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Mitochondria as sensors and regulators of calcium signalling

Nature Reviews Molecular Cell Biology volume 13, pages 566–578 (2012)Cite this article

Subjects

Key Points

  • The regulation of mitochondrial Ca2+ transport in physiological and pathological conditions is controlled by channels and exchangers that are located in the outer and inner mitochondrial membrane (OMM and IMM, respectively). Whereas the OMM is permeable to solutes and ions, Ca2+ transport across the IMM is highly regulated.

  • The strategic positioning of mitochondria in close proximity to Ca2+ release channels of the endoplasmic reticulum (ER) and the sarcoplasmic reticulum explains the high rate of mitochondrial Ca2+ uptake in stimulated cells, despite the low affinity of the mitochondrial Ca2+ uniporter (MCU), which mediates Ca2+ transfer through the IMM.

  • The sites of contacts between mitochondria and the ER or the sarcoendoplasmic reticulum (called mitochondria associated membranes (MAMs)) are microdomains of high Ca2+ concentration. Several proteins and chaperones are responsible for the maintenance of these structures and for efficient uptake of Ca2+ released from the ER and the sarcoendoplasmic reticulum.

  • Mitochondria act as intracellular Ca2+ buffers in the proximity of Ca2+ channels at the ER or the sarcoendoplasmic reticulum and the plasma membrane, thus affecting the Ca2+ feedback regulation of channel activity. Some cell types exhibit a defined distribution of mitochondria, and this affects the diffusion of Ca2+ waves through the cytosol.

  • Ca2+ accumulation into the mitochondria stimulates aerobic metabolism and thus ATP production by modulating the activity of the enzymes of the tricarboxylic acid cycle (TCA cycle) and other effectors.

  • Mitochondrial Ca2+ waves control cell fate. Increased levels of intracellular Ca2+ may trigger cell death by necrosis or apoptosis by causing the sustained or transient opening of a high-conductance channel of the IMM, termed the permeability transition pore (PTP). Conversely, low Ca2+ concentration levels in mitochondria cause a decrease in ATP production, which promotes pro-survival autophagy.

Abstract

During the past two decades calcium (Ca2+) accumulation in energized mitochondria has emerged as a biological process of utmost physiological relevance. Mitochondrial Ca2+ uptake was shown to control intracellular Ca2+ signalling, cell metabolism, cell survival and other cell-type specific functions by buffering cytosolic Ca2+ levels and regulating mitochondrial effectors. Recently, the identity of mitochondrial Ca2+ transporters has been revealed, opening new perspectives for investigation and molecular intervention.

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Figure 1: The build-up of the ER–mitochondria junctions.
Figure 2: Ca2+ buffering by mitochondria regulates Ca2+ release from the ER.
Figure 3: Spatial Ca2+ buffering by mitochondria in polarized cells.
Figure 4: The regulation of aerobic metabolism and autophagy.
Figure 5: Mitochondrial Ca2+ signals in the regulation of cell death pathways.

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Acknowledgements

The experimental work in the authors' laboratory is supported by grants from the Italian Ministry of Health, the Italian Ministry of Education, Universities and Research, the European Union (ERC mitoCalcium, no. 294777 and FP7 'MyoAGE', no. 223576), the US National Institues of Health (NIH; grant #1P01AG025532-01A1), the Cariparo Foundation (Padua), the Italian Association for Cancer Research (AIRC) and Telethon-Italy (GPP10005A and GGP11082B).

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  1. Department of Biomedical Sciences, University of Padua and CNR Neuroscience Institute, Via G. Colombo 3, Padua, 35131, Italy

    Rosario Rizzuto, Diego De Stefani, Anna Raffaello & Cristina Mammucari

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Glossary

Immunological synapse

The site of functional apposition between an antigen-presenting cell (APC) and a T cell. During antigen presentation, the T cell undergoes a gross morphological rearrangement, with T cell receptors, adhesion molecules, cytoskeletal elements and organelles (including mitochondria) spatially relocating at clusters at the contact site with the APC.

Energized mitochondria

When oxidizable substrates are provided to mitochondria, electrons are fed into the respiratory chain, which couples electron flow to proton pumps across the inner mitochondrial membrane. An electrochemical proton gradient is established that drives ATP synthesis and provides the thermodynamic force for Ca2+ accumulation in these energized mitochondria.

Necrosis

A common form of cell death that frequently results from toxic injury, hypoxia or stress. Necrosis involves cell swelling, dysregulation of cell-membrane ion and water fluxes, mitochondrial swelling and the eventual release of cell contents into the interstitium. This form of cell death usually causes tissue inflammation.

Autophagy

A cellular process (also known as macroautophagy) that mediates the bulk degradation of cytosolic components. Molecules and organelles are surrounded by a double-membrane vesicle (the autophagosome). After fusion with a lysosome, an autolysosome (also known as autophagolysosome) is formed, and the content is degraded by lysosomal hydrolases. Basal autophagy has a function in quality control, whereas higher levels of autophagy are induced during starvation and other stress conditions.

Chemiosmotic theory

The energy that is required for the endergonic synthesis of ATP by the F1F0 ATPase is provided by the electrochemical gradient that is generated by the respiratory chain across the inner mitochondrial membrane. In respiring mitochondria, reducing equivalents are transported by carrier molecules (such as NADH and FADH2) to the electron transport chain, whereas matrix protons are transported outwards. Re-equilibration of H+ into the matrix down its electrochemical gradient is coupled to ATP production.

Electrochemical proton gradient

Gradient generated by the activity of the electron transport chain that translocates H+ across the inner mitochondrial membrane. It is composed of a membrane potential difference (ΔΨ) and a cation concentration difference (ΔpH), but the ΔΨ component is predominant. The electrochemical proton gradient represents the driving force for H+ entry and thus ATP synthesis.

Membrane potential

The charge difference (measured in mV) between the two surfaces of a biological membrane that arises from the different concentrations of ions such as H+, Na+ or K+ on either side. The Na+/K+-ATPase creates a membrane potential by using the energy stored in ATP to maintain a low concentration of Na+ and a high concentration of K+ inside the cell, and a high concentration of Na+ and a low concentration of K+ on the outside.

Nernst equation

Calculates the equilibrium potential for an ion on the basis of the charge of the ion and the concentration gradient.

Veq is the equilibrium potential, R the universal gas constant, T the temperature, z the valence of the ion, F the Faraday's constant and [CATz+] is the concentration of any cation.

Mitochondrial Ca2+ uniporter

(MCU). The inner mitochondrial membrane channel responsible for mitochondrial Ca2+ uptake. Early biochemical work in the1960s showed that energized mitochondria rapidly accumulate Ca2+ via an electrogenic mechanism with a net charge transfer of 2. Because of the lack of evidence for other ions being co-transported or exchanged during this process, this channel has been defined as a 'uniporter'.

Na+/Ca2+ exchangers

(NCX). Antiporters that exchange Na+ with Ca2+ at the membrane. Although fully reversible, the function of NCX at the plasma membrane is to extrude Ca2+ from the cytosol, while Na+ enters down its concentration gradient. At the inner mitochondrial membrane, mitochondrial Ca2+ is extruded while Na+ enters into the matrix.

H+/Ca2+ exchangers

(HCX). Na+-independent antiporter membrane protein that permits the extrusion of Ca2+ from the matrix and the entrance of H+.

Aequorin

Ca2+-sensitive photoprotein isolated from luminescent jellyfish that is used to detect the Ca2+ content in different subcellular compartments.

Inositol-1,4,5-trisphosphate-sensitive channels

(Ins(1,4,5)P3-sensitive channels). Ca2+-selective channels that are activated by the second messenger Ins(1,4,5)P3 and are mainly located in the endoplasmic reticulum (ER) membrane. Given the difference in the Ca2+ concentration between the ER lumen and the cytosol, opening of this channel results in a transient increase in intracellular Ca2+ concentration.

Ryanodine-sensitive channels

Ca2+-selective channels that are mainly located in the membrane of the sarcoplasmic reticulum of skeletal muscle and heart, but they are also expressed in the endoplasmic reticulum of other tissues (in particular in the brain). They are activated by Ca2+ and blocked by the plant alkaloid ryanodine.

Voltage-operated channels

Plasma membrane located, highly selective Ca2+ channels that are activated by membrane depolarization. They are divided in several different subfamilies on the basis of their subunit composition, which also reflects their different tissue distribution, Ca2+-current type and pharmacological profile. Present nomenclature uses a numerical system (that is, Cav1.x, Cav2.x and Cav3.x), but older nomenclature uses an alphabetical system (that is, L-, P/Q-, R-, N- and T-type) according to their Ca2+-current features.

Store-operated channels

Highly selective Ca2+ channels located at the plasma membrane that open in response to depletion of internal Ca2+ stores. Upon endoplasmic reticulum (ER) Ca2+ depletion, the Ca2+ sensors of the STIM family, which are located at the ER surface, cause the opening of plasma membrane store-operated channels, termed ORAI. The ORAI family includes three members (ORAI1, ORAI2 and ORAI3), and the STIM family is composed of STIM1 and STIM2.

Voltage-dependent anion channels

(VDACs). Abundant and highly conserved proteins of the outer mitochondrial membrane. VDAC exists in three isoforms in mammals (termed VDAC1, VDAC2 and VDAC3) and is permeable to many solutes below 5 kDa.

Mitocarta

Inventory of 1098 mouse genes encoding proteins that are likely to be localized at mitochondria. The data were generated by mass spectrometry of mitochondria isolated from 14 tissues and protein localization was confirmed by large-scale tagging of candidate proteins with GFP and microscopy. The data were integrated with six other genome-scale data sets of mitochondrial localization.

Permeability transition pore

(PTP). High conductance inner mitochondrial membrane (IMM) channel that requires a permissive load of matrix Ca2+ for opening and is specifically inhibited by cyclosporin A. Persistent PTP opening irreversibly commits cells to death by causing IMM depolarization (which blocks of oxidative phosphorylation and reactive oxygen species production), matrix swelling and cristae unfolding and results in the release of stored Ca2+ and of apoptogenic proteins.

Cyclophilin D

(CYPD). Major inducer of the opening of the permeability transition pore (PTP). CYPD binds to the inner mitochondrial membrane (IMM) in a process that is regulated by Ca2+, inorganic phosphate and reactive oxygen species. This interaction is prevented by cyclosporin A and by other CYPD-interacting molecules that are usually described as PTP inhibitors.

Ca2+ buffers

Molecules and organelles that bind or sequester Ca2+ and thereby act as Ca2+ sponges and modulate Ca2+ concentration in subcellular subdomains.

ORAI channels

Pore-forming subunits of store-operated channels. They are predicted to have four transmembrane domains and three family members have been identified thus far.

Store-operated Ca2+ entry (SOCE)

The activation of a Ca2+ channel in the plasma membrane in response to the depletion of Ca2+ levels in the endoplasmic reticulum. SOCE is also known as capacitative Ca2+ entry.

Ca2+-dependent inactivation

(CDI). The process whereby increases of cytosolic Ca2+ leads to inactivation of the Ca2+ release-activated Ca2+ (CRAC) channel.

EF-hand

A highly conserved Ca2+-binding domain comprising two helices (that is, E and F after the 5th and 6th helices of parvalbumin) that are linked by a short acidic Ca2+-binding loop.

Excitoxicity

The pathological process in which neurons undergo cell death caused by excessive stimulation. Classically, overactivation of glutamate receptors leads to excessive Ca2+ entry, which causes activation of enzymes, such as calpains, that break down key cellular components leading to cell death.

N-methyl-D-aspartate receptors

(NMDRs). Subtypes of plasma membrane ionotropic glutamate receptors that are mainly involved in memory formation and excitotoxicity. Ionotropic glutamate receptors are classified on the basis of their selective agonists (such as NMDA, AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and kainate).

L-type Ca2+ channels

Voltage-operated channels that belong to the Cav1.x family and that are activated by strong depolarizations. They are long-lasting and are inhibited by dihydropyridines and phenylalkylamines.

NLRP3 inflammasome

(Nucleotide-binding oligomerization domain- Leu-rich repeat- and pyrin domain-containing 3 inflammasome). A high molecular weight signalling complex that consists of a family of cytoplasmic proteins, the NLRP proteins. This complex recruits pro-caspase 1, which is then activated by autocatalytic cleavage. Active caspase 1 catalyses the cleavage of pro-interleukin1β, pro-IL-18 and pro-IL-33, resulting in the secretion of biologically active forms of these pro-inflammatory cytokines.

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Rizzuto, R., De Stefani, D., Raffaello, A. et al. Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol 13, 566–578 (2012). https://doi.org/10.1038/nrm3412

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