Calcium and Bioenergetics

Abstract

Calcium (Ca2+) is one of the most abundant divalent cations found in the biological systems and has numerous vital roles in cellular physiology and pathophysiology. It is involved in the regulation of ionic homeostasis in the cytosol and different cellular organelles. The Ca2+ directly regulates cellular bioenergetics, cell survival/death and acts as a messenger to regulate various cellular signalling events. Mitochondria, the bioenergetics hub of the cell, are one of the major reservoirs of cellular Ca2+. The Ca2+ plays a major role in shaping the metabolic outcome of the mitochondria and whole cell. In recent years, the molecular identity of a mitochondrial Ca2+ uniporter (MCU) has been revealed along with various regulators. However, the molecular mechanism of uniporter regulation in different stimuli and other determinants of mitochondrial Ca2+ homeostasis are still elusive. In this article, we present the current understanding of cytosolic/mitochondrial Ca2+ homeostasis, its role in energy metabolism and cell survival and its involvement in different cell systems and tissue/organ physiology.

Key Concepts

  • Ca2+ signalling is the key determinant for cellular metabolism and bioenergetics.
  • Mitochondrial Ca2+ ([Ca2+]m) homeostasis is maintained by balanced [Ca2+]m influx and efflux.
  • Mitochondria sequester cytosolic Ca2+ ([Ca2+]c) into the matrix through the mitochondrial Ca2+ uniporter MCU.
  • [Ca2+]m efflux is mediated by mitochondrial Na+/Ca2+ (NCLX).
  • [Ca2+]m uptake modulates spatiotemporal patterns of intracellular Ca2+ (iCa2+) signalling.
  • Under physiological conditions, [Ca2+]m uptake regulates bioenergetics and promotes ATP production.
  • Under pathological conditions, impaired [Ca2+]m exchange or [Ca2+]m overload leads to cell death depending on the cell type involved.
  • Defective [Ca2+]m signalling is associated with many human diseases.

Keywords: calcium; bioenergetics; mitochondria; metabolism; cell death; mitochondrial calcium uniporter; MCU; MCUR1; MICU1; NCLX

Figure 1. Major routes of Ca2+ entry in the cell. The entry of Ca2+ into cells across the plasma membrane can occur by any of these channels, including voltage‐dependent Ca2+ channels (VDCC), receptor operated channels (ROC), Na+/Ca2+‐exchanger (NCX), second messenger‐operated channels (SMOC) and store‐operated Ca2+ channels (SOCC). The depolarisation of membrane stimulates the VDCC, ROC is activated by direct binding of a ligand to receptor, NCX is a Na+−Ca2+ exchanger (NCX) operating in a reverse mode enters Ca2+ in cells, and SMOC is induced by any of a number of small messenger molecules, including inositol phosphates, cAMP (cyclic adenosine monophosphate) and cyclic nucleotides, diacylglycerol and other lipid‐derived messengers and SOCC are activated by intracellular Ca2+ stores.
Figure 2. [Ca2+]m influx and efflux system. The [Ca2+]m enters the OMM via VDAC and the IMM via MCU. The [Ca2+]m export is mediated via the Na+/Ca2+ exchanger (NCLX) or H+/Ca2+ exchanger (Letm1) and through the opening of the mPTP. The NCX3 present on the OMM also promotes [Ca2+]m efflux. The [Ca2+]m plays a major role in cell death and cell survival. It activates several matrix enzymes of the TCA (tricarboxylic acid) cycle to regulate bioenergetics, but excessive mitochondrial uptake induces oxidative stress and cell death.
Figure 3. Calcium and bioenergetics. Cellular bioenergetic fuel sources such as fatty acids and glucose are imported in the cytosol and subsequently converted to acetyl‐CoA. Fatty acids are converted to acetyl‐CoA through the process of β‐oxidation and subsequently inside the mitochondria, used for the generation of ATP (adenosine triphosphate) through the process of OXPHOS. Glucose is converted into the pyruvate through the process of glycolysis and imported to the mitochondrial matrix. The pyruvate is converted to acetyl‐CoA for entry into the TCA cycle using the enzyme PDH. The [Ca2+]m activates PDH and other matrix enzymes of the TCA cycle including, KDH and IDH. This results in the balance between NADH production and NADH oxidation. The [Ca2+]m uptake increases the supply of reducing equivalents (NADH production) to the ETC and stimulates the production of ATP through the F1‐Fo ATP synthase activity (NADH consumption) and flux through Complex‐III of ETC, thus controlling bioenergetics.
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References

Ames BN, Shigenaga MK and Hagen TM (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proceedings of the National Academy of Sciences of the United States of America 90: 7915–7922.

Andreyev AY, Kushnareva YE, Murphy AN, et al. (2015) Mitochondrial ROS metabolism: 10 years later. Biochemistry (Mosc) 80: 517–531.

Antony AN, Paillard M, Moffat C, et al. (2016) MICU1 regulation of mitochondrial Ca(2+) uptake dictates survival and tissue regeneration. Nature Communications 7: 10955.

Aubert G, Martin OJ, Horton JL, et al. (2016) The failing heart relies on ketone bodies as a fuel. Circulation 133: 698–705.

Bagur R and Hajnoczky G (2017) Intracellular Ca2+ sensing: its role in calcium homeostasis and signaling. Molecular Cell 66: 780–788.

Baines CP, Kaiser RA, Purcell NH, et al. (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434: 658–662.

Balaban RS (2009) The role of Ca(2+) signaling in the coordination of mitochondrial ATP production with cardiac work. Biochimica et Biophysica Acta 1787: 1334–1341.

Baughman JM, Perocchi F, Girgis HS, et al. (2011) Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476: 341–345.

van den Berghe G (1991) The role of the liver in metabolic homeostasis: implications for inborn errors of metabolism. Journal of Inherited Metabolic Disease 14: 407–420.

Bernardi P and Rasola A (2007) Calcium and cell death: the mitochondrial connection. Subcellular Biochemistry 45: 481–506.

Bernardi P and 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.

Berridge MJ, Bootman MD and Roderick HL (2003a) Calcium signalling: dynamics, homeostasis and remodelling. Nature Reviews. Molecular Cell Biology 4: 517–529.

Bragadin M, Pozzan T and Azzone GF (1979) Kinetics of Ca2+ carrier in rat liver mitochondria. Biochemistry 18: 5972–5978.

Carafoli E, Tiozzo R, Lugli G, et al. (1974) The release of calcium from heart mitochondria by sodium. Journal of Molecular and Cellular Cardiology 6: 361–371.

Catterall WA (2011) Voltage‐gated calcium channels. Cold Spring Harbor Perspectives in Biology 3: a003947.

Darley‐Usmar V (2004) The powerhouse takes control of the cell; the role of mitochondria in signal transduction. Free Radical Biology and Medicine 37: 753–754.

De Stefani D, Raffaello A, Teardo E, et al. (2011) A forty‐kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476: 336–340.

Dong Z, Shanmughapriya S, Tomar D, et al. (2017) Mitochondrial Ca2+ uniporter is a mitochondrial luminal redox sensor that augments MCU channel activity. Molecular Cell 65: 1014–1028.e1017.

Doonan PJ, Chandramoorthy HC, Hoffman NE, et al. (2014) LETM1‐dependent mitochondrial Ca2+ flux modulates cellular bioenergetics and proliferation. FASEB Journal 28: 4936–4949.

Giorgio V, von Stockum S, Antoniel M, et al. (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proceedings of the National Academy of Sciences of the United States of America 110: 5887–5892.

Houten SM, Violante S, Ventura FV, et al. (2016) The biochemistry and physiology of mitochondrial fatty acid beta‐oxidation and its genetic disorders. Annual Review of Physiology 78: 23–44.

Ivanov AI, Malkov AE, Waseem T, et al. (2014) Glycolysis and oxidative phosphorylation in neurons and astrocytes during network activity in hippocampal slices. Journal of Cerebral Blood Flow and Metabolism 34: 397–407.

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

Jouaville LS, Pinton P, Bastianutto C, et al. (1999) Regulation of mitochondrial ATP synthesis by calcium: evidence for a long‐term metabolic priming. Proceedings of the National Academy of Sciences of the United States of America 96: 13807–13812.

Kamer KJ and Mootha VK (2014) MICU1 and MICU2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter. EMBO Reports 15: 299–307.

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

Kokoszka JE, Waymire KG, Levy SE, et al. (2004) The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427: 461–465.

Kroemer G, Galluzzi L and Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiological Reviews 87: 99–163.

Kwong JQ, Lu X, Correll RN, et al. (2015) The mitochondrial calcium uniporter selectively matches metabolic output to acute contractile stress in the heart. Cell Reports 12: 15–22.

Lloyd‐Evans E, Waller‐Evans H, Peterneva K, et al. (2010) Endolysosomal calcium regulation and disease. Biochemical Society Transactions 38: 1458–1464.

Luongo TS, Lambert JP, Yuan A, et al. (2015) The mitochondrial calcium uniporter matches energetic supply with cardiac workload during stress and modulates permeability transition. Cell Reports 12: 23–34.

Luongo TS, Lambert JP, Gross P, et al. (2017) The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability. Nature 545: 93–97.

Mallilankaraman K, Doonan P, Cardenas C, et al. (2012) MICU1 is an essential gatekeeper for MCU‐mediated mitochondrial Ca(2+) uptake that regulates cell survival. Cell 151: 630–644.

Moudy AM, Handran SD, Goldberg MP, et al. (1995) Abnormal calcium homeostasis and mitochondrial polarization in a human encephalomyopathy. Proceedings of the National Academy of Sciences of the United States of America 92: 729–733.

Palty R and Sekler I (2012) The mitochondrial Na(+)/Ca(2+) exchanger. Cell Calcium 52: 9–15.

Parekh AB and Putney JW Jr (2005) Store‐operated calcium channels. Physiological Reviews 85: 757–810.

Perocchi F, Gohil VM, Girgis HS, et al. (2010) MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake. Nature 467: 291–296.

Raffaello A, De Stefani D, Sabbadin D, et al. (2013) The mitochondrial calcium uniporter is a multimer that can include a dominant‐negative pore‐forming subunit. EMBO Journal 32: 2362–2376.

Raffaello A, Mammucari C, Gherardi G, et al. (2016) Calcium at the center of cell signaling: interplay between endoplasmic reticulum, mitochondria, and lysosomes. Trends in Biochemical Sciences 41: 1035–1049.

Rasola A and Bernardi P (2007) The mitochondrial permeability transition pore and its involvement in cell death and in disease pathogenesis. Apoptosis 12: 815–833.

Rizzuto R, De Stefani D, Raffaello A, et al. (2012) Mitochondria as sensors and regulators of calcium signalling. Nature Reviews. Molecular Cell Biology 13: 566–578.

Rowlands DJ, Islam MN, Das SR, et al. (2011) Activation of TNFR1 ectodomain shedding by mitochondrial Ca2+ determines the severity of inflammation in mouse lung microvessels. Journal of Clinical Investigation 121: 1986–1999.

Sancak Y, Markhard AL, Kitami T, et al. (2013) EMRE is an essential component of the mitochondrial calcium uniporter complex. Science 342: 1379–1382.

Satrustegui J, Pardo B and Del Arco A (2007) Mitochondrial transporters as novel targets for intracellular calcium signaling. Physiological Reviews 87: 29–67.

Shanmughapriya S, Rajan S, Hoffman NE, et al. (2015) SPG7 is an essential and conserved component of the mitochondrial permeability transition pore. Molecular Cell 60: 47–62.

Slater EC and Cleland KW (1953) The effect of calcium on the respiratory and phosphorylative activities of heart‐muscle sarcosomes. Biochemical Journal 55: 566–590.

Soboloff J, Rothberg BS, Madesh M, et al. (2012) STIM proteins: dynamic calcium signal transducers. Nature Reviews. Molecular Cell Biology 13: 549–565.

Sullivan LB and Chandel NS (2014) Mitochondrial reactive oxygen species and cancer. Cancer & Metabolism 2: 17.

Tomar D, Dong Z, Shanmughapriya S, et al. (2016) MCUR1 is a scaffold factor for the MCU complex function and promotes mitochondrial bioenergetics. Cell Reports 15: 1673–1685.

Unitt JF, McCormack JG, Reid D, et al. (1989) Direct evidence for a role of intramitochondrial Ca2+ in the regulation of oxidative phosphorylation in the stimulated rat heart. Studies using 31P n.m.r. and ruthenium red. Biochemical Journal 262: 293–301.

Further Reading

Berridge MJ, Bootman MD and Roderick HL (2003b) Calcium signalling: dynamics, homeostasis and remodelling. Nature Reviews. Molecular Cell Biology 4: 517–529.

Bootman MD (2012) Calcium signaling: a subject collection from Cold Spring Harbor perspectives in biology. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.

Clapham DE (2007) Calcium signaling. Cell 131: 1047–1058.

De Stefani D, Rizzuto R and Pozzan T (2016) Enjoy the trip: calcium in mitochondria back and forth. Annual Review of Biochemistry 85: 161–192.

Hofer AM and Brown EM (2003) Extracellular calcium sensing and signalling. Nature Reviews. Molecular Cell Biology 4: 530–538.

Kamer KJ and Mootha VK (2015) The molecular era of the mitochondrial calcium uniporter. Nature Reviews. Molecular Cell Biology 16: 545–553.

Lambert DG and Rainbow RD (2013) Calcium Signaling Protocols, 3rd edn. New York: Humana Press.

Papa S, Guerrieri F and Tager JM (1999) Frontiers of cellular bioenergetics: molecular biology, biochemistry, and physiopathology. New York: Kluwer Academic/Plenum Press.

Putney JW (2006) Calcium Signaling, 2nd edn. Boca Raton, FL: CRC/Taylor & Francis.

Wallace DC, Fan W and Procaccio V (2010) Mitochondrial energetics and therapeutics. Annual Review of Pathology 5: 297–348.

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Jadiya, Pooja, and Tomar, Dhanendra(Feb 2018) Calcium and Bioenergetics. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027818]