Mitochondria and Ca2+ signaling

Emil C Toescu

doi:10.1111/j.1582-4934.2000.tb00114.x

. 2007 May 1;4(3):164–175. doi: 10.1111/j.1582-4934.2000.tb00114.x

Mitochondria and Ca²⁺ signaling

Emil C Toescu ^1,^✉

PMCID: PMC6741319 PMID: 12167285

Abstract

Mitochondria play a central role in cell homeostasis. Amongst others, one of the important functions of mitochondria is to integrate its metabolic response with one of the major signaling pathways ‐ the Ca²⁺ signaling. Mitochondria are capable to sense the levels of cytosolic Ca²⁺ and generate mitochondrial Ca²⁺ responses. Specific mechanisms for both Ca²⁺ uptake and Ca²⁺ release exist in the mitochondrial membranes. In turn, the mitochondrial Ca²⁺ signals are able to produce changes in the mitochondrial function and metabolism, which provide the required level of functional integration. This essay reviews briefly the current available information regarding the mitochondrial Ca²⁺ transport systems and some of the functional consequences of mitochondrial Ca²⁺ uptake

Keywords: mitochondria, Ca²⁺ signaling, Ca²⁺ transport, mitochondrial permeability transition pore cell necrosis, apoptosis

References

1. Rutter G. A., Burnett P., Rizzuto R., Brini M., Murgia M., Pozzan T., Tavare J., Denton R., Subcellular imaging of intramitochondrial Ca²⁺ with recombinant targeted aequorin: significance for the regulation of pyruvate dehydrogenase activity, Proc.Natl.Acad.Sci.USA, 93: 5489–5494, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
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4. McCormack J., Denton R., Signal transduction by intramitochondrial Ca²⁺ in mammalian energy metabolism, NIPS, 9: 71–76, 1994. [Google Scholar]
5. Zoratti M., Szabo I., The mitochondrial permeability transition, Biochim.Biophys.Acta, 1241: 139–176, 1995. [DOI] [PubMed] [Google Scholar]
6. Bernardi P., Mitochondrial transport of cations: channels, exchangers, and permeability transition, Physiol.Rev., 79: 1127–1155, 1999. [DOI] [PubMed] [Google Scholar]
7. Nicholls D., Budd S., Mitochondria and neuronal survival, Physiol.Rev., 80: 315–360, 2000. [DOI] [PubMed] [Google Scholar]
8. Azzone G., Pietrobon D., Zoratti M., Determination of the proton electrochemical gradient across biological membranes, Curr.Top.Bioenerg., 13: 1–77, 1984. [Google Scholar]
9. Azzone G., Bragadin M., Pozzan T., Dell'Antone P., Proton electrochemical potential in steady state rat liver mitochondria, Biochim.Biophys.Acta, 459: 96–109, 1977. [DOI] [PubMed] [Google Scholar]
10. Gunter T., Pfeiffer D., Mechanisms by which mitochondria transport calcium, Am.J.Physiol., 258: C755–C786, 1990. [DOI] [PubMed] [Google Scholar]
11. Gunter T., Buntinas L., Sparagna G., Gunter K., The Ca²⁺ transport mechanisms of mitochondria and Ca²⁺ uptake from physiological‐type Ca²⁺ transients, Biochim.Biophys.Acta, 1366: 5–15, 1998. [DOI] [PubMed] [Google Scholar]
12. Reed K., Bygrave F., The inhibition of mitochondrial calcium transport by lanthanides and ruthenium red, Biochem.J., 140: 143–155, 1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
13. Matlib M. A., Zhou Z., Knight S., Ahmen S., Choi K., Krause‐Bauer J., Phillips R., Altschuld R., Katsube Y., Sperelakis N., Oxygen‐bridged dinuclear ruthenium amine complex specifically inhibits Ca²⁺ uptake into mitochondria in vitro and in situ in single cardiac myocytes, J.Biol. Chem, 273: 10223–10231, 1998. [DOI] [PubMed] [Google Scholar]
14. Jung D., Baysal K., Brierley G., The sodium‐calcium antiport of heart mitochondria is not electroneutral, J.Biol. Chem, 270: 672–678, 1995. [DOI] [PubMed] [Google Scholar]
15. White R., Reynolds I., Mitochondrial depolarization in glutamate‐stimulated neurons ‐ an early signal specific to excitotoxin exposure, J.Neurosci., 16: 5688–5697, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
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17. Petronilli V., Cola C., Massari S., Colonna R., Bernardi P., Physiological effectors modify voltage sensing by the cyclosporin A‐sensitive permeability transition pore of mitochondria, J.Biol. Chem, 268: 21939–21945, 1993. [PubMed] [Google Scholar]
18. Ruck A., Dolder M., Wallimann T., Brdiczka D., Reconstituted adenine nucleotide translocase forms a channel for small molecules comparable to the mitochondrial permeability transition pore, FEBS Lett., 426: 97–101, 1998. [DOI] [PubMed] [Google Scholar]
19. Crompton M., Ellinger H., Costi A., Inhibition by cyclosporin A of a Ca²⁺‐dependent pore in heart mitochondira activated by inorganic phosphate and oxidative stress, Biochem.J., 255: 357–360, 1988. [PMC free article] [PubMed] [Google Scholar]
20. Barford D., Molecular mechanisms of the protein serine/threonine phosphatases, Trends Biochem.Sci., 21: 407–412, 1996. [DOI] [PubMed] [Google Scholar]
21. Budd S., Nicholls D., A re‐evaluation of the role of mitochondria in neuronal Ca²⁺ homeostasis, J.Neurochem., 66: 403–411, 1996. [DOI] [PubMed] [Google Scholar]
22. Hajnoczky G., Robb‐Gaspers L. D., Seitz M. B., Thomas A. P., Decoding of cytosolic calcium oscillations in the mitochondria, Cell, 82: 415–424, 1995. [DOI] [PubMed] [Google Scholar]
23. Rizzuto R., Pinton P., Carrington W., Fay F., Fogarty K., Lifshitz L., Tuft R., Pozzan T., Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca²⁺ responses, Science, 280: 1763–1766, 1998. [DOI] [PubMed] [Google Scholar]
24. Drummond R., Tuft R., Release of Ca²⁺ from the sarcoplasmic reticulum increases mitochondrial [Ca²⁺] in rat pulmonary artery smooth muscle cells, J.Physiol., 516: 139–147, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
25. Peng T., Greenamyre T., Privileged access to mitochondria of calcium influx through N‐methyl‐D‐aspartate receptors, Mol.Pharmacol., 53: 974–980, 1998. [PubMed] [Google Scholar]
26. Monteith G., Blaustein M. P., Heterogeneity of mitochondrial matrix free Ca²⁺: resolution of Ca²⁺ dynamics in individual mitochondria in situ, Am.J.Physiol., 276: C1193–C1204, 1999. [DOI] [PubMed] [Google Scholar]
27. Fein A., Tsacopoulous M., Activation of mitochondrial oxidative metabolism by calcium ions in Limulus ventral photoreceptors., Nature, 331: 437–440, 1988. [DOI] [PubMed] [Google Scholar]
28. Robb‐Gaspers L., Burnett P., Rutter G., Denton R., Rizzuto R., Thomas A., Integrating cytosolic calcium signals into mitochondrial metabolic responses, EMBO J., 17: 4987–5000, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
29. Friel D., Tsien R., An FCCP‐sensitive Ca²⁺ store in bullfrog sympathetic neurons and its participation in stimulusevoked changes in [Ca²⁺]_i , J.Neurosci., 14: 4007–4024, 1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
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31. Jouaville L., Ichas F., Holmuhamedov E., Camacho P., Lechleiter J., Synchronization of calcium waves by mitochondrial substrates in Xenopus laevis oocytes, Nature, 377: 438–441, 1995. [DOI] [PubMed] [Google Scholar]
32. McCarron J., Muir T., Mitochondrial regulation of the cytosolic Ca²⁺ concentration and the InsP₃‐sensitive Ca²⁺ store in guinea‐pig colonic smooth muscle, J.Physiol., 516: 149–161, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
33. Bezprozvanny I., Watras J., Ehrlich, B. E. , Bell‐shaped calcium‐response curves of Ins(1,4,5)P₃‐ and calciumgated channels from endoplasmic reticulum of cerebellum, Nature, 351: 751–754, 1991. [DOI] [PubMed] [Google Scholar]
34. Toescu E. C., Gardner J. M., Petersen O. H., Mitochondrial Ca²⁺ uptake at submicromolar [Ca²⁺]_i in permeabilized pancreatic acinar cells, Biochem. Biophys. Res. Commun., 192: 854–859, 1993. [DOI] [PubMed] [Google Scholar]
35. Toescu, E. C. , Temporal and spatial heterogeneities of Ca²⁺ signaling: mechanisms and physiological roles, Am.J.Physiol., 269: G173–G185, 1995. [DOI] [PubMed] [Google Scholar]
36. Hagar R., Burgstahler A., Nathanson N., Ehrlich, B. , Type III InsP₃ receptor channel stays open in the presence of increased calcium, Nature, 396: 81–84, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
37. Hoth M., Fanger C., Lewis R., Mitochondrial regulation of store‐operated calcium signaling in T lymphocytes, J.Cell Biol., 137: 633–648, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
38. Ichas F., Jouaville L., Mazat J., Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals, Cell, 89: 1145–1153, 1997. [DOI] [PubMed] [Google Scholar]
39. Toescu E. C., Apoptosis and cell death in neuronal cells: where does Ca²⁺ fit in?, Cell Calcium, 24, 1998. [DOI] [PubMed] [Google Scholar]
40. Simonian N., Coyle J., Oxidative stress in neurodegenerative disease, Annual Review of Pharmacology and Toxicology, 36: 83–106, 1996. [DOI] [PubMed] [Google Scholar]
41. Mattson M., Mark R., Excitoxicity and excitoprotection in vitro. In: Siesjo B. and Wieloch T. (Eds.), Adv. Neurology 71: Cellular and molecular mechanisms of ischemic brain damage, Lippincott‐Raven, Philadelphia , 1996, pp. 1–35. [Google Scholar]
42. Kroemer G., Mitochondrial control of apoptosis: an overview, Biochemical Society Symposium, 66: 1–15, 1999. [DOI] [PubMed] [Google Scholar]
43. Mignotte B., Vayssiere J., Mitochondria and apoptosis, Eur. J.Biochem., 252: 1–15, 1998. [DOI] [PubMed] [Google Scholar]
44. Murphy A., Fiskum G., Bcl‐2 and Ca²⁺‐mediated mitochondrial dysfunction in neural cell death, Biochemical Society Symposium, 66: 33–41, 1999. [DOI] [PubMed] [Google Scholar]

[b1] 1. Rutter G. A., Burnett P., Rizzuto R., Brini M., Murgia M., Pozzan T., Tavare J., Denton R., Subcellular imaging of intramitochondrial Ca²⁺ with recombinant targeted aequorin: significance for the regulation of pyruvate dehydrogenase activity, Proc.Natl.Acad.Sci.USA, 93: 5489–5494, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b2] 2. Duchen M., Contributions of mitochondria to animal physiology: from homeostatic sensor to calcium signaling and cell death, J.Physiol., 516: 1–17, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b3] 3. Szabo I., Zoratti M., The mitochondrial megachannel is the permeability transition pore, J.Bioenerg.Biomembr., 24: 111–117, 1992. [DOI] [PubMed] [Google Scholar]

[b4] 4. McCormack J., Denton R., Signal transduction by intramitochondrial Ca²⁺ in mammalian energy metabolism, NIPS, 9: 71–76, 1994. [Google Scholar]

[b5] 5. Zoratti M., Szabo I., The mitochondrial permeability transition, Biochim.Biophys.Acta, 1241: 139–176, 1995. [DOI] [PubMed] [Google Scholar]

[b6] 6. Bernardi P., Mitochondrial transport of cations: channels, exchangers, and permeability transition, Physiol.Rev., 79: 1127–1155, 1999. [DOI] [PubMed] [Google Scholar]

[b7] 7. Nicholls D., Budd S., Mitochondria and neuronal survival, Physiol.Rev., 80: 315–360, 2000. [DOI] [PubMed] [Google Scholar]

[b8] 8. Azzone G., Pietrobon D., Zoratti M., Determination of the proton electrochemical gradient across biological membranes, Curr.Top.Bioenerg., 13: 1–77, 1984. [Google Scholar]

[b9] 9. Azzone G., Bragadin M., Pozzan T., Dell'Antone P., Proton electrochemical potential in steady state rat liver mitochondria, Biochim.Biophys.Acta, 459: 96–109, 1977. [DOI] [PubMed] [Google Scholar]

[b10] 10. Gunter T., Pfeiffer D., Mechanisms by which mitochondria transport calcium, Am.J.Physiol., 258: C755–C786, 1990. [DOI] [PubMed] [Google Scholar]

[b11] 11. Gunter T., Buntinas L., Sparagna G., Gunter K., The Ca²⁺ transport mechanisms of mitochondria and Ca²⁺ uptake from physiological‐type Ca²⁺ transients, Biochim.Biophys.Acta, 1366: 5–15, 1998. [DOI] [PubMed] [Google Scholar]

[b12] 12. Reed K., Bygrave F., The inhibition of mitochondrial calcium transport by lanthanides and ruthenium red, Biochem.J., 140: 143–155, 1974. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b13] 13. Matlib M. A., Zhou Z., Knight S., Ahmen S., Choi K., Krause‐Bauer J., Phillips R., Altschuld R., Katsube Y., Sperelakis N., Oxygen‐bridged dinuclear ruthenium amine complex specifically inhibits Ca²⁺ uptake into mitochondria in vitro and in situ in single cardiac myocytes, J.Biol. Chem, 273: 10223–10231, 1998. [DOI] [PubMed] [Google Scholar]

[b14] 14. Jung D., Baysal K., Brierley G., The sodium‐calcium antiport of heart mitochondria is not electroneutral, J.Biol. Chem, 270: 672–678, 1995. [DOI] [PubMed] [Google Scholar]

[b15] 15. White R., Reynolds I., Mitochondrial depolarization in glutamate‐stimulated neurons ‐ an early signal specific to excitotoxin exposure, J.Neurosci., 16: 5688–5697, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b16] 16. Mannella C., Marko M., Buttle K., Reconsidering mitochondrial structure: new views of an old organelle, Trends Biochem.Sci., 22: 37–38, 1997. [DOI] [PubMed] [Google Scholar]

[b17] 17. Petronilli V., Cola C., Massari S., Colonna R., Bernardi P., Physiological effectors modify voltage sensing by the cyclosporin A‐sensitive permeability transition pore of mitochondria, J.Biol. Chem, 268: 21939–21945, 1993. [PubMed] [Google Scholar]

[b18] 18. Ruck A., Dolder M., Wallimann T., Brdiczka D., Reconstituted adenine nucleotide translocase forms a channel for small molecules comparable to the mitochondrial permeability transition pore, FEBS Lett., 426: 97–101, 1998. [DOI] [PubMed] [Google Scholar]

[b19] 19. Crompton M., Ellinger H., Costi A., Inhibition by cyclosporin A of a Ca²⁺‐dependent pore in heart mitochondira activated by inorganic phosphate and oxidative stress, Biochem.J., 255: 357–360, 1988. [PMC free article] [PubMed] [Google Scholar]

[b20] 20. Barford D., Molecular mechanisms of the protein serine/threonine phosphatases, Trends Biochem.Sci., 21: 407–412, 1996. [DOI] [PubMed] [Google Scholar]

[b21] 21. Budd S., Nicholls D., A re‐evaluation of the role of mitochondria in neuronal Ca²⁺ homeostasis, J.Neurochem., 66: 403–411, 1996. [DOI] [PubMed] [Google Scholar]

[b22] 22. Hajnoczky G., Robb‐Gaspers L. D., Seitz M. B., Thomas A. P., Decoding of cytosolic calcium oscillations in the mitochondria, Cell, 82: 415–424, 1995. [DOI] [PubMed] [Google Scholar]

[b23] 23. Rizzuto R., Pinton P., Carrington W., Fay F., Fogarty K., Lifshitz L., Tuft R., Pozzan T., Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca²⁺ responses, Science, 280: 1763–1766, 1998. [DOI] [PubMed] [Google Scholar]

[b24] 24. Drummond R., Tuft R., Release of Ca²⁺ from the sarcoplasmic reticulum increases mitochondrial [Ca²⁺] in rat pulmonary artery smooth muscle cells, J.Physiol., 516: 139–147, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b25] 25. Peng T., Greenamyre T., Privileged access to mitochondria of calcium influx through N‐methyl‐D‐aspartate receptors, Mol.Pharmacol., 53: 974–980, 1998. [PubMed] [Google Scholar]

[b26] 26. Monteith G., Blaustein M. P., Heterogeneity of mitochondrial matrix free Ca²⁺: resolution of Ca²⁺ dynamics in individual mitochondria in situ, Am.J.Physiol., 276: C1193–C1204, 1999. [DOI] [PubMed] [Google Scholar]

[b27] 27. Fein A., Tsacopoulous M., Activation of mitochondrial oxidative metabolism by calcium ions in Limulus ventral photoreceptors., Nature, 331: 437–440, 1988. [DOI] [PubMed] [Google Scholar]

[b28] 28. Robb‐Gaspers L., Burnett P., Rutter G., Denton R., Rizzuto R., Thomas A., Integrating cytosolic calcium signals into mitochondrial metabolic responses, EMBO J., 17: 4987–5000, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b29] 29. Friel D., Tsien R., An FCCP‐sensitive Ca²⁺ store in bullfrog sympathetic neurons and its participation in stimulusevoked changes in [Ca²⁺]_i , J.Neurosci., 14: 4007–4024, 1994. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b30] 30. Tinel H., Cancela J., Mogami H., Gerasimenko J., Gerasimenko O., Tepikin A., Petersen O., Active mitochondria surrounding the pancreatic acinar granule region prevent spreading of inositol trisphosphateevoked cytosolic Ca²⁺ signals, EMBO J., 18: 4999–5008, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b31] 31. Jouaville L., Ichas F., Holmuhamedov E., Camacho P., Lechleiter J., Synchronization of calcium waves by mitochondrial substrates in Xenopus laevis oocytes, Nature, 377: 438–441, 1995. [DOI] [PubMed] [Google Scholar]

[b32] 32. McCarron J., Muir T., Mitochondrial regulation of the cytosolic Ca²⁺ concentration and the InsP₃‐sensitive Ca²⁺ store in guinea‐pig colonic smooth muscle, J.Physiol., 516: 149–161, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b33] 33. Bezprozvanny I., Watras J., Ehrlich, B. E. , Bell‐shaped calcium‐response curves of Ins(1,4,5)P₃‐ and calciumgated channels from endoplasmic reticulum of cerebellum, Nature, 351: 751–754, 1991. [DOI] [PubMed] [Google Scholar]

[b34] 34. Toescu E. C., Gardner J. M., Petersen O. H., Mitochondrial Ca²⁺ uptake at submicromolar [Ca²⁺]_i in permeabilized pancreatic acinar cells, Biochem. Biophys. Res. Commun., 192: 854–859, 1993. [DOI] [PubMed] [Google Scholar]

[b35] 35. Toescu, E. C. , Temporal and spatial heterogeneities of Ca²⁺ signaling: mechanisms and physiological roles, Am.J.Physiol., 269: G173–G185, 1995. [DOI] [PubMed] [Google Scholar]

[b36] 36. Hagar R., Burgstahler A., Nathanson N., Ehrlich, B. , Type III InsP₃ receptor channel stays open in the presence of increased calcium, Nature, 396: 81–84, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b37] 37. Hoth M., Fanger C., Lewis R., Mitochondrial regulation of store‐operated calcium signaling in T lymphocytes, J.Cell Biol., 137: 633–648, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b38] 38. Ichas F., Jouaville L., Mazat J., Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals, Cell, 89: 1145–1153, 1997. [DOI] [PubMed] [Google Scholar]

[b39] 39. Toescu E. C., Apoptosis and cell death in neuronal cells: where does Ca²⁺ fit in?, Cell Calcium, 24, 1998. [DOI] [PubMed] [Google Scholar]

[b40] 40. Simonian N., Coyle J., Oxidative stress in neurodegenerative disease, Annual Review of Pharmacology and Toxicology, 36: 83–106, 1996. [DOI] [PubMed] [Google Scholar]

[b41] 41. Mattson M., Mark R., Excitoxicity and excitoprotection in vitro. In: Siesjo B. and Wieloch T. (Eds.), Adv. Neurology 71: Cellular and molecular mechanisms of ischemic brain damage, Lippincott‐Raven, Philadelphia , 1996, pp. 1–35. [Google Scholar]

[b42] 42. Kroemer G., Mitochondrial control of apoptosis: an overview, Biochemical Society Symposium, 66: 1–15, 1999. [DOI] [PubMed] [Google Scholar]

[b43] 43. Mignotte B., Vayssiere J., Mitochondria and apoptosis, Eur. J.Biochem., 252: 1–15, 1998. [DOI] [PubMed] [Google Scholar]

[b44] 44. Murphy A., Fiskum G., Bcl‐2 and Ca²⁺‐mediated mitochondrial dysfunction in neural cell death, Biochemical Society Symposium, 66: 33–41, 1999. [DOI] [PubMed] [Google Scholar]

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Mitochondria and Ca²⁺ signaling

Emil C Toescu

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Mitochondria and Ca2+ signaling

Emil C Toescu

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