Skip to main content

Molecular Players of Mitochondrial Calcium Signaling: Similarities and Different Aspects in Various Organisms

  • Chapter
  • First Online:
  • 1014 Accesses

Part of the book series: Biological and Medical Physics, Biomedical Engineering ((BIOMEDICAL))

Abstract

In living organisms different developmental and environmental stimuli can trigger Ca2+ transients of specific signature that can modulate gene expression and metabolism. Mitochondria play an important role in shaping intracellular calcium dynamics. Recently, several molecular players involved in mitochondrial Ca2+ signalling have been identified both in animals and plants, including those of the mitochondrial Ca2+ uniporter complex, MCUC. In he present review the significance of mitochondrial Ca2+ control is discussed in the light of the cytosolic calcium signalling and of specific metabolic and energetic needs of different organisms.

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Akerman KE (1978) Effect of pH and Ca2+ on the retention of Ca2+ by rat liver mitochondria. Arch Biochem Biophys 189:256–262

    Article  Google Scholar 

  • Akerman KE, Moore AL (1983) Phosphate dependent, ruthenium red insensitive CA2+ uptake in mung bean mitochondria. Biochem Biophys Res Commun 114:1176–1181

    Article  Google Scholar 

  • Bathori G, Csordas G, Garcia-Perez C, Davies E, Hajnoczky G (2006) Ca2+−dependent control of the permeability properties of the mitochondrial outer membrane and voltage-dependent anion-selective channel (VDAC). J Biol Chem 281:17347–17358

    Article  Google Scholar 

  • Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA, Sancak Y, Bao XR, Strittmatter L, Goldberger O, Bogorad RL, Koteliansky V, Mootha VK (2011) Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476:341–345

    Article  ADS  Google Scholar 

  • Bernardi P, Von Stockum S (2012) The permeability transition pore as a Ca(2+) release channel: new answers to an old question. Cell Calcium 52:22–27

    Article  Google Scholar 

  • Bernardi P, Rasola A, Forte M, Lippe G (2015) The mitochondrial permeability transition pore: channel formation by F-ATP synthase, integration in signal transduction, and role in pathophysiology. Physiol Rev 95:1111–1155

    Article  Google Scholar 

  • Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4:517–529

    Article  Google Scholar 

  • Beutner G, Sharma VK, Giovannucci DR, Yule DI, Sheu SS (2001) Identification of a ryanodine receptor in rat heart mitochondria. J Biol Chem 276:21482–21488

    Article  Google Scholar 

  • Beutner G, Sharma VK, Lin L, Ryu SY, Dirksen RT, Sheu SS (2005) Type 1 ryanodine receptor in cardiac mitochondria: transducer of excitation-metabolism coupling. Biochim Biophys Acta 1717:1–10

    Article  Google Scholar 

  • Bezprozvanny I, Watras J, Ehrlich BE (1991) Bell-shaped calcium-response curves of Ins(1,4,5)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum. Nature 351:751–754

    Article  ADS  Google Scholar 

  • Bick AG, Calvo SE, Mootha VK (2012) Evolutionary diversity of the mitochondrial calcium uniporter. Science 336:886

    Article  ADS  Google Scholar 

  • Bondarenko AI, Jean-Quartier C, Parichatikanond W, Alam MR, Waldeck-Weiermair M, Malli R, Graier WF (2014) Mitochondrial Ca(2+) uniporter (MCU)-dependent and MCU-independent Ca(2+) channels coexist in the inner mitochondrial membrane. Pflugers Arch 466:1411–1420

    Article  Google Scholar 

  • Bondarenko AI, Parichatikanond W, Madreiter CT, Rost R, Waldeck-Weiermair M, Malli R, Graier WF (2015) UCP2 modulates single-channel properties of a MCU-dependent Ca(2+) inward current in mitochondria. Pflugers Arch 467:2509–2518

    Article  Google Scholar 

  • Brookes PS, Parker N, Buckingham JA, Vidal-Puig A, Halestrap AP, Gunter TE, Nicholls DG, Bernardi P, Lemasters JJ, Brand MD (2008) UCPs – unlikely calcium porters. Nat Cell Biol 10:1235–1237. author reply 1237-40

    Article  Google Scholar 

  • Budde RJ, Fang TK, Randall DD (1988) Regulation of the phosphorylation of mitochondrial pyruvate dehydrogenase complex in situ: effects of respiratory substrates and calcium. Plant Physiol 88:1031–1036

    Article  Google Scholar 

  • Carafoli E (1979) The calcium cycle of mitochondria. FEBS Lett 104:1–5

    Article  Google Scholar 

  • Chaudhuri D, Sancak Y, Mootha VK, Clapham DE (2013) MCU encodes the pore conducting mitochondrial calcium currents. elife 2:e00704

    Article  Google Scholar 

  • Chen CH, Lehninger AL (1973) Ca 2+ transport activity in mitochondria from some plant tissues. Arch Biochem Biophys 157:183–196

    Article  Google Scholar 

  • Crompton M, Kunzi M, Carafoli E (1977) The calcium-induced and sodium-induced effluxes of calcium from heart mitochondria. Evidence for a sodium-calcium carrier. Eur J Biochem 79:549–558

    Article  Google Scholar 

  • Crompton M, Moser R, Ludi H, Carafoli E (1978) The interrelations between the transport of sodium and calcium in mitochondria of various mammalian tissues. Eur J Biochem 82:25–31

    Article  Google Scholar 

  • Csordas G, Golenar T, Seifert EL, Kamer KJ, Sancak Y, Perocchi F, Moffat C, Weaver D, de la Fuente Perez S, Bogorad R, Koteliansky V, Adijanto J, Mootha VK, Hajnoczky G (2013) MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca(2)(+) uniporter. Cell Metab 17:976–987

    Article  Google Scholar 

  • Day DA, Bertagnolli BL, Hanson JB (1978) The effect of calcium on the respiratory responses of corn mitochondria. Biochim Biophys Acta 502:289–297

    Article  Google Scholar 

  • De Marchi U, Castelbou C, Demaurex N (2011) Uncoupling protein 3 (UCP3) modulates the activity of Sarco/endoplasmic reticulum Ca2+−ATPase (SERCA) by decreasing mitochondrial ATP production. J Biol Chem 286:32533–32541

    Article  Google Scholar 

  • De Marchi U, Santo-Domingo J, Castelbou C, Sekler I, Wiederkehr A, Demaurex N (2014) 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

    Article  Google Scholar 

  • De Stefani D, Raffaello A, Teardo E, Szabo I, Rizzuto R (2011) A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476:336–340

    Article  ADS  Google Scholar 

  • De Stefani D, Bononi A, Romagnoli A, Messina A, De Pinto V, Pinton P, Rizzuto R (2012) VDAC1 selectively transfers apoptotic Ca2+ signals to mitochondria. Cell Death Differ 19:267–273

    Article  Google Scholar 

  • Deluca HF, Engstrom GW (1961) Calcium uptake by rat kidney mitochondria. Proc Natl Acad Sci U S A 47:1744–1750

    Article  ADS  Google Scholar 

  • Denton RM (2009) Regulation of mitochondrial dehydrogenases by calcium ions. Biochim Biophys Acta 1787:1309–1316

    Article  Google Scholar 

  • Denton RM, Mccormack JG (1980) On the role of the calcium transport cycle in heart and other mammalian mitochondria. FEBS Lett 119:1–8

    Article  Google Scholar 

  • Denton RM, Randle PJ, Martin BR (1972) Stimulation by calcium ions of pyruvate dehydrogenase phosphate phosphatase. Biochem J 128:161–163

    Article  Google Scholar 

  • Denton RM, Richards DA, Chin JG (1978) Calcium ions and the regulation of NAD+−linked isocitrate dehydrogenase from the mitochondria of rat heart and other tissues. Biochem J 176:899–906

    Article  Google Scholar 

  • Denton RM, Mccormack JG, Edgell NJ (1980) Role of calcium ions in the regulation of intramitochondrial metabolism. Effects of Na+, Mg2+ and ruthenium red on the Ca2+−stimulated oxidation of oxoglutarate and on pyruvate dehydrogenase activity in intact rat heart mitochondria. Biochem J 190:107–117

    Article  Google Scholar 

  • Dieter P, Marme D (1980) Ca(2+) transport in mitochondrial and microsomal fractions from higher plants. Planta 150:1–8

    Article  Google Scholar 

  • Dimmer KS, Navoni F, Casarin A, Trevisson E, Endele S, Winterpacht A, Salviati L, Scorrano L (2008) LETM1, deleted in Wolf-Hirschhorn syndrome is required for normal mitochondrial morphology and cellular viability. Hum Mol Genet 17:201–214

    Article  Google Scholar 

  • Doonan PJ, Chandramoorthy HC, Hoffman NE, Zhang X, Cardenas C, Shanmughapriya S, Rajan S, Vallem S, Chen X, Foskett JK, Cheung JY, Houser SR, Madesh M (2014) LETM1-dependent mitochondrial Ca2+ flux modulates cellular bioenergetics and proliferation. FASEB J 28:4936–4949

    Article  Google Scholar 

  • Drago I, Davis RL (2016) Inhibiting the mitochondrial calcium uniporter during development impairs memory in adult drosophila. Cell Rep 16:2763–2776

    Article  Google Scholar 

  • Endele S, Fuhry M, Pak SJ, Zabel BU, Winterpacht A (1999) LETM1, a novel gene encoding a putative EF-hand Ca(2+)-binding protein, flanks the Wolf-Hirschhorn syndrome (WHS) critical region and is deleted in most WHS patients. Genomics 60:218–225

    Article  Google Scholar 

  • Feng S, Li H, Tai Y, Huang J, Su Y, Abramowitz J, Zhu MX, Birnbaumer L, Wang Y (2013) Canonical transient receptor potential 3 channels regulate mitochondrial calcium uptake. Proc Natl Acad Sci U S A 110:11011–11016

    Article  ADS  Google Scholar 

  • Fieni F, Lee SB, Jan YN, Kirichok Y (2012) Activity of the mitochondrial calcium uniporter varies greatly between tissues. Nat Commun 3:1317

    Article  Google Scholar 

  • Fiskum G, Lehninger AL (1979) Regulated release of Ca2+ from respiring mitochondria by Ca2+/2H+ antiport. J Biol Chem 254:6236–6239

    Google Scholar 

  • Garg V, Kirichok Y (2016) Keeping a lid on calcium uptake. elife 5:e17293

    Article  Google Scholar 

  • Gazit N, Vertkin I, Shapira I, Helm M, Slomowitz E, Sheiba M, Mor Y, Rizzoli S, Slutsky I (2016) IGF-1 receptor differentially regulates spontaneous and evoked transmission via mitochondria at hippocampal synapses. Neuron 89:583–597

    Article  Google Scholar 

  • Gelhaye E, Rouhier N, Gerard J, Jolivet Y, Gualberto J, NAVROT N, Ohlsson PI, Wingsle G, Hirasawa M, Knaff DB, Wang H, Dizengremel P, Meyer Y, Jacquot JP (2004) A specific form of thioredoxin h occurs in plant mitochondria and regulates the alternative oxidase. Proc Natl Acad Sci U S A 101:14545–14550

    Article  ADS  Google Scholar 

  • Gincel D, Zaid H, Shoshan-Barmatz V (2001) Calcium binding and translocation by the voltage-dependent anion channel: a possible regulatory mechanism in mitochondrial function. Biochem J 358:147–155

    Article  Google Scholar 

  • Gonzalez S, Berthelot J, Jiner J, Perrin-Tricaud C, Fernando R, Chrast R, Lenaers G, Tricaud N (2016) Blocking mitochondrial calcium release in Schwann cells prevents demyelinating neuropathies. J Clin Invest 126:1023–1038

    Article  Google Scholar 

  • Greenawalt JW, Rossi CS, Lehninger AL (1964) Effect of active accumulation of calcium and phosphate ions on the structure of rat liver mitochondria. J Cell Biol 23:21–38

    Article  Google Scholar 

  • Hashimi H, Mcdonald L, Stribrna E, Lukes J (2013) Trypanosome Letm1 protein is essential for mitochondrial potassium homeostasis. J Biol Chem 288:26914–26925

    Article  Google Scholar 

  • Hodges TK, Hanson JB (1965) Calcium accumulation by maize mitochondria. Plant Physiol 40:101–109

    Article  Google Scholar 

  • Holness MJ, Sugden MC (2003) Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation. Biochem Soc Trans 31:1143–1151

    Article  Google Scholar 

  • Huang G, Vercesi AE, Docampo R (2013) Essential regulation of cell bioenergetics in Trypanosoma brucei by the mitochondrial calcium uniporter. Nat Commun 4:2865

    ADS  Google Scholar 

  • Hung V, Zou P, Rhee HW, Udeshi ND, Cracan V, Svinkina T, Carr SA, Mootha VK, Ting AY (2014) Proteomic mapping of the human mitochondrial intermembrane space in live cells via ratiometric APEX tagging. Mol Cell 55:332–341

    Article  Google Scholar 

  • Israelson A, Abu-Hamad S, Zaid H, Nahon E, Shoshan-Barmatz V (2007) Localization of the voltage-dependent anion channel-1 Ca2+−binding sites. Cell Calcium 41:235–244

    Article  Google Scholar 

  • Jiang D, Zhao L, Clapham DE (2009) Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter. Science 326:144–147

    Article  ADS  Google Scholar 

  • Jouaville LS, Ichas F, Holmuhamedov EL, Camacho P, Lechleiter JD (1995) Synchronization of calcium waves by mitochondrial substrates in Xenopus laevis oocytes. Nature 377:438–441

    Article  ADS  Google Scholar 

  • Kirichok Y, Krapivinsky G, Clapham DE (2004) The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427:360–364

    Article  ADS  Google Scholar 

  • Klodmann J, Senkler M, Rode C, Braun HP (2011) Defining the protein complex proteome of plant mitochondria. Plant Physiol 157:587–598

    Article  Google Scholar 

  • Kovacs-Bogdan E, Sancak Y, Kamer KJ, Plovanich M, Jambhekar A, Huber RJ, Myre MA, Blower MD, Mootha VK (2014) Reconstitution of the mitochondrial calcium uniporter in yeast. Proc Natl Acad Sci U S A 111:8985–8990

    Article  ADS  Google Scholar 

  • Krinke O, Novotna Z, Valentova O, Martinec J (2007) Inositol trisphosphate receptor in higher plants: is it real? J Exp Bot 58:361–376

    Article  Google Scholar 

  • Kwon SK, Sando R 3rd, Lewis TL, Hirabayashi Y, Maximov A, Polleux F (2016) LKB1 regulates mitochondria-dependent presynaptic calcium clearance and neurotransmitter release properties at excitatory synapses along cortical axons. PLoS Biol 14:e1002516

    Google Scholar 

  • Lee Y, Min CK, Kim TG, Song HK, Lim Y, Kim D, Shin K, Kang M, Kang JY, Youn HS, Lee JG, An JY, Park KR, Lim JJ, Kim JH, Kim JH, Park ZY, Kim YS, Wang J, Kim Do H, Eom SH (2015) Structure and function of the N-terminal domain of the human mitochondrial calcium uniporter. EMBO Rep 16:1318–1333

    Article  Google Scholar 

  • Lewis-Smith D, Kamer KJ, Griffin H, Childs AM, Pysden K, Titov D, Duff J, Pyle A, Taylor RW, Yu-Wai-Man P, Ramesh V, Horvath R, Mootha VK, Chinnery PF (2016) Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood. Neurol Genet 2:e59

    Article  Google Scholar 

  • Li N, Zheng Y, Xuan C, Lin Z, Piao L, Liu S (2015) LETM1 overexpression is correlated with the clinical features and survival outcome of breast cancer. Int J Clin Exp Pathol 8:12893–12900

    Google Scholar 

  • Liu JC, Liu J, Holmstrom KM, Menazza S, Parks RJ, Fergusson MM, Yu ZX, Springer DA, Halsey C, Liu C, Murphy E, Finkel T (2016) MICU1 serves as a molecular gatekeeper to prevent in vivo mitochondrial calcium overload. Cell Rep 16:1561–1573

    Article  Google Scholar 

  • Logan CV, Szabadkai G, Sharpe JA, Parry DA, Torelli S, Childs AM, Kriek M, Phadke R, Johnson CA, Roberts NY, Bonthron DT, Pysden KA, Whyte T, Munteanu I, Foley AR, Wheway G, Szymanska K, Natarajan S, Abdelhamed ZA, Morgan JE, Roper H, Santen GW, Niks EH, Van Der Pol WL, Lindhout D, Raffaello A, De Stefani D, Den Dunnen JT, Sun Y, Ginjaar I, Sewry CA, Hurles M, Rizzuto R, Duchen MR, Muntoni F, Sheridan E (2014) Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling. Nat Genet 46:188–193

    Article  Google Scholar 

  • Mallilankaraman K, Cardenas C, Doonan PJ, Chandramoorthy HC, Irrinki KM, Golenar T, Csordas G, Madireddi P, Yang J, Muller M, Miller R, Kolesar JE, Molgo J, Kaufman B, Hajnoczky G, Foskett JK, Madesh M (2012a) MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism. Nat Cell Biol 14:1336–1343

    Article  Google Scholar 

  • Mallilankaraman K, Doonan P, Cardenas C, Chandramoorthy HC, Muller M, Miller R, Hoffman NE, Gandhirajan RK, Molgo J, Birnbaum MJ, Rothberg BS, Mak DO, Foskett JK, Madesh M (2012b) MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca(2+) uptake that regulates cell survival. Cell 151:630–644

    Article  Google Scholar 

  • Mammucari C, Gherardi G, Zamparo I, Raffaello A, Boncompagni S, Chemello F, Cagnin S, Braga A, Zanin S, Pallafacchina G, Zentilin L, Sandri M, De Stefani D, Protasi F, Lanfranchi G, Rizzuto R (2015) The mitochondrial calcium uniporter controls skeletal muscle trophism in vivo. Cell Rep 10:1269–1279

    Article  Google Scholar 

  • Martins IS, Vercesi AE (1985) Some characteristics of Ca2+ transport in plant mitochondria. Biochem Biophys Res Commun 129:943–948

    Article  Google Scholar 

  • Mccormack JG, Denton RM (1979) The effects of calcium ions and adenine nucleotides on the activity of pig heart 2-oxoglutarate dehydrogenase complex. Biochem J 180:533–544

    Article  Google Scholar 

  • Mccormack JG, Denton RM (1981) A comparative study of the regulation of Ca2+ of the activities of the 2-oxoglutarate dehydrogenase complex and NAD+−isocitrate dehydrogenase from a variety of sources. Biochem J 196:619–624

    Article  Google Scholar 

  • Mccormack JG, Halestrap AP, Denton RM (1990) Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev 70:391–425

    Google Scholar 

  • Meng Q, Chen Y, Zhang M, Chen Y, Yuan J, Murray SC (2015) Molecular characterization and phylogenetic analysis of ZmMCUs in maize. Biologia 70:599–605

    Article  Google Scholar 

  • Michels G, Khan IF, Endres-Becker J, Rottlaender D, Herzig S, Ruhparwar A, Wahlers T, Hoppe UC (2009) Regulation of the human cardiac mitochondrial Ca2+ uptake by 2 different voltage-gated Ca2+ channels. Circulation 119:2435–2443

    Article  Google Scholar 

  • Miernyk JA, Randall DD (1987) Some properties of pea mitochondrial phospho-pyruvate dehydrogenase-phosphatase. Plant Physiol 83:311–315

    Article  Google Scholar 

  • Millar AH, Eubel H, Jansch L, Kruft V, Heazlewood JL, Braun HP (2004) Mitochondrial cytochrome c oxidase and succinate dehydrogenase complexes contain plant specific subunits. Plant Mol Biol 56:77–90

    Article  Google Scholar 

  • Monaco G, Decrock E, Arbel N, Van Vliet AR, La Rovere RM, De Smedt H, Parys JB, Agostinis P, Leybaert L, Shoshan-Barmatz V, Bultynck G (2015) 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

    Article  Google Scholar 

  • Moore CL (1971) Specific inhibition of mitochondrial Ca++ transport by ruthenium red. Biochem Biophys Res Commun 42:298–305

    Article  ADS  Google Scholar 

  • Moore AL, Bonner WD Jr (1977) The effect of calcium on the respiratory responses of mung bean mitochondria. Biochim Biophys Acta 460:455–466

    Article  Google Scholar 

  • Murgia M, Rizzuto R (2015) Molecular diversity and pleiotropic role of the mitochondrial calcium uniporter. Cell Calcium 58:11–17

    Article  Google Scholar 

  • Nichols BJ, Rigoulet M, Denton RM (1994) Comparison of the effects of Ca2+, adenine nucleotides and pH on the kinetic properties of mitochondrial NAD(+)-isocitrate dehydrogenase and oxoglutarate dehydrogenase from the yeast Saccharomyces cerevisiae and rat heart. Biochem J 303(Pt 2):461–465

    Article  Google Scholar 

  • Nowikovsky K, Bernardi P (2014) LETM1 in mitochondrial cation transport. Front Physiol 5:83

    Article  Google Scholar 

  • Nowikovsky K, Froschauer EM, Zsurka G, Samaj J, Reipert S, Kolisek M, Wiesenberger G, Schweyen RJ (2004) 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

    Article  Google Scholar 

  • Oxenoid K, Dong Y, Cao C, Cui T, Sancak Y, Markhard AL, Grabarek Z, Kong L, Liu Z, Ouyang B, Cong Y, Mootha VK, Chou JJ (2016) Architecture of the mitochondrial calcium uniporter. Nature 533:269–273

    Article  ADS  Google Scholar 

  • Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB, Ong SE, Walford GA, Sugiana C, Boneh A, Chen WK, Hill DE, Vidal M, Evans JG, Thorburn DR, Carr SA, Mootha VK (2008) A mitochondrial protein compendium elucidates complex I disease biology. Cell 134:112–123

    Article  Google Scholar 

  • Palty R, Silverman WF, Hershfinkel M, Caporale T, Sensi SL, Parnis J, Nolte C, Fishman D, Shoshan-Barmatz V, Herrmann S, Khananshvili D, Sekler I (2010) NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. Proc Natl Acad Sci U S A 107:436–441

    Article  ADS  Google Scholar 

  • Pan X, Liu J, Nguyen T, Liu C, Sun J, Teng Y, Fergusson MM, Rovira II, Allen M, Springer DA, Aponte AM, Gucek M, Balaban RS, Murphy E, Finkel T (2013) The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter. Nat Cell Biol 15:1464–1472

    Article  Google Scholar 

  • Patron M, Checchetto V, Raffaello A, Teardo E, Vecellio Reane D, Mantoan M, Granatiero V, Szabo I, De Stefani D, Rizzuto R (2014) MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity. Mol Cell 53:726–737

    Article  Google Scholar 

  • Paupe V, Prudent J, Dassa EP, Rendon OZ, Shoubridge EA (2015) CCDC90A (MCUR1) is a cytochrome c oxidase assembly factor and not a regulator of the mitochondrial calcium uniporter. Cell Metab 21:109–116

    Article  Google Scholar 

  • Peruzzo R, Biasutto L, Szabo I, Leanza L (2016) Impact of intracellular ion channels on cancer development and progression. Eur Biophys J 45:685–707

    Article  Google Scholar 

  • Petrungaro C, Zimmermann KM, Kuttner V, Fischer M, Dengjel J, Bogeski I, Riemer J (2015) The Ca(2+)-dependent release of the Mia40-induced MICU1-MICU2 Dimer from MCU regulates mitochondrial Ca(2+) uptake. Cell Metab 22:721–733

    Article  Google Scholar 

  • Plovanich M, Bogorad RL, Sancak Y, Kamer KJ, Strittmatter L, Li AA, Girgis HS, Kuchimanchi S, De Groot J, Speciner L, Taneja N, Oshea J, Koteliansky V, Mootha VK (2013) MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling. PLoS One 8:e55785

    Article  ADS  Google Scholar 

  • Prudent J, Popgeorgiev N, Bonneau B, Thibaut J, Gadet R, Lopez J, Gonzalo P, Rimokh R, Manon S, Houart C, Herbomel P, Aouacheria A, Gillet G (2013) Bcl-wav and the mitochondrial calcium uniporter drive gastrula morphogenesis in zebrafish. Nat Commun 4:2330

    Article  ADS  Google Scholar 

  • Quintana A, Schwindling C, Wenning AS, Becherer U, Rettig J, Schwarz EC, Hoth M (2007) T cell activation requires mitochondrial translocation to the immunological synapse. Proc Natl Acad Sci U S A 104:14418–14423

    Article  ADS  Google Scholar 

  • Quintana A, Pasche M, Junker C, Al-Ansary D, Rieger H, Kummerow C, Nunez L, Villalobos C, Meraner P, Becherer U, Rettig J, Niemeyer BA, Hoth M (2011) Calcium microdomains at the immunological synapse: how ORAI channels, mitochondria and calcium pumps generate local calcium signals for efficient T-cell activation. EMBO J 30:3895–3912

    Article  Google Scholar 

  • Raffaello A, De Stefani D, Sabbadin D, Teardo E, Merli G, Picard A, Checchetto V, Moro S, Szabò I, Rizzuto R (2013) The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit. EMBO J 32:2362–2376.

    Google Scholar 

  • Raffaello A, Mammucari C, Gherardi G, Rizzuto R (2016) Calcium at the center of cell signaling: interplay between endoplasmic reticulum, mitochondria, and lysosomes. Trends Biochem Sci 41:1035–1049

    Article  Google Scholar 

  • Rapizzi E, Pinton P, Szabadkai G, Wieckowski MR, Vandecasteele G, Baird G, Tuft RA, Fogarty KE, Rizzuto R (2002) Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca2+ microdomains to mitochondria. J Cell Biol 159:613–624

    Article  Google Scholar 

  • Reed KC, Bygrave FL (1974) The inhibition of mitochondrial calcium transport by lanthanides and ruthenium red. Biochem J 140:143–155

    Article  Google Scholar 

  • Rizzuto R, Pozzan T (2006) Microdomains of intracellular Ca2+: molecular determinants and functional consequences. Physiol Rev 86:369–408

    Article  Google Scholar 

  • Rizzuto R, Simpson AW, Brini M, Pozzan T (1992) Rapid changes of mitochondrial Ca2+ revealed by specifically targeted recombinant aequorin. Nature 358:325–327

    Article  ADS  Google Scholar 

  • Rizzuto R, Marchi S, Bonora M, Aguiari P, Bononi A, De Stefani D, Giorgi C, Leo S, Rimessi A, Siviero R, Zecchini E, Pinton P (2009) Ca(2+) transfer from the ER to mitochondria: when, how and why. Biochim Biophys Acta 1787:1342–1351

    Article  Google Scholar 

  • Rizzuto R, De Stefani D, Raffaello A, Mammucari C (2012) Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol 13:566–578

    Article  Google Scholar 

  • Rostovtseva TK (2012) VDAC structure, function, and regulation of mitochondrial and cellular metabolism. Biochim Biophys Acta 1818:1437

    Article  Google Scholar 

  • Rotmann A, Sanchez C, Guiguemde A, Rohrbach P, Dave A, Bakouh N, Planelles G, Lanzer M (2010) PfCHA is a mitochondrial divalent cation/H+ antiporter in Plasmodium falciparum. Mol Microbiol 76:1591–1606

    Article  Google Scholar 

  • Rottenberg H, Scarpa A (1974) Calcium uptake and membrane potential in mitochondria. Biochemistry 13:4811–4817

    Article  Google Scholar 

  • Rueda CB, Traba J, Amigo I, Llorente-Folch I, Gonzalez-Sanchez P, Pardo B, Esteban JA, Del Arco A, Satrustegui J (2015) Mitochondrial ATP-Mg/Pi carrier SCaMC-3/Slc25a23 counteracts PARP-1-dependent fall in mitochondrial ATP caused by excitotoxic insults in neurons. J Neurosci 35:3566–3581

    Article  Google Scholar 

  • Sancak Y, Markhard AL, Kitami T, Kovacs-Bogdan E, Kamer KJ, Udeshi ND, Carr SA, Chaudhuri D, Clapham DE, Li AA, Calvo SE, Goldberger O, Mootha VK (2013) EMRE is an essential component of the mitochondrial calcium uniporter complex. Science 342:1379–1382

    Article  ADS  Google Scholar 

  • Shao J, Fu Z, Ji Y, Guan X, Guo S, Ding Z, Yang X, Cong Y, Shen Y (2016) Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) forms a Ca2+/H+ antiporter. Sci Rep 6:34174

    Article  ADS  Google Scholar 

  • Shimizu H, Schredelseker J, Huang J, Lu K, Naghdi S, Lu F, Franklin S, Fiji HD, Wang K, Zhu H, Tian C, Lin B, Nakano H, Ehrlich A, Nakai J, Stieg AZ, Gimzewski JK, Nakano A, Goldhaber JI, Vondriska TM, Hajnoczky G, Kwon O, Chen JN (2015) Mitochondrial Ca(2+) uptake by the voltage-dependent anion channel 2 regulates cardiac rhythmicity. Elife 4 doi: 10.7554/eLife.04801

  • Shoshan-Barmatz V, De Pinto V, Zweckstetter M, Raviv Z, Keinan N, Arbel N (2010) VDAC, a multi-functional mitochondrial protein regulating cell life and death. Mol Asp Med 31:227–285

    Article  Google Scholar 

  • Silva MA, Carnieri EG, Vercesi AE (1992) Calcium transport by corn mitochondria: evaluation of the role of phosphate. Plant Physiol 98:452–457

    Article  Google Scholar 

  • Sparagna GC, Gunter KK, Sheu SS, Gunter TE (1995) Mitochondrial calcium uptake from physiological-type pulses of calcium. A description of the rapid uptake mode. J Biol Chem 270:27510–27515

    Article  Google Scholar 

  • Stael S, Wurzinger B, Mair A, Mehlmer N, Vothknecht UC, Teige M (2012) Plant organellar calcium signalling: an emerging field. J Exp Bot 63:1525–1542

    Article  Google Scholar 

  • Szabo I, Zoratti M (2014) Mitochondrial channels: ion fluxes and more. Physiol Rev 94:519–608

    Article  Google Scholar 

  • Takahashi Y, Tateda C (2013) The functions of voltage-dependent anion channels in plants. Apoptosis 18:917–924

    Article  Google Scholar 

  • Talavera K, Nilius B (2006) Biophysics and structure-function relationship of T-type Ca2+ channels. Cell Calcium 40:97–114

    Article  Google Scholar 

  • Teardo E, Carraretto L, Wagner S, Formentin E, Behera S, De Bortoli S, Larosa V, Fuschs P, Lo Schiavo F, Raffaello A, Rizzuto R, Costa A, Schwarzlander M, Szabo I (2017) Physiological characterization of a plant mitochondrial calcium uniporter in vitro and in vivo. Plant Physiol 173:1355–1370

    Google Scholar 

  • Tovar-Mendez A, Miernyk JA, Randall DD (2003) Regulation of pyruvate dehydrogenase complex activity in plant cells. Eur J Biochem 270:1043–1049

    Article  Google Scholar 

  • Trenker M, Malli R, Fertschai I, Levak-Frank S, Graier WF (2007) Uncoupling proteins 2 and 3 are fundamental for mitochondrial Ca2+ uniport. Nat Cell Biol 9:445–452

    Article  Google Scholar 

  • Tsai MF, Jiang D, Zhao L, Clapham D, Miller C (2014) Functional reconstitution of the mitochondrial Ca2+/H+ antiporter Letm1. J Gen Physiol 143:67–73

    Article  Google Scholar 

  • Tsai MF, Phillips CB, Ranaghan M, Tsai CW, Wu Y, Willliams C, Miller C (2016) Dual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex. Elife 5 doi: 10.7554/eLife.15545

  • Vais H, Tanis JE, Muller M, Payne R, Mallilankaraman K, Foskett JK (2015) MCUR1, CCDC90A, is a regulator of the mitochondrial calcium uniporter. Cell Metab 22:533–535

    Article  Google Scholar 

  • Vais H, Mallilankaraman K, Mak DO, Hoff H, Payne R, Tanis JE, Foskett JK (2016) EMRE is a matrix Ca(2+) sensor that governs gatekeeping of the mitochondrial Ca(2+) uniporter. Cell Rep 14:403–410

    Article  Google Scholar 

  • Vasington FD, Murphy JV (1962) Ca ion uptake by rat kidney mitochondria and its dependence on respiration and phosphorylation. J Biol Chem 237:2670–2677

    Google Scholar 

  • Vasington FD, Gazzotti P, Tiozzo R, Carafoli E (1972) The effect of ruthenium red on Ca 2+ transport and respiration in rat liver mitochondria. Biochim Biophys Acta 256:43–54

    Article  Google Scholar 

  • Vecellio Reane D, Vallese F, Checchetto V, Acquasaliente L, Butera G, De Filippis V, Szabo I, Zanotti G, Rizzuto R, Raffaello A (2016) A MICU1 splice variant confers high sensitivity to the mitochondrial Ca2+ uptake machinery of skeletal muscle. Mol Cell 64:760–773

    Article  Google Scholar 

  • Wagner S, Behera S, De Bortoli S, Logan DC, Fuchs P, Carraretto L, Teardo E, Cendron L, Nietzel T, Fussl M, Doccula FG, Navazio L, Fricker MD, Van Aken O, Finkemeier I, Meyer AJ, Szabo I, Costa A, Schwarzlander M (2015) The EF-hand Ca2+ binding protein MICU choreographs mitochondrial Ca2+ dynamics in arabidopsis. Plant Cell 27:3190–3212

    Article  Google Scholar 

  • Wagner S, De Bortoli S, Schwarzlander M, Szabo I (2016) Regulation of mitochondrial calcium in plants versus animals. J Exp Bot 67:3809–3829

    Article  Google Scholar 

  • Waldeck-Weiermair M, Jean-Quartier C, Rost R, Khan MJ, Vishnu N, Bondarenko AI, Imamura H, Malli R, Graier WF (2011) 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

    Article  Google Scholar 

  • Waldeck-Weiermair M, Malli R, Parichatikanond W, Gottschalk B, Madreiter-Sokolowski CT, Klec C, Rost R, Graier WF (2015) Rearrangement of MICU1 multimers for activation of MCU is solely controlled by cytosolic Ca(2.) Sci Rep 5:15602

    Article  ADS  Google Scholar 

  • Wang L, Yang X, Li S, Wang Z, Liu Y, Feng J, Zhu Y, Shen Y (2014b) Structural and mechanistic insights into MICU1 regulation of mitochondrial calcium uptake. EMBO J 33:594–604

    Article  Google Scholar 

  • Wang L, Yang X, Shen Y (2015) Molecular mechanism of mitochondrial calcium uptake. Cell Mol Life Sci 72:1489–1498

    Article  Google Scholar 

  • Wang Z, Liu D, Varin A, Nicolas V, Courilleau D, Mateo P, Caubere C, Rouet P, Gomez AM, Vandecasteele G, Fischmeister R, Brenner C (2016) A cardiac mitochondrial cAMP signaling pathway regulates calcium accumulation, permeability transition and cell death. Cell Death Dis 7:e2198

    Article  Google Scholar 

  • Wu Y, Rasmussen TP, Koval OM, Joiner ML, Hall DD, Chen B, Luczak ED, Wang Q, Rokita AG, Wehrens XH, Song LS, Anderson ME (2015) The mitochondrial uniporter controls fight or flight heart rate increases. Nat Commun 6:6081

    Article  Google Scholar 

  • Zhang B, Carrie C, Ivanova A, Narsai R, Murcha MW, Duncan O, Wang Y, Law SR, Albrecht V, Pogson B, Giraud E, Van Aken O, Whelan J (2012) LETM proteins play a role in the accumulation of mitochondrially encoded proteins in Arabidopsis thaliana and AtLETM2 displays parent of origin effects. J Biol Chem 287:41757–41773

    Article  Google Scholar 

  • Zollino M, Lecce R, Fischetto R, Murdolo M, Faravelli F, Selicorni A, Butte C, Memo L, Capovilla G, Neri G (2003) Mapping the Wolf-Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2. Am J Hum Genet 72:590–597

    Article  Google Scholar 

Download references

Acknowledgments

The authors are grateful for financial support by the Italian Association for Cancer Research (15544 to I.S. and 10016 to R.R.), the Italian Ministry (Progetti di Rilevanza Nazionale PRIN 2015795S5W to I.S.), the French Muscular Dystrophy Association (19471 to A.R.), and the European Research Council (ERC mitoCalcium no. 294777 to R.R.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ildiko Szabo .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Checchetto, V., De Stefani, D., Raffaello, A., Rizzuto, R., Szabo, I. (2017). Molecular Players of Mitochondrial Calcium Signaling: Similarities and Different Aspects in Various Organisms. In: Rostovtseva, T. (eds) Molecular Basis for Mitochondrial Signaling. Biological and Medical Physics, Biomedical Engineering. Springer, Cham. https://doi.org/10.1007/978-3-319-55539-3_2

Download citation

Publish with us

Policies and ethics