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The machineries, regulation and cellular functions of mitochondrial calcium

Abstract

Calcium ions (Ca2+) are some of the most versatile signalling molecules, and they have many physiological functions, prominently including muscle contraction, neuronal excitability, cell migration and cell growth. By sequestering and releasing Ca2+, mitochondria serve as important regulators of cellular Ca2+. Mitochondrial Ca2+ also has other important functions, such as regulation of mitochondrial metabolism, ATP production and cell death. In recent years, identification of the molecular machinery regulating mitochondrial Ca2+ accumulation and efflux has expanded the number of (patho)physiological conditions that rely on mitochondrial Ca2+ homeostasis. Thus, expanding the understanding of the mechanisms of mitochondrial Ca2+ regulation and function in different cell types is an important task in biomedical research, which offers the possibility of targeting mitochondrial Ca2+ machinery for the treatment of several disorders.

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Change history

  • 24 September 2018

    In the original version of the article, sentences highlighting references 108, 137 and 175 incorrectly refer to other items in the reference list: reference 106, 132 and 169, respectively, which were corrected — in order — to reference 110, 136 and 176. The changes have been made in the HTML and PDF versions of the manuscript.

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Acknowledgements

The authors apologize to the many scientists whose work we were not able to credit owing to space restrictions. The authors thank V. De Pinto, G. A. Rutter, G. Santulli, I. Sekler and G. Campo for helpful discussions and A. Danese for the help in collecting the images for the figure in Box 1. P.P. is grateful to C. degli Scrovegni for continuous support. P.P. is supported by the Italian Ministry of Education, University and Research; the Italian Ministry of Health; Telethon (GGP15219/B); the Italian Association for Cancer Research (AIRC IG-18624); and by local funds from the University of Ferrara. C.G. is supported by local funds from the University of Ferrara, the Italian Association for Cancer Research (AIRC IG-19803), the Italian Ministry of Health and a Fondazione Cariplo grant. S.M. is supported by Fondazione Umberto Veronesi and the Italian Ministry of Health.

Reviewer information

Nature Reviews Molecular Cell Biology thanks J. Elrod and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

All authors researched data for the article, contributed to discussion of the content, wrote the article and edited the manuscript.

Competing interests

The authors declare no competing interests.

Correspondence to Paolo Pinton.

Supplementary information

  1. Supplementary table 1

Glossary

Membrane contact sites

The close apposition between two (or more) organelles in which membranes do not fuse, thereby maintaining their specific characteristics.

Membrane potential

The difference in electrical potential (measured in mV) between the interior and the exterior of a biological membrane generated from different concentrations of ions, such as H+, Na+, K+ and Cl.

Respiratory chain

Also known as the electron transport chain, a series of proteins in the inner mitochondrial membrane that consists of four complexes that transfer electrons from NADH and FADH2 to oxygen, which is reduced to water. Electron flow within these transmembrane complexes leads to the transport of H+ across the inner mitochondrial membrane, generating an electrochemical proton gradient (negative inside the matrix).

Caspase

An endoprotease involved in cell death and inflammation that contains catalytic cysteine residues in its active site that hydrolyse substrate peptides after specific aspartic acid residues.

Photodynamic therapy

A clinically approved therapeutic procedure that uses photosensitizing agents that, when exposed to a specific wavelength of light, produce a form of oxygen that kills tumour cells.

Ruthenium red

A polycationic dye that acts as an inhibitor of a wide number of ion channels, including all transient receptor potential channels (TRPCs), voltage-dependent anion-selective channel proteins (VDACs), mitochondrialcalcium uniporter (MCU) and ryanodine receptors.

Dissociation constant

(Kd). A measure that indicates the strength of the binding interaction between a single biomolecule (for example, a protein) and its ligand or binding partner (for example, Ca2+ ions). The smaller the Kd value is, the greater the binding affinity of the ligand for its target.

Chemiosmotic theory

States that the energy stored in the form of the transmembrane electrochemical gradient is used to produce ATP inside the mitochondrial matrix. The protons move back across the inner mitochondrial membrane through the F1F0 ATPase enzyme, coupling the electrochemical gradient to ATP production by combining ADP with inorganic phosphate.

Förster resonance energy transfer

(FRET). A distance-dependent energy transfer process that involves a donor molecule in an excited electronic state that may transfer energy to an acceptor chromophore, leading to a reduction in the donor’s fluorescence intensity and excited state lifetime and an increase in the acceptor’s emission. Its efficiency depends on the inverse sixth distance between donor and acceptor.

Ratiometric measurement

A measurement based on the use of a ratio between two fluorescence intensities that display a shift in their emission or excitation spectra when they bind to Ca2+. The intensity ratio is calculated at wavelengths for which the difference in fluorescence between bound and free indicator reaches its maximum.

Mitochondrial permeability transition pore

(mPTP). A protein complex that, under certain pathological conditions, including Ca2+ overload and oxidative stress, opens in the inner mitochondrial membrane, allowing the free passage of molecules >1,500 Daltons and leading to mitochondrial swelling and cell death through apoptosis or necrosis.

BCL-2 family

A large group of evolutionarily conserved proteins that share BCL-2 homology domains. BCL-2 family members are deeply involved in cell death regulation, consisting of both anti-apoptotic (BCL-2 and apoptosis regulator BCL-XL (also known as BCL2L1)) and pro-apoptotic (apoptosis regulator BAX and BCL-2 homologous antagonist/killer (BAK)) factors.

ER–mitochondrial encounter structure complex

(ERMES complex). Characterized in yeast, a protein complex consisting of four core components, whose major function is to mechanically link the endoplasmic reticulum (ER) with mitochondria.

PTEN-induced putative kinase 1

(PINK1). A serine/threonine kinase that is imported inside mitochondria in healthy conditions, whereas it accumulates at the outer mitochondrial membrane in dysfunctional mitochondria to promote their degradation through mitophagy. Mutations in PINK1 cause one form of autosomal recessive early-onset Parkinson disease.

Neointimal hyperplasia

The thickening of the intima layer (tunica) of arteries and veins that results from accumulation of fibroblasts and smooth muscle cells. The result of such excessive cellular deposition is the loss of luminal area.

Astrocytes

The most numerous and heterogeneous neuroglial cells in the central nervous system, distinguished by a star-like morphology with multiple primary processes originating from the soma.

Acinar cells

The exocrine cells of the pancreas that produce and transport the majority of enzymes required for the digestion of food.

Zymogen

An inactive precursor of an enzyme, also termed a pro-enzyme, which displays no catalytic activity and requires a specific biochemical transformation to become fully active.

Nutrient secretagogues

Substances that promote secretion.

ER stress

A stressful condition of the endoplasmic reticulum (ER) that triggers a signalling cascade, termed the unfolded protein response, which is aimed to restore ER homeostasis.

Excitation–contraction coupling

(EC coupling). A process whereby the action potential travelling along the plasmalemma evokes initiation of mechanical shortening of the myofibrils through Ca2+ release from the sarcoplasmic reticulum.

Excitation–transcription coupling

(ET coupling). A process initiated by Ca2+ signals that results in changes in gene expression.

Excitation–metabolism coupling

(EM coupling). A process initiated by Ca2+ signals that results in changes in cell metabolism.

Action potential

A movement of charge sufficient to generate a large and brief deviation in the membrane potential. It is used to communicate information between neurons and from neurons to muscle fibres.

Funny current

(If). A mixed Na+/K+ inward current with several unusual features.

Troponin C

(TN-C). A component of the troponin complex, together with troponin I and troponin T, which regulates muscle contraction by Ca2+ binding. Through its multiple EF-hand domains, TN-C acts as the Ca2+ sensor of the troponin complex, initiating the cascade of events that leads to contraction of striated muscle by interacting with troponin I after Ca2+ binding.

Myofilaments

The principal molecular regulators of contraction in cardiac and skeletal muscles, responsible for force generation and motion. Myofilaments consist primarily of thick filament myosin and thin filament actin proteins, as well as additional components, including troponin, titin and nebulin.

Fight-or-flight response

The physiological reaction that helps an animal in response to emergency situations such as a harmful event or an attack.

NACHT, LRR and PYD domains-containing protein 3 inflammasome

(NLRP3 inflammasome). A complex whose formation leads to the activation of caspase 1, the secretion of pro-inflammatory cytokines and the induction of inflammatory cell death (or pyroptosis).

Mitochondrial antiviral signalling

(MAVS). A CARD domain-containing protein located on the outer mitochondrial membrane.

Excitotoxicity

A pathological process by which neurons are damaged or killed by an excessive activation of receptors for excitatory neurotransmitters, such as glutamate. Such hyper-stimulation produces a massive entry of Ca2+ inside the cell and induces mitochondrial damage.

N-methyl-d-aspartate receptors

(NMDARs). Glutamate-gated cation channels showing high Ca2+ permeability. They can be found at most excitatory synapses and exhibit the highest affinity for glutamate among the glutamate receptors.

Purkinje cells

A class of large inhibitory neurons located in the cerebellar cortex of the brain and characterized by an intricate dendritic arbor. They have crucial roles in motor coordination.

Oligodendrocyte

A type of neuroglia that provides support to axons in the central nervous system by producing myelin sheaths. In the peripheral nervous system, the equivalent to oligodendrocytes is Schwann cells.

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Fig. 1: Intracellular Ca2+ signalling.
Fig. 2: The mitochondrial Ca2+ uptake pathway.
Fig. 3: Role of mitochondrial Ca2+ in pathophysiological processes.