Mitochondrial calcium ion transport (Homo sapiens)

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1, 2, 12, 22, 25...3, 4, 7-10, 14...5, 16, 20, 326, 11, 13, 18, 19, 24...18, 23mitochondrial intermembrane spacecytosolmitochondrial matrixCa2+VDAC1 MICU2 SLC8B1SLC8A3 VDAC3 MCU AKAP1 SMDT1 VDAC1,2,3LETM1 hexamerMICU1 Processing of SMDT1MICU3 LETM1 H+Na+VDAC2 Na+MCU complexH+SLC8A3:AKAP1Na+Ca2+MCUB Ca2+10, 14, 15, 17, 28...29


Description

Divalent calcium ions (Ca2+) are transported from the cytosol into the mitochondrial matrix and back out of the matrix into the cytosol (reviewed in Santo-Domingo et al. 2010, De Stefani et al. 2016). In the matrix, Ca2+ binds and allosterically regulates pyruvate dehydrogenase, isocitrate dehydrogenase, 2-oxoglutarate dehydrogenase, and possibly other enzymes (Rizzuto et al. 2012). Matrix calcium is also observed to regulate release of caspase cofactors and calcium flux through channels on neighboring membranes, The pathway into the mitochondrion involves VDAC1, VDAC2, and VDAC3 in the outer membrane and the mitochondrial calcium uniporter (MCU) complex in the inner membrane. VDACs in the open conformation are anion channels. However in the closed conformation they transport Ca2+ from the cytosol to the intermembrane space. When calcium concentrations in the cytosol and intermembrane space are high, the MCU complex opens and transports Ca2+ from the intermembrane space to the mitochondrial matrix using the driving force of the membrane potential (reviewed in Drago et al. 2011, Marchi et al. 2014, De Stefani et al. 2015).
Efflux of Ca2+ from the matrix to the intermembrane space is catalyzed by the Na+/Ca2+ antiporter SLC8B1 (NCLX) located in the inner membrane. LETM1 is also observed to export calcium from the matrix to the intermembrane space by acting as an H+/Ca2+ antiporter, although somewhat contradictory results have been found in knockdowns of LETM1. Calcium in the intermembrane space may be transported to the cytosol by the Na+/Ca2+ antiporter SLC8A3 (NCX3), however the mitochondrial localization of SLC8A3 is controversial and SLC8A3 has a limited distribution among tissues. View original pathway at Reactome.

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Reactome-Converter 
Pathway is converted from Reactome ID: 8949215
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: May, Bruce

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Bibliography

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  1. De Stefani D, Patron M, Rizzuto R.; ''Structure and function of the mitochondrial calcium uniporter complex.''; PubMed Europe PMC Scholia
  2. Rizzuto R, De Stefani D, Raffaello A, Mammucari C.; ''Mitochondria as sensors and regulators of calcium signalling.''; PubMed Europe PMC Scholia
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  4. Perocchi F, Gohil VM, Girgis HS, Bao XR, McCombs JE, Palmer AE, Mootha VK.; ''MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake.''; PubMed Europe PMC Scholia
  5. De Stefani D, Bononi A, Romagnoli A, Messina A, De Pinto V, Pinton P, Rizzuto R.; ''VDAC1 selectively transfers apoptotic Ca2+ signals to mitochondria.''; PubMed Europe PMC Scholia
  6. Doonan PJ, Chandramoorthy HC, Hoffman NE, Zhang X, Cárdenas C, Shanmughapriya S, Rajan S, Vallem S, Chen X, Foskett JK, Cheung JY, Houser SR, Madesh M.; ''LETM1-dependent mitochondrial Ca2+ flux modulates cellular bioenergetics and proliferation.''; PubMed Europe PMC Scholia
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  8. Liao Y, Hao Y, Chen H, He Q, Yuan Z, Cheng J.; ''Mitochondrial calcium uniporter protein MCU is involved in oxidative stress-induced cell death.''; PubMed Europe PMC Scholia
  9. Patron M, Checchetto V, Raffaello A, Teardo E, Vecellio Reane D, Mantoan M, Granatiero V, Szabò I, De Stefani D, Rizzuto R.; ''MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity.''; PubMed Europe PMC Scholia
  10. De Stefani D, Raffaello A, Teardo E, Szabò I, Rizzuto R.; ''A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter.''; PubMed Europe PMC Scholia
  11. Jiang D, Zhao L, Clish CB, Clapham DE.; ''Letm1, the mitochondrial Ca2+/H+ antiporter, is essential for normal glucose metabolism and alters brain function in Wolf-Hirschhorn syndrome.''; PubMed Europe PMC Scholia
  12. Drago I, Pizzo P, Pozzan T.; ''After half a century mitochondrial calcium in- and efflux machineries reveal themselves.''; PubMed Europe PMC Scholia
  13. Froschauer E, Nowikovsky K, Schweyen RJ.; ''Electroneutral K+/H+ exchange in mitochondrial membrane vesicles involves Yol027/Letm1 proteins.''; PubMed Europe PMC Scholia
  14. 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.; ''MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling.''; PubMed Europe PMC Scholia
  15. 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.; ''Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter.''; PubMed Europe PMC Scholia
  16. Szabadkai G, Bianchi K, Várnai P, De Stefani D, Wieckowski MR, Cavagna D, Nagy AI, Balla T, Rizzuto R.; ''Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels.''; PubMed Europe PMC Scholia
  17. Mallilankaraman K, Cárdenas C, Doonan PJ, Chandramoorthy HC, Irrinki KM, Golenár T, Csordás G, Madireddi P, Yang J, Müller M, Miller R, Kolesar JE, Molgó J, Kaufman B, Hajnóczky G, Foskett JK, Madesh M.; ''MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism.''; PubMed Europe PMC Scholia
  18. De Marchi U, Santo-Domingo J, Castelbou C, Sekler I, Wiederkehr A, Demaurex N.; ''NCLX protein, but not LETM1, mediates mitochondrial Ca2+ extrusion, thereby limiting Ca2+-induced NAD(P)H production and modulating matrix redox state.''; PubMed Europe PMC Scholia
  19. Tsai MF, Jiang D, Zhao L, Clapham D, Miller C.; ''Functional reconstitution of the mitochondrial Ca2+/H+ antiporter Letm1.''; PubMed Europe PMC Scholia
  20. Rapizzi E, Pinton P, Szabadkai G, Wieckowski MR, Vandecasteele G, Baird G, Tuft RA, Fogarty KE, Rizzuto R.; ''Recombinant expression of the voltage-dependent anion channel enhances the transfer of Ca2+ microdomains to mitochondria.''; PubMed Europe PMC Scholia
  21. Kamer KJ, Mootha VK.; ''MICU1 and MICU2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter.''; PubMed Europe PMC Scholia
  22. De Stefani D, Rizzuto R, Pozzan T.; ''Enjoy the Trip: Calcium in Mitochondria Back and Forth.''; PubMed Europe PMC Scholia
  23. 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.; ''NCLX is an essential component of mitochondrial Na+/Ca2+ exchange.''; PubMed Europe PMC Scholia
  24. Tamai S, Iida H, Yokota S, Sayano T, Kiguchiya S, Ishihara N, Hayashi J, Mihara K, Oka T.; ''Characterization of the mitochondrial protein LETM1, which maintains the mitochondrial tubular shapes and interacts with the AAA-ATPase BCS1L.''; PubMed Europe PMC Scholia
  25. Foskett JK, Philipson B.; ''The mitochondrial Ca(2+) uniporter complex.''; PubMed Europe PMC Scholia
  26. Shao J, Fu Z, Ji Y, Guan X, Guo S, Ding Z, Yang X, Cong Y, Shen Y.; ''Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) forms a Ca(2+)/H(+) antiporter.''; PubMed Europe PMC Scholia
  27. Chaudhuri D, Artiga DJ, Abiria SA, Clapham DE.; ''Mitochondrial calcium uniporter regulator 1 (MCUR1) regulates the calcium threshold for the mitochondrial permeability transition.''; PubMed Europe PMC Scholia
  28. Paupe V, Prudent J, Dassa EP, Rendon OZ, Shoubridge EA.; ''CCDC90A (MCUR1) is a cytochrome c oxidase assembly factor and not a regulator of the mitochondrial calcium uniporter.''; PubMed Europe PMC Scholia
  29. König T, Tröder SE, Bakka K, Korwitz A, Richter-Dennerlein R, Lampe PA, Patron M, Mühlmeister M, Guerrero-Castillo S, Brandt U, Decker T, Lauria I, Paggio A, Rizzuto R, Rugarli EI, De Stefani D, Langer T.; ''The m-AAA Protease Associated with Neurodegeneration Limits MCU Activity in Mitochondria.''; PubMed Europe PMC Scholia
  30. Bondarenko AI, Jean-Quartier C, Parichatikanond W, Alam MR, Waldeck-Weiermair M, Malli R, Graier WF.; ''Mitochondrial Ca(2+) uniporter (MCU)-dependent and MCU-independent Ca(2+) channels coexist in the inner mitochondrial membrane.''; PubMed Europe PMC Scholia
  31. Tomar D, Dong Z, Shanmughapriya S, Koch DA, Thomas T, Hoffman NE, Timbalia SA, Goldman SJ, Breves SL, Corbally DP, Nemani N, Fairweather JP, Cutri AR, Zhang X, Song J, Jaña F, Huang J, Barrero C, Rabinowitz JE, Luongo TS, Schumacher SM, Rockman ME, Dietrich A, Merali S, Caplan J, Stathopulos P, Ahima RS, Cheung JY, Houser SR, Koch WJ, Patel V, Gohil VM, Elrod JW, Rajan S, Madesh M.; ''MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics.''; PubMed Europe PMC Scholia
  32. Checchetto V, Reina S, Magrì A, Szabo I, De Pinto V.; ''Recombinant human voltage dependent anion selective channel isoform 3 (hVDAC3) forms pores with a very small conductance.''; PubMed Europe PMC Scholia
  33. Sancak Y, Markhard AL, Kitami T, Kovács-Bogdán E, Kamer KJ, Udeshi ND, Carr SA, Chaudhuri D, Clapham DE, Li AA, Calvo SE, Goldberger O, Mootha VK.; ''EMRE is an essential component of the mitochondrial calcium uniporter complex.''; PubMed Europe PMC Scholia
  34. Tsai MF, Phillips CB, Ranaghan M, Tsai CW, Wu Y, Willliams C, Miller C.; ''Dual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex.''; PubMed Europe PMC Scholia
  35. Chaudhuri D, Sancak Y, Mootha VK, Clapham DE.; ''MCU encodes the pore conducting mitochondrial calcium currents.''; PubMed Europe PMC Scholia
  36. Marchi S, Pinton P.; ''The mitochondrial calcium uniporter complex: molecular components, structure and physiopathological implications.''; PubMed Europe PMC Scholia
  37. Jiang D, Zhao L, Clapham DE.; ''Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter.''; PubMed Europe PMC Scholia
  38. Santo-Domingo J, Demaurex N.; ''Calcium uptake mechanisms of mitochondria.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114654view16:12, 25 January 2021ReactomeTeamReactome version 75
113102view11:16, 2 November 2020ReactomeTeamReactome version 74
112336view15:26, 9 October 2020ReactomeTeamReactome version 73
101236view11:13, 1 November 2018ReactomeTeamreactome version 66
100775view20:40, 31 October 2018ReactomeTeamreactome version 65
100319view19:17, 31 October 2018ReactomeTeamreactome version 64
99864view16:00, 31 October 2018ReactomeTeamreactome version 63
99421view14:36, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99104view12:39, 31 October 2018ReactomeTeamreactome version 62
93493view11:25, 9 August 2017ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
AKAP1 ProteinQ92667 (Uniprot-TrEMBL)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
LETM1 ProteinO95202 (Uniprot-TrEMBL)
LETM1 hexamerComplexR-HSA-8951831 (Reactome)
MCU ProteinQ8NE86 (Uniprot-TrEMBL)
MCU complexComplexR-HSA-8949151 (Reactome)
MCUB ProteinQ9NWR8 (Uniprot-TrEMBL)
MICU1 ProteinQ9BPX6 (Uniprot-TrEMBL)
MICU2 ProteinQ8IYU8 (Uniprot-TrEMBL)
MICU3 ProteinQ86XE3 (Uniprot-TrEMBL)
Na+MetaboliteCHEBI:29101 (ChEBI)
Processing of SMDT1PathwayR-HSA-8949664 (Reactome) Proteolytic processing of proSMDT1 (proEMRE) regulates assembly of properly regulated mitochondrial calcium uniporter (MCU) complex (Konig et al. 2016). C2orf47 (MAIP) in a complex with AFG3L2 (m-AAA protease) binds the transit peptide of proSMDT1, promotes cleavage of the transit peptide by mitochondrial processing endopeptidase, and prevents proteolytic destruction of proSMDT1. SMDT1 that is not then incorporated with the regulatory subunits MICU1 and MICU2 (or MICU1 and MICU3 in neurons) into the MCU complex is degraded by AFG3L2, preventing assembly of unregulated MCU. Unprocessed proSMDT1 is proteolyzed by YME1L1.
SLC8A3 ProteinP57103 (Uniprot-TrEMBL)
SLC8A3:AKAP1ComplexR-HSA-8951817 (Reactome)
SLC8B1ProteinQ6J4K2 (Uniprot-TrEMBL)
SMDT1 ProteinQ9H4I9 (Uniprot-TrEMBL)
VDAC1 ProteinP21796 (Uniprot-TrEMBL)
VDAC1,2,3ComplexR-HSA-8949214 (Reactome)
VDAC2 ProteinP45880 (Uniprot-TrEMBL)
VDAC3 ProteinQ9Y277 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
Ca2+ArrowR-HSA-8949145 (Reactome)
Ca2+ArrowR-HSA-8949178 (Reactome)
Ca2+ArrowR-HSA-8949687 (Reactome)
Ca2+ArrowR-HSA-8949688 (Reactome)
Ca2+ArrowR-HSA-8949703 (Reactome)
Ca2+R-HSA-8949145 (Reactome)
Ca2+R-HSA-8949178 (Reactome)
Ca2+R-HSA-8949687 (Reactome)
Ca2+R-HSA-8949688 (Reactome)
Ca2+R-HSA-8949703 (Reactome)
H+ArrowR-HSA-8949687 (Reactome)
H+R-HSA-8949687 (Reactome)
LETM1 hexamermim-catalysisR-HSA-8949687 (Reactome)
MCU complexmim-catalysisR-HSA-8949178 (Reactome)
Na+ArrowR-HSA-8949688 (Reactome)
Na+ArrowR-HSA-8949703 (Reactome)
Na+R-HSA-8949688 (Reactome)
Na+R-HSA-8949703 (Reactome)
R-HSA-8949145 (Reactome) VDAC1, VDAC2, and VDAC3 are voltage dependent anion channels that also preferentially transport divalent calcium ions (Ca2+) in their closed state (Rapizzi et al. 2002, De Stefani et al. 2012, Checchetto et al. 2014, and inferred from rat VDAC1). VDAC1, VDAC2, and VDAC3, located in the mitochondrial outer membrane, transport Ca2+ from the cytosol to the mitochondrial intermembrane space. Transfer of cytosolic calcium to the intermembrane space appears to occur preferentially at sites where the endoplasmic reticulum is in close proximity to the mitochondrial outer membrane. This apposition is due to the physical interaction of VDAC channels on the mitochondrial outer membrane with the ITPR1 (IP3R) channel on the endoplasmic reticulum via the chaperone HSPA9 (GRP75) (Szabadkai et al. 2006).
R-HSA-8949178 (Reactome) The mitochondrial calcium uniporter (MCU) is a protein complex located in the mitochondrial inner membrane that transports divalent calcium ions (Ca2+) from the mitochondrial intermembrane space, across the mitochondrial inner membrane, and into the mitochondrial matrix (De Stefani et al. 2011, Baughman et al. 2011, Chaudhuri et al. 2013) where the Ca2+ allosterically regulates matrix enzymes such as pyruvate dehydrogenase, isocitrate dehydrogenase, and the 2-oxoglutarate dehydrogenase complex (Denton and McCormack 1980). The MCU subunit of the complex forms the actual pore in the inner membrane and is suggested to interact with VDAC1 (Liao et al. 2015). MCUB is a differentially expressed paralog of MCU that is likewise located in the inner membrane but acts as an inhibitor of calcium import (Raffaello et al. 2013). MICU1 and MICU2 (or MICU3 in neurons) regulate the pore so that it opens only when cellular calcium concentrations are high (Perocchi et al. 2010, Plovanich et al. 2013, Patron et al. 2014, Kamer and Mootha et al. 2014). The SMDT1 (EMRE) subunit forms part of the pore and binds MICU1 and MICU2 (Sancak et al. 2013, Tsai et al. 2016). MCUR1 appears to associate with MCU, but its function is uncertain (Paupe et al. 2015, Chaudhuri et al. 2016). Other calcium channels are also detected in the mitochondrial inner membrane (Bondarenko et al. 2014).
R-HSA-8949687 (Reactome) LETM1, which is located in the mitochondrial inner membrane (Tamai et al. 2008), exchanges two protons from the mitochondrial intermembrane space for a divalent calcium ion from the mitochondrial matrix (Tsai et al. 2014, Shao et al. 2016). LETM1 appears to participate in both calcium efflux and calcium influx (Doonan et al. 2014). Overexpression of LETM1, however, does not elevate calcium efflux from the mitochondrial matrix so the role of LETM1 in mitochondrial calcium flux is controversial (De Marchi et al. 2014). In human HeLa cells, knockdown of LETM1 causes an increase in mitochondrial calcium (Shao et al. 2016) however in mice, knockdown of Letm1 causes a reduction in mitochondrial calcium uptake and proton extrusion at low cytosolic calcium concentration (Jiang et al. 2013). LETM1 has also been proposed to act as a K+/H+ exchanger (Froschauer et al. 2005).
R-HSA-8949688 (Reactome) NCLX catalyzes the exchange of 3-4 sodium ions from the intermembrane space for 1 calcium ion from the mitochondrial matrix (Palty et al. 2010, De Marchi et al. 2014). As a result, NCLX causes an efflux of calcium from the mitochondrial matrix and thereby attenuates calcium regulation of enzymatic activity within the mitochondrial matrix.
R-HSA-8949703 (Reactome) As inferred from rat Slc8a3 and mouse Akap1 (Akap121), SLC8A3 in a complex with AKAP1 exchanges cytosolic sodium ions for divalent calcium from the mitochondrial intermembrane space resulting in an efflux of calcium from the mitochondrion. The mitochondrial localization of SLC8A3 is controversial, however, and SLC8A3 has a limited tissue distribution.
SLC8A3:AKAP1mim-catalysisR-HSA-8949703 (Reactome)
SLC8B1mim-catalysisR-HSA-8949688 (Reactome)
VDAC1,2,3mim-catalysisR-HSA-8949145 (Reactome)
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