostasis. J. Biol. Chem. 288, 26914–26925 (2013).
Tsai, M. F., Jiang, D., Zhao, L., Clapham, D. & Miller, C. Functional reconstitution of the mitochondrial Ca2+/H+ antiporter Letm1. J. Gen. Physiol. 143, 67–73 (2014).
Quan, X. et al. Essential role of mitochondrial Ca2+ uniporter in the generation of mitochondrial pH gradient and metabolism-secretion coupling in insulin-releasing cells. J. Biol. Chem. 290, 4086–4096 (2015).
Doonan, P. J. et al. LETM1-dependent mitochondrial Ca2+ flux modulates cellular bioenergetics and proliferation. FASEB J. 28, 4936–4949 (2014).
Waldeck-Weiermair, M. et al. Leucine zipper EF hand-containing transmembrane protein 1 (Letm1) and uncoupling proteins 2 and 3 (UCP2/3) contribute to two distinct mitochondrial Ca2+ uptake pathways. J. Biol. Chem. 286, 28444–28455 (2011).
Elrod, J. W. et al. Cyclophilin D controls mitochondrial pore-dependent Ca(2+) exchange, metabolic flexibility, and propensity for heart failure in mice. J. Clin. Invest. 120, 3680–3687 (2010).
Lu, X., Kwong, J. Q., Molkentin, J. D. & Bers, D. M. Individual cardiac mitochondria undergo rare transient permeability transition pore openings. Circ. Res. 118, 834–841 (2016).
De Marchi, E., Bonora, M., Giorgi, C. & Pinton, P. The mitochondrial permeability transition pore is a dispensable element for mitochondrial calcium efflux. Cell Calcium 56, 1–13 (2014).
Rostovtseva, T. K. & Bezrukov, S. M. VDAC regulation: role of cytosolic proteins and mitochondrial lipids. J. Bioenerg. Biomembr. 40, 163–170 (2008).
Huang, H. et al. An interaction between Bcl-xL and the voltage-dependent anion channel (VDAC) promotes mitochondrial Ca2+ uptake. J. Biol. Chem. 288, 19870–19881 (2013).
Arbel, N., Ben-Hail, D. & Shoshan-Barmatz, V. Mediation of the antiapoptotic activity of Bcl-xL protein upon interaction with VDAC1 protein. J. Biol. Chem. 287, 23152–23161 (2012).
Vander Heiden, M. G. et al. Bcl-xL promotes the open configuration of the voltage-dependent anion channel and metabolite passage through the outer mitochondrial membrane. J. Biol. Chem. 276, 19414–19419 (2001).
Pavlov, E. et al. The mitochondrial channel VDAC has a cation-selective open state. Biochim. Biophys. Acta 1710, 96–102 (2005).
Monaco, G. et al. The BH4 domain of anti-apoptotic Bcl-XL, but not that of the related Bcl-2, limits the voltage-dependent anion channel 1 (VDAC1)-mediated transfer of pro-apoptotic Ca2+ signals to mitochondria. J. Biol. Chem. 290, 9150–9161 (2015).
Mallilankaraman, K. et al. MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism. Nat. Cell Biol. 14, 1336–1343 (2012).
Lee, Y. et al. Structure and function of the N-terminal domain of the human mitochondrial calcium uniporter. EMBO Rep. 16, 1318–1333 (2015).
Vais, H. et al. MCUR1, CCDC90A, is a regulator of the mitochondrial calcium uniporter. Cell Metab. 22, 533–535 (2015).
Chaudhuri, D., Artiga, D. J., Abiria, S. A. & Clapham, D. E. Mitochondrial calcium uniporter regulator 1 (MCUR1) regulates the calcium threshold for the mitochondrial permeability transition. Proc. Natl Acad. Sci. USA 113, E1872–E1880 (2016).
Tomar, D. et al. MCUR1 Is a scaffold factor for the MCU complex function and promotes mitochondrial bioenergetics. Cell Rep. 15, 1673–1685 (2016).
Paupe, V., Prudent, J., Dassa, E. P., Rendon, O. Z. & Shoubridge, E. A. CCDC90A (MCUR1) is a cytochrome c oxidase assembly factor and not a regulator of the mitochondrial calcium uniporter. Cell Metab. 21, 109–116 (2015).
Ren, T. et al. MCUR1-mediated mitochondrial calcium signaling facilitates cell survival of hepatocellular carcinoma via reactive oxygen species-dependent p53 degradation. Antioxid. Redox Signal. https://doi.org/10.1089/ars.2017.6990 (2017).
Hoffman, N. E. et al. SLC25A23 augments mitochondrial Ca(2)(+) uptake, interacts with MCU, and induces oxidative stress-mediated cell death. Mol. Biol. Cell 25, 936–947 (2014).
del Arco, A. & Satrustegui, J. Identification of a novel human subfamily of mitochondrial carriers with calcium-binding domains. J. Biol. Chem. 279, 24701–24713 (2004).
Fiermonte, G. et al. Identification of the mitochondrial ATP-Mg/Pi transporter. Bacterial expression, reconstitution, functional characterization, and tissue distribution. J. Biol. Chem. 279, 30722–30730 (2004).
de Brito, O. M. & Scorrano, L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456, 605–610 (2008).
Filadi, R. et al. Mitofusin 2 ablation increases endoplasmic reticulum-mitochondria coupling. Proc. Natl Acad. Sci. USA 112, E2174–E2181 (2015).
Zhang, S. & Sodroski, J. Efficient human immunodeficiency virus (HIV-1) infection of cells lacking PDZD8. Virology 481, 73–78 (2015).
Hirabayashi, Y. et al. ER-mitochondria tethering by PDZD8 regulates Ca(2+) dynamics in mammalian neurons. Science 358, 623–630 (2017). This study identifies PDZD8 as the mammalian orthologue of Mmm1, the yeast ER component of the ERMES complex, a protein complex that tethers the ER to mitochondria.
De Vos, K. J. et al. VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis. Hum. Mol. Genet. 21, 1299–1311 (2012).
Paillusson, S. et al. alpha-Synuclein binds to the ER-mitochondria tethering protein VAPB to disrupt Ca(2+) homeostasis and mitochondrial ATP production. Acta Neuropathol. 134, 129–149 (2017).
Stoica, R. et al. ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43. Nat. Commun. 5, 3996 (2014).
Pinton, P., Leo, S., Wieckowski, M. R., Di Benedetto, G. & Rizzuto, R. Long-term modulation of mitochondrial Ca2+ signals by protein kinase C isozymes. J. Cell Biol. 165, 223–232 (2004).
Kostic, M. et al. PKA phosphorylation of NCLX reverses mitochondrial calcium overload and depolarization, promoting survival of PINK1-deficient dopaminergic neurons. Cell Rep. 13, 376–386 (2015).
Huang, E. et al. PINK1-mediated phosphorylation of LETM1 regulates mitochondrial calcium transport and protects neurons against mitochondrial stress. Nat. Commun. 8, 1399 (2017).
Martel, C. et al. Glycogen synthase kinase 3-mediated voltage-dependent anion channel phosphorylation controls outer mitochondrial membrane permeability during lipid accumulation. Hepatology 57, 93–102 (2013).
Dong, Z. et al. Mitochondrial Ca(2+) uniporter is a mitochondrial luminal redox sensor that augments MCU channel activity. Mol. Cell 65, 1014–1028 (2017).
O.-Uchi, J. et al. Adrenergic signaling regulates mitochondrial Ca2+ uptake through Pyk2-dependent tyrosine phosphorylation of the mitochondrial Ca2+ uniporter. Antioxid. Redox Signal. 21, 863–879 (2014).
Joiner, M. L. et al. CaMKII determines mitochondrial stress responses in heart. Nature 491, 269–273 (2012). This study describes the first post-translational modification (phosphorylation) of the MCU complex and its role in heart failure. This work is in conflict with reference 110.
Nguyen, E. K. et al. CaMKII (Ca(2+)/calmodulin-dependent kinase II) in mitochondria of smooth muscle cells controls mitochondrial mobility, migration, and neointima formation. Arterioscler. Thromb. Vasc. Biol. 38, 1333–1345 (2018).
Fieni, F., Johnson, D. E., Hudmon, A. & Kirichok, Y. Mitochondrial Ca2+ uniporter and CaMKII in heart. Nature 513, E1–E2 (2014).
Madreiter-Sokolowski, C. T. et al. PRMT1-mediated methylation of MICU1 determines the UCP2/3 dependency of mitochondrial Ca(2+) uptake in immortalized cells. Nat. Commun. 7, 12897 (2016).
Konig, T. et al. The m-AAA protease associated with neurodegeneration limits MCU activity in mitochondria. Mol. Cell 64, 148–162 (2016).
Tsai, C. W. et al. Proteolytic control of the mitochondrial calcium uniporter complex. Proc. Natl Acad. Sci. USA 114, 4388–4393 (2017).
Pizzo, P., Drago, I., Filadi, R. & Pozzan, T. Mitochondrial Ca(2)(+) homeostasis: mechanism, role, and tissue specificities. Pflugers Arch. 464, 3–17 (2012).
Bers, D. M. Cardiac excitation-contraction coupling. Nature 415, 198–205 (2002).
Williams, G. S., Boyman, L., Chikando, A. C., Khairallah, R. J. & Lederer, W. J. Mitochondrial calcium uptake. Proc. Natl Acad. Sci. USA 110, 10479–10486 (2013).
Parnis, J. et al. Mitochondrial exchanger NCLX plays a major role in the intracellular Ca2+ signaling, gliotransmission, and proliferation of astrocytes. J. Neurosci. 33, 7206–7219 (2013).
Deak, A. T. et al. IP3-mediated STIM1 oligomerization requires intact mitochondrial Ca2+ uptake. J. Cell Sci. 127, 2944–2955 (2014).
Gilabert, J. A., Bakowski, D. & Parekh, A. B. Energized mitochondria increase the dynamic range over which inositol 1,4,5-trisphosphate activates store-operated calcium influx. EMBO J. 20, 2672–2679 (2001).
Rizzuto, R., De Stefani, D., Raffaello, A. & Mammucari, C. Mitochondria as sensors and regulators of calcium signalling. Nat. Rev. Mol. Cell Biol. 13, 566–578 (2012).
Parekh, A. B. Regulation of CRAC channels by Ca2+-dependent inactivation. Cell Calcium 63, 20–23 (2017).
Samanta, K., Douglas, S. & Parekh, A. B. Mitochondrial calcium uniporter MCU supports cytoplasmic Ca2+ oscillations, store-operated Ca2+ entry and Ca2+-dependent gene expression in response to receptor stimulation. PLOS One 9, e101188 (2014).
Wacquier, B., Combettes, L., Van Nhieu, G. T. & Dupont, G. Interplay between intracellular Ca(2+) oscillations and Ca(2+)-stimulated mitochondrial metabolism. Sci. Rep. 6, 19316 (2016).
Tinel, H. et al. Active mitochondria surrounding the pancreatic acinar granule region prevent spreading of inositol trisphosphate-evoked local cytosolic Ca(2+) signals. EMBO J. 18, 4999–5008 (1999). This study demonstrates that mitochondrial Ca 2+ -buffering capacity is essential to shape cytosolic Ca 2+ signals and to regulate secretion in acinar cells.
Billups, B. & Forsythe, I. D. Presynaptic mitochondrial calcium sequestration influences transmission at mammalian central synapses. J. Neurosci. 22, 5840–5847 (2002).
Drago, I., De Stefani, D., Rizzuto, R. & Pozzan, T. Mitochondrial Ca2+ uptake contributes to buffering cytoplasmic Ca2+ peaks in cardiomyocytes. Proc. Natl Acad. Sci. USA 109, 12986–12991 (2012).
Kwong, J. Q. et al. The mitochondrial calcium uniporter selectively matches metabolic output to acute contractile stress in the heart. Cell Rep. 12, 15–22 (2015).
Lu, X. et al. Measuring local gradients of intramitochondrial [Ca(2+)] in cardiac myocytes during sarcoplasmic reticulum Ca(2+) release. Circ. Res. 112, 424–431 (2013).
Tang, S. et al. Mitochondrial Ca(2)(+) uniporter is critical for store-operated Ca(2)(+) entry-dependent breast cancer cell migration. Biochem. Biophys. Res. Commun. 458, 186–193 (2015).
Tosatto, A. et al. The mitochondrial calcium uniporter regulates breast cancer progression via HIF-1alpha. EMBO Mol. Med. 8, 569–585 (2016).
Quintana, A. et al. T cell activation requires mitochondrial translocation to the immunological synapse. Proc. Natl Acad. Sci. USA 104, 14418–14423 (2007).
Medina, D. L. et al. Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB. Nat. Cell Biol. 17, 288–299 (2015).
Sbano, L. et al. TFEB-mediated increase in peripheral lysosomes regulates store-operated calcium entry. Sci. Rep. 7, 40797 (2017).
Lee, K. P., Yuan, J. P., So, I., Worley, P. F. & Muallem, S. STIM1-dependent and STIM1-independent function of transient receptor potential canonical (TRPC) channels tunes their store-operated mode. J. Biol. Chem. 285, 38666–38673 (2010).
Ben-Kasus Nissim, T. et al. Mitochondria control store-operated Ca2+ entry through Na+ and redox signals. EMBO J. 36, 797–815 (2017).
McCormack, J. G. & Denton, R. M. The effects of calcium ions and adenine nucleotides on the activity of pig heart 2-oxoglutarate dehydrogenase complex. Biochem. J. 180, 533–544 (1979). This study demonstrates that increases in intramitochondrial free Ca 2+ result in activation of mitochondrial dehydrogenases and stimulation of ATP synthesis.
Jouaville, L. S., Pinton, P., Bastianutto, C., Rutter, G. A. & Rizzuto, R. Regulation of mitochondrial ATP synthesis by calcium: evidence for a long-term metabolic priming. Proc. Natl Acad. Sci. USA 96, 13807–13812 (1999). Reinforces findings presented in reference 136, showing that mitochondrial Ca 2+ rises stably elevate mitochondrial [ATP].
Giorgi, C. et al. Mitochondrial Ca(2+) and apoptosis. Cell Calcium 52, 36–43 (2012).
Rimessi, A. et al. Perturbed mitochondrial Ca signals as causes or consequences of mitophagy induction. Autophagy 9, 1677–1686 (2013).
Marchi, S. et al. Mitochondrial and endoplasmic reticulum calcium homeostasis and cell death. Cell Calcium 69, 62–72 (2018).
Schuit, F. C., In’t Veld, P. A. & Pipeleers, D. G. Glucose stimulates proinsulin biosynthesis by a dose-dependent recruitment of pancreatic beta cells. Proc. Natl Acad. Sci. USA 85, 3865–3869 (1988).
Wiederkehr, A. & Wollheim, C. B. Mitochondrial signals drive insulin secretion in the pancreatic beta-cell. Mol. Cell Endocrinol. 353, 128–137 (2012).
Hoppa, M. B. et al. Chronic palmitate exposure inhibits insulin secretion by dissociation of Ca(2+) channels from secretory granules. Cell Metab. 10, 455–465 (2009).
Tarasov, A. I. et al. The mitochondrial Ca2+ uniporter MCU is essential for glucose-induced ATP increases in pancreatic beta-cells. PLOS One 7, e39722 (2012).
Gilon, P., Chae, H. Y., Rutter, G. A. & Ravier, M. A. Calcium signaling in pancreatic beta-cells in health and in Type 2 diabetes. Cell Calcium 56, 340–361 (2014).
Rutter, G. A., Tsuboi, T. & Ravier, M. A. Ca2+ microdomains and the control of insulin secretion. Cell Calcium 40, 539–551 (2006).
Pinton, P. et al. Dynamics of glucose-induced membrane recruitment of protein kinase C beta II in living pancreatic islet beta-cells. J. Biol. Chem. 277, 37702–37710 (2002).
Wiederkehr, A. et al. Mitochondrial matrix calcium is an activating signal for hormone secretion. Cell Metab. 13, 601–611 (2011). This study demonstrates a key role of mitochondrial Ca 2+ in metabolism-driven insulin and aldosterone secretion.
Tarasov, A. I. et al. Frequency-dependent mitochondrial Ca(2+) accumulation regulates ATP synthesis in pancreatic beta cells. Pflugers Arch. 465, 543–554 (2013).
Varadi, A. & Rutter, G. A. Ca2+-induced Ca2+ release in pancreatic islet beta-cells: critical evaluation of the use of endoplasmic reticulum-targeted “cameleons”. Endocrinology 145, 4540–4549 (2004).
Santulli, G. et al. Calcium release channel RyR2 regulates insulin release and glucose homeostasis. J. Clin. Invest. 125, 1968–1978 (2015).
Wright, L. E. et al. Increased mitochondrial calcium uniporter in adipocytes underlies mitochondrial alterations associated with insulin resistance. Am. J. Physiol. Endocrinol. Metab. 313, E641–E650 (2017).
Vierra, N. C. et al. TALK-1 channels control beta cell endoplasmic reticulum Ca(2+) homeostasis. Sci. Signal 10, eaan2883 (2017).
Alam, M. R. et al. Mitochondrial Ca2+ uptake 1 (MICU1) and mitochondrial ca2+ uniporter (MCU) contribute to metabolism-secretion coupling in clonal pancreatic beta-cells. J. Biol. Chem. 287, 34445–34454 (2012).
Murgia, M., Giorgi, C., Pinton, P. & Rizzuto, R. Controlling metabolism and cell death: at the heart of mitochondrial calcium signalling. J. Mol. Cell Cardiol. 46, 781–788 (2009).
Bers, D. M. Calcium cycling and signaling in cardiac myocytes. Annu. Rev. Physiol. 70, 23–49 (2008).
Torrente, A. G. et al. Burst pacemaker activity of the sinoatrial node in sodium-calcium exchanger knockout mice. Proc. Natl Acad. Sci. USA 112, 9769–9774 (2015).
Mesirca, P. et al. Cardiac arrhythmia induced by genetic silencing of ‘funny’ (f) channels is rescued by GIRK4 inactivation. Nat. Commun. 5, 4664 (2014).
Perez-Reyes, E. Molecular physiology of low-voltage-activated t-type calcium channels. Physiol. Rev. 83, 117–161 (2003).
Mesirca, P., Torrente, A. G. & Mangoni, M. E. Functional role of voltage gated Ca(2+) channels in heart automaticity. Front. Physiol. 6, 19 (2015).
Viola, H. M., Arthur, P. G. & Hool, L. C. Evidence for regulation of mitochondrial function by the L-type Ca2+ channel in ventricular myocytes. J. Mol. Cell Cardiol. 46, 1016–1026 (2009).
Cannell, M. B., Cheng, H. & Lederer, W. J. The control of calcium release in heart muscle. Science 268, 1045–1049 (1995).
Santulli, G., Nakashima, R., Yuan, Q. & Marks, A. R. Intracellular calcium release channels: an update. J. Physiol. 595, 3041–3051 (2017).
Gambardella, J., Trimarco, B., Iaccarino, G. & Santulli, G. New insights in cardiac calcium handling and excitation-contraction coupling. Adv. Exp. Med. Biol. 1067, 373–385 (2017).
Gambardella, J. et al. Functional Role of Mitochondria in Arrhythmogenesis. Adv. Exp. Med. Biol. 982, 191–202 (2017).
Wu, Y. et al. The mitochondrial uniporter controls fight or flight heart rate increases. Nat. Commun. 6, 6081 (2015).
Bick, A. G. et al. Cardiovascular homeostasis dependence on MICU2, a regulatory subunit of the mitochondrial calcium uniporter. Proc. Natl Acad. Sci. USA 114, E9096–E9104 (2017).
O’Rourke, B. & Blatter, L. A. Mitochondrial Ca2+ uptake: tortoise or hare? J. Mol. Cell Cardiol. 46, 767–774 (2009).
Griffiths, E. J. Mitochondrial calcium transport in the heart: physiological and pathological roles. J. Mol. Cell Cardiol. 46, 789–803 (2009).
Piot, C. et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N. Engl. J. Med. 359, 473–481 (2008).
Cung, T. T. et al. Cyclosporine before PCI in patients with acute myocardial infarction. N. Engl. J. Med. 373, 1021–1031 (2015).
Bonora, M. et al. Mitochondrial permeability transition involves dissociation of F1FO ATP synthase dimers and C-ring conformation. EMBO Rep. 18, 1077–1089 (2017).
Luongo, T. S. et al. The mitochondrial calcium uniporter matches energetic supply with cardiac workload during stress and modulates permeability transition. Cell Rep. 12, 23–34 (2015). This study details the generation of conditional cardiac tissue-specific MCU-knockout mice, highlighting the critical role of mitochondrial Ca 2+ and the MCU complex in cardiac functions.
de Jesus Garcia-Rivas, G., Guerrero-Hernandez, A., Guerrero-Serna, G., Rodriguez-Zavala, J. S. & Zazueta, C. Inhibition of the mitochondrial calcium uniporter by the oxo-bridged dinuclear ruthenium amine complex (Ru360) prevents from irreversible injury in postischemic rat heart. FEBS J. 272, 3477–3488 (2005).
Pan, X. et al. The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter. Nat. Cell Biol. 15, 1464–1472 (2013). This study details the generation of whole-body MCU-knockout mice, which display a very mild phenotype. This finding is unexpected to most investigators in the field (see also reference 176).
Rasmussen, T. P. et al. Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart. Proc. Natl Acad. Sci. USA 112, 9129–9134 (2015).
Holmstrom, K. M. et al. Assessment of cardiac function in mice lacking the mitochondrial calcium uniporter. J. Mol. Cell Cardiol. 85, 178–182 (2015).
Qiao, X. et al. PTPIP51 regulates mouse cardiac ischemia/reperfusion through mediating the mitochondria-SR junction. Sci. Rep. 7, 45379 (2017).
Mercadier, J. J. et al. Altered sarcoplasmic reticulum Ca2(+)-ATPase gene expression in the human ventricle during end-stage heart failure. J. Clin. Invest. 85, 305–309 (1990).
Santulli, G., Lewis, D., des Georges, A., Marks, A. R. & Frank, J. Ryanodine receptor structure and function in health and disease. Subcell. Biochem. 87, 329–352 (2018).
Terentyev, D. et al. Redox modification of ryanodine receptors contributes to sarcoplasmic reticulum Ca2+ leak in chronic heart failure. Circ. Res. 103, 1466–1472 (2008).
Xie, W. et al. Mitochondrial oxidative stress promotes atrial fibrillation. Sci. Rep. 5, 11427 (2015).
Ai, X., Curran, J. W., Shannon, T. R., Bers, D. M. & Pogwizd, S. M. Ca2+/calmodulin-dependent protein kinase modulates cardiac ryanodine receptor phosphorylation and sarcoplasmic reticulum Ca2+ leak in heart failure. Circ. Res. 97, 1314–1322 (2005).
Marx, S. O. et al. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 101, 365–376 (2000).
Santulli, G., Xie, W., Reiken, S. R. & Marks, A. R. Mitochondrial calcium overload is a key determinant in heart failure. Proc. Natl Acad. Sci. USA 112, 11389–11394 (2015).
Zhang, T. et al. Phospholamban ablation rescues sarcoplasmic reticulum Ca(2+) handling but exacerbates cardiac dysfunction in CaMKIIdelta(C) transgenic mice. Circ. Res. 106, 354–362 (2010).
Gomez, A. M. et al. Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science 276, 800–806 (1997).
Shiferaw, Y., Aistrup, G. L. & Wasserstrom, J. A. Intracellular Ca2+ waves, afterdepolarizations, and triggered arrhythmias. Cardiovasc. Res. 95, 265–268 (2012).
Brandenburg, S., Arakel, E. C., Schwappach, B. & Lehnart, S. E. The molecular and functional identities of atrial cardiomyocytes in health and disease. Biochim. Biophys. Acta 1863, 1882–1893 (2016).
Maack, C. et al. Elevated cytosolic Na+ decreases mitochondrial Ca2+ uptake during excitation-contraction coupling and impairs energetic adaptation in cardiac myocytes. Circ. Res. 99, 172–182 (2006).
Somasundaram, S. & Sadique, J. The role of mitochondrial calcium transport during inflammation and the effect of anti-inflammatory drugs. Biochem. Med. Metab. Biol. 36, 220–230 (1986).
Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011).
Rimessi, A. et al. Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis. Nat. Commun. 6, 6201 (2015). This study demonstrates the importance of mitochondrial Ca 2+ homeostasis and the MCU complex in the modulation of the immune response and inflammation.
Cheng, J. et al. Amplified RLR signaling activation through an interferon-stimulated gene-endoplasmic reticulum stress-mitochondrial calcium uniporter protein loop. Sci. Rep. 6, 20158 (2016).
Antony, A. N. et al. MICU1 regulation of mitochondrial Ca(2+) uptake dictates survival and tissue regeneration. Nat. Commun. 7, 10955 (2016).
Sheng, Z. H. & Cai, Q. Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration. Nat. Rev. Neurosci. 13, 77–93 (2012).
Pivovarova, N. B. & Andrews, S. B. Calcium-dependent mitochondrial function and dysfunction in neurons. FEBS J. 277, 3622–3636 (2010).
Abramov, A. Y. & Duchen, M. R. Mechanisms underlying the loss of mitochondrial membrane potential in glutamate excitotoxicity. Biochim. Biophys. Acta 1777, 953–964 (2008).
Qiu, J. et al. Mitochondrial calcium uniporter Mcu controls excitotoxicity and is transcriptionally repressed by neuroprotective nuclear calcium signals. Nat. Commun. 4, 2034 (2013).
Di Bella, D. et al. Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28. Nat. Genet. 42, 313–321 (2010).
Maltecca, F. et al. Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model. J. Clin. Invest. 125, 263–274 (2015).
Patron, M., Sprenger, H. G. & Langer, T. m-AAA proteases, mitochondrial calcium homeostasis and neurodegeneration. Cell Res. 28, 296–306 (2018).
Filadi, R. et al. Presenilin 2 modulates endoplasmic reticulum-mitochondria coupling by tuning the antagonistic effect of mitofusin 2. Cell Rep. 15, 2226–2238 (2016).
Cali, T., Ottolini, D., Negro, A. & Brini, M. alpha-Synuclein controls mitochondrial calcium homeostasis by enhancing endoplasmic reticulum-mitochondria interactions. J. Biol. Chem. 287, 17914–17929 (2012).
Grassi, D. et al. Identification of a highly neurotoxic alpha-synuclein species inducing mitochondrial damage and mitophagy in Parkinson’s disease. Proc. Natl Acad. Sci. USA 115, E2634–E2643 (2018).
Bonora, M. et al. Tumor necrosis factor-alpha impairs oligodendroglial differentiation through a mitochondria-dependent process. Cell Death Differ. 21, 1198–1208 (2014).
Warne, J. et al. Selective inhibition of the mitochondrial permeability transition pore protects against neurodegeneration in experimental multiple sclerosis. J. Biol. Chem. 291, 4356–4373 (2016).
Parone, P. A. et al. Enhancing mitochondrial calcium buffering capacity reduces aggregation of misfolded SOD1 and motor neuron cell death without extending survival in mouse models of inherited amyotrophic lateral sclerosis. J. Neurosci. 33, 4657–4671 (2013).
Agarwal, A. et al. Transient opening of the mitochondrial permeability transition pore induces microdomain calcium transients in astrocyte processes. Neuron 93, 587–605 (2017).
Tang, T. S. et al. Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington’s disease. Proc. Natl Acad. Sci. USA 102, 2602–2607 (2005).
Panov, A. V. et al. Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat. Neurosci. 5, 731–736 (2002). This study demonstrates in human patients and transgenic animal models that mitochondrial Ca 2+ alterations are a hallmark of early phases of Huntington disease.
Kon, N. et al. DS16570511 is a small-molecule inhibitor of the mitochondrial calcium uniporter. Cell Death Discov. 3, 17045 (2017).
Arduino, D. M. et al. Systematic identification of MCU modulators by orthogonal interspecies chemical screening. Mol. Cell 67, 711–723 (2017).
Uzhachenko, R. et al. Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: critical roles of calcium and energy homeostasis. Aging (Albany NY) 9, 627–649 (2017).
Lee, S. et al. Polo kinase phosphorylates Miro to control ER-mitochondria contact sites and mitochondrial Ca(2+) homeostasis in neural stem cell development. Dev. Cell 37, 174–189 (2016).
Clapham, D. E. Calcium signalling. Cell 131, 1047–1058 (2007).
Schwaller, B. Cytosolic Ca2+ buffers. Cold Spring Harb Perspect. Biol. 2, a004051 (2010).
Han, Y. et al. Ca(2+)-induced mitochondrial ROS regulate the early embryonic cell cycle. Cell Rep. 22, 218–231 (2018).
Sattler, R. & Tymianski, M. Molecular mechanisms of calcium-dependent excitotoxicity. J. Mol. Med. 78, 3–13 (2000).
Hardingham, G. E. & Bading, H. The Yin and Yang of NMDA receptor signalling. Trends Neurosci. 26, 81–89 (2003).
Danese, A. et al. Calcium regulates cell death in cancer: roles of the mitochondria and mitochondria-associated membranes (MAMs). Biochim. Biophys. Acta 1858, 615–627 (2017).
Mattson, M. P. & Chan, S. L. Neuronal and glial calcium signaling in Alzheimer’s disease. Cell Calcium 34, 385–397 (2003).
Bittremieux, M., Parys, J. B., Pinton, P. & Bultynck, G. ER functions of oncogenes and tumor suppressors: modulators of intracellular Ca(2+) signalling. Biochim. Biophys. Acta 1863, 1364–1378 (2016).
Chakraborty, P. K. et al. MICU1 drives glycolysis and chemoresistance in ovarian cancer. Nat. Commun. 8, 14634 (2017).
Huang, B. et al. Suppression of LETM1 by siRNA inhibits cell proliferation and invasion of bladder cancer cells. Oncol. Rep. 38, 2935–2940 (2017).
Liberti, M. V. & Locasale, J. W. The Warburg effect: how does it benefit cancer cells? Trends Biochem. Sci. 41, 211–218 (2016).
Giorgi, C. et al. Intravital imaging reveals p53-dependent cancer cell death induced by phototherapy via calcium signaling. Oncotarget 6, 1435–1445 (2015).
Kuchay, S. et al. PTEN counteracts FBXL2 to promote IP3R3- and Ca2+-mediated apoptosis limiting tumour growth. Nature 546, 554–558 (2017). This study identifies the ubiquitin E3 ligase (F box/LRR-repeat protein 2 (FBXL2)) responsible for Ins(1,4,5)P 3 R isoform 3 (Ins(1,4,5)P 3 R3; also known as ITPR3) degradation and demonstrates the importance of the Ins(1,4,5)P 3 R3–FBXL2 complex in cancer.
Bonora, M. et al. Subcellular calcium measurements in mammalian cells using jellyfish photoprotein aequorin-based probes. Nat. Protoc. 8, 2105–2118 (2013).
Fonteriz, R. I. et al. Monitoring mitochondrial [Ca(2+)] dynamics with rhod-2, ratiometric pericam and aequorin. Cell Calcium 48, 61–69 (2010).
Rodriguez-Garcia, A. et al. GAP, an aequorin-based fluorescent indicator for imaging Ca2+ in organelles. Proc. Natl Acad. Sci. USA 111, 2584–2589 (2014).
Austin, S. et al. LETM1-mediated K(+) and Na(+) homeostasis regulates mitochondrial Ca(2+) efflux. Front. Physiol. 8, 839 (2017).
Chaudhuri, A. D., Choi, D. C., Kabaria, S., Tran, A. & Junn, E. MicroRNA-7 regulates the function of mitochondrial permeability transition pore by targeting VDAC1 expression. J. Biol. Chem. 291, 6483–6493 (2016).
Stary, C. M., Sun, X., Ouyang, Y., Li, L. & Giffard, R. G. miR-29a differentially regulates cell survival in astrocytes from cornu ammonis 1 and dentate gyrus by targeting VDAC1. Mitochondrion 30, 248–254 (2016).
Marchi, S. et al. Downregulation of the mitochondrial calcium uniporter by cancer-related miR-25. Curr. Biol. 23, 58–63 (2013). This is the first report showing epigenetic control of MCU complex expression mediated by microRNA.
Pan, L. et al. MiR-25 protects cardiomyocytes against oxidative damage by targeting the mitochondrial calcium uniporter. Int. J. Mol. Sci. 16, 5420–5433 (2015).
Hong, Z. et al. MicroRNA-138 and microRNA-25 down-regulate mitochondrial calcium uniporter, causing the pulmonary arterial hypertension cancer phenotype. Am. J. Respir. Crit. Care Med. 195, 515–529 (2017).
Zaglia, T. et al. Content of mitochondrial calcium uniporter (MCU) in cardiomyocytes is regulated by microRNA-1 in physiologic and pathologic hypertrophy. Proc. Natl Acad. Sci. USA 114, E9006–E9015 (2017).
Yu, C. et al. Mitochondrial calcium uniporter as a target of microRNA-340 and promoter of metastasis via enhancing the Warburg effect. Oncotarget 8, 83831–83844 (2017).
Schneeberger, M. et al. Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. Cell 155, 172–187 (2013).
Wang, P. T. et al. Distinct mechanisms controlling rough and smooth endoplasmic reticulum contacts with mitochondria. J. Cell Sci. 128, 2759–2765 (2015).
Doghman-Bouguerra, M. et al. FATE1 antagonizes calcium- and drug-induced apoptosis by uncoupling ER and mitochondria. EMBO Rep. 17, 1264–1280 (2016).
Zampese, E. et al. Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ cross-talk. Proc. Natl Acad. Sci. USA 108, 2777–2782 (2011).
Simmen, T. et al. PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis. EMBO J. 24, 717–729 (2005).
Arruda, A. P. et al. Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity. Nat. Med. 20, 1427–1435 (2014).
Honrath, B. et al. SK2 channels regulate mitochondrial respiration and mitochondrial Ca(2+) uptake. Cell Death Differ. 24, 761–773 (2017).
The authors apologize to the many scientists whose work we were not able to credit owing to space restrictions. The authors thank V. De Pinto, G. A. Rutter, G. Santulli, I. Sekler and G. Campo for helpful discussions and A. Danese for the help in collecting the images for the figure in Box 1. P.P. is grateful to C. degli Scrovegni for continuous support. P.P. is supported by the Italian Ministry of Education, University and Research; the Italian Ministry of Health; Telethon (GGP15219/B); the Italian Association for Cancer Research (AIRC IG-18624); and by local funds from the University of Ferrara. C.G. is supported by local funds from the University of Ferrara, the Italian Association for Cancer Research (AIRC IG-19803), the Italian Ministry of Health and a Fondazione Cariplo grant. S.M. is supported by Fondazione Umberto Veronesi and the Italian Ministry of Health.
Nature Reviews Molecular Cell Biology thanks J. Elrod and the other anonymous reviewer(s) for their contribution to the peer review of this work.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Membrane contact sites
The close apposition between two (or more) organelles in which membranes do not fuse, thereby maintaining their specific characteristics.
- Membrane potential
The difference in electrical potential (measured in mV) between the interior and the exterior of a biological membrane generated from different concentrations of ions, such as H+, Na+, K+ and Cl−.
- Respiratory chain
Also known as the electron transport chain, a series of proteins in the inner mitochondrial membrane that consists of four complexes that transfer electrons from NADH and FADH2 to oxygen, which is reduced to water. Electron flow within these transmembrane complexes leads to the transport of H+ across the inner mitochondrial membrane, generating an electrochemical proton gradient (negative inside the matrix).
An endoprotease involved in cell death and inflammation that contains catalytic cysteine residues in its active site that hydrolyse substrate peptides after specific aspartic acid residues.
- Photodynamic therapy
A clinically approved therapeutic procedure that uses photosensitizing agents that, when exposed to a specific wavelength of light, produce a form of oxygen that kills tumour cells.
- Ruthenium red
A polycationic dye that acts as an inhibitor of a wide number of ion channels, including all transient receptor potential channels (TRPCs), voltage-dependent anion-selective channel proteins (VDACs), mitochondrialcalcium uniporter (MCU) and ryanodine receptors.
- Dissociation constant
(Kd). A measure that indicates the strength of the binding interaction between a single biomolecule (for example, a protein) and its ligand or binding partner (for example, Ca2+ ions). The smaller the Kd value is, the greater the binding affinity of the ligand for its target.
- Chemiosmotic theory
States that the energy stored in the form of the transmembrane electrochemical gradient is used to produce ATP inside the mitochondrial matrix. The protons move back across the inner mitochondrial membrane through the F1F0 ATPase enzyme, coupling the electrochemical gradient to ATP production by combining ADP with inorganic phosphate.
- Förster resonance energy transfer
(FRET). A distance-dependent energy transfer process that involves a donor molecule in an excited electronic state that may transfer energy to an acceptor chromophore, leading to a reduction in the donor’s fluorescence intensity and excited state lifetime and an increase in the acceptor’s emission. Its efficiency depends on the inverse sixth distance between donor and acceptor.
- Ratiometric measurement
A measurement based on the use of a ratio between two fluorescence intensities that display a shift in their emission or excitation spectra when they bind to Ca2+. The intensity ratio is calculated at wavelengths for which the difference in fluorescence between bound and free indicator reaches its maximum.
- Mitochondrial permeability transition pore
(mPTP). A protein complex that, under certain pathological conditions, including Ca2+ overload and oxidative stress, opens in the inner mitochondrial membrane, allowing the free passage of molecules >1,500 Daltons and leading to mitochondrial swelling and cell death through apoptosis or necrosis.
- BCL-2 family
A large group of evolutionarily conserved proteins that share BCL-2 homology domains. BCL-2 family members are deeply involved in cell death regulation, consisting of both anti-apoptotic (BCL-2 and apoptosis regulator BCL-XL (also known as BCL2L1)) and pro-apoptotic (apoptosis regulator BAX and BCL-2 homologous antagonist/killer (BAK)) factors.
- ER–mitochondrial encounter structure complex
(ERMES complex). Characterized in yeast, a protein complex consisting of four core components, whose major function is to mechanically link the endoplasmic reticulum (ER) with mitochondria.
- PTEN-induced putative kinase 1
(PINK1). A serine/threonine kinase that is imported inside mitochondria in healthy conditions, whereas it accumulates at the outer mitochondrial membrane in dysfunctional mitochondria to promote their degradation through mitophagy. Mutations in PINK1 cause one form of autosomal recessive early-onset Parkinson disease.
- Neointimal hyperplasia
The thickening of the intima layer (tunica) of arteries and veins that results from accumulation of fibroblasts and smooth muscle cells. The result of such excessive cellular deposition is the loss of luminal area.
The most numerous and heterogeneous neuroglial cells in the central nervous system, distinguished by a star-like morphology with multiple primary processes originating from the soma.
- Acinar cells
The exocrine cells of the pancreas that produce and transport the majority of enzymes required for the digestion of food.
An inactive precursor of an enzyme, also termed a pro-enzyme, which displays no catalytic activity and requires a specific biochemical transformation to become fully active.
- Nutrient secretagogues
Substances that promote secretion.
- ER stress
A stressful condition of the endoplasmic reticulum (ER) that triggers a signalling cascade, termed the unfolded protein response, which is aimed to restore ER homeostasis.
- Excitation–contraction coupling
(EC coupling). A process whereby the action potential travelling along the plasmalemma evokes initiation of mechanical shortening of the myofibrils through Ca2+ release from the sarcoplasmic reticulum.
- Excitation–transcription coupling
(ET coupling). A process initiated by Ca2+ signals that results in changes in gene expression.
- Excitation–metabolism coupling
(EM coupling). A process initiated by Ca2+ signals that results in changes in cell metabolism.
- Action potential
A movement of charge sufficient to generate a large and brief deviation in the membrane potential. It is used to communicate information between neurons and from neurons to muscle fibres.
- Funny current
(If). A mixed Na+/K+ inward current with several unusual features.
- Troponin C
(TN-C). A component of the troponin complex, together with troponin I and troponin T, which regulates muscle contraction by Ca2+ binding. Through its multiple EF-hand domains, TN-C acts as the Ca2+ sensor of the troponin complex, initiating the cascade of events that leads to contraction of striated muscle by interacting with troponin I after Ca2+ binding.
The principal molecular regulators of contraction in cardiac and skeletal muscles, responsible for force generation and motion. Myofilaments consist primarily of thick filament myosin and thin filament actin proteins, as well as additional components, including troponin, titin and nebulin.
- Fight-or-flight response
The physiological reaction that helps an animal in response to emergency situations such as a harmful event or an attack.
- NACHT, LRR and PYD domains-containing protein 3 inflammasome
(NLRP3 inflammasome). A complex whose formation leads to the activation of caspase 1, the secretion of pro-inflammatory cytokines and the induction of inflammatory cell death (or pyroptosis).
- Mitochondrial antiviral signalling
(MAVS). A CARD domain-containing protein located on the outer mitochondrial membrane.
A pathological process by which neurons are damaged or killed by an excessive activation of receptors for excitatory neurotransmitters, such as glutamate. Such hyper-stimulation produces a massive entry of Ca2+ inside the cell and induces mitochondrial damage.
- N-methyl-d-aspartate receptors
(NMDARs). Glutamate-gated cation channels showing high Ca2+ permeability. They can be found at most excitatory synapses and exhibit the highest affinity for glutamate among the glutamate receptors.
- Purkinje cells
A class of large inhibitory neurons located in the cerebellar cortex of the brain and characterized by an intricate dendritic arbor. They have crucial roles in motor coordination.
A type of neuroglia that provides support to axons in the central nervous system by producing myelin sheaths. In the peripheral nervous system, the equivalent to oligodendrocytes is Schwann cells.
About this article
Cite this article
Giorgi, C., Marchi, S. & Pinton, P. The machineries, regulation and cellular functions of mitochondrial calcium. Nat Rev Mol Cell Biol 19, 713–730 (2018). https://doi.org/10.1038/s41580-018-0052-8
Nature Reviews Genetics (2021)
Mitochondrial dysfunction induces radioresistance in colorectal cancer by activating [Ca2+]m-PDP1-PDH-histone acetylation retrograde signaling
Cell Death & Disease (2021)
British Journal of Cancer (2021)
Nature Communications (2021)
Investigation into the difference in mitochondrial-cytosolic calcium coupling between adult cardiomyocyte and hiPSC-CM using a novel multifunctional genetic probe
Pflügers Archiv - European Journal of Physiology (2021)