Calcium and Bioenergetics


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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Further Reading

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