Mitochondria as all‐round players of the calcium game (original) (raw)

The renaissance of mitochondrial calcium transport

European Journal of Biochemistry, 2000

Although the capacity of mitochondria for accumulating Ca 21 down the electrical gradient generated by the respiratory chain has been known for over three decades, the physiological significance of this phenomenon has been re-evaluated only recently. Indeed, it was long believed that the low affinity of the mitochondrial Ca 21 transporters would allow significant uptake only in conditions of cellular Ca 21 overload. Conversely, the direct measurement of [Ca 21 ] in the mitochondrial matrix revealed major [Ca 21 ] increases upon agonist stimulation. In this review, we will summarize: (a) the mechanisms that allow this large response, reconciling the biochemical properties of the transporters and the large amplitude of the mitochondrial [Ca 21 ] rises, and (b) the biological role of mitochondrial Ca 21 signalling, that encompasses the regulation of mitochondrial function and the modulation of the spatio-temporal pattern of cytosolic [Ca 21 ] increases.

Calcium and mitochondria: mechanisms and functions of a troubled relationship

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2004

Mitochondria promptly respond to Ca 2+ -mediated cell stimulations with a rapid accumulation of the cation into the matrix. In this article, we review (i) the basic principles of mitochondrial Ca 2+ transport, (ii) the physiological/pathological role of mitochondrial Ca 2+ uptake, (iii) the regulatory mechanisms that may operate in vivo, and (iv) the new targeted Ca 2+ probes that allowed the brediscoveryQ of these organelles in calcium signalling. D

Calcium uptake mechanisms of mitochondria

Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2010

The ability of mitochondria to capture Ca 2+ ions has important functional implications for cells, because mitochondria shape cellular Ca 2+ signals by acting as a Ca 2+ buffer and respond to Ca 2+ elevations either by increasing the cell energy supply or by triggering the cell death program of apoptosis. A mitochondrial Ca 2+ channel known as the uniporter drives the rapid and massive entry of Ca 2+ ions into mitochondria. The uniporter operates at high, micromolar cytosolic Ca 2+ concentrations that are only reached transiently in cells, near Ca 2+ release channels. Mitochondria can also take up Ca 2+ at low, nanomolar concentrations, but this high affinity mode of Ca 2+ uptake is not well characterized. Recently, leucine-zipper-EF hand-containing transmembrane region (Letm1) was proposed to be an electrogenic 1:1 mitochondrial Ca 2+ /H + antiporter that drives the uptake of Ca 2+ into mitochondria at nanomolar cytosolic Ca 2+ concentrations. In this article, we will review the properties of the Ca 2+ import systems of mitochondria and discuss how Ca 2+ uptake via an electrogenic 1:1 Ca 2+ /H + antiport challenges our current thinking of the mitochondrial Ca 2+ uptake mechanism.

Calcium transport across the inner mitochondrial membrane: Molecular mechanisms and pharmacology

Molecular and Cellular Endocrinology, 2012

Growing evidence supports that mitochondrial calcium uptake is important for cell metabolism, signaling and survival. However, both the molecular nature of the mitochondrial Ca 2+ transport sites and the calcium signals they respond to remained elusive. Recent RNA interference studies have identified new candidate proteins for Ca 2+ transport across the inner mitochondrial membrane, including LETM1, MCU, MICU1 and NCLX. The sensitivity of these factors to several drugs has been tested and in parallel, some new inhibitors of mitochondrial Ca 2+ uptake have been described. This paper provides an update on the pharmacological aspects of the molecular mechanisms of the inner mitochondrial membrane Ca 2+ transport.

Mitochondrial Transporters as Novel Targets for Intracellular Calcium Signaling

Physiological Reviews, 2007

transition in rat liver mitochondria is modulated by the ATP-Mg/Pi carrier. Am J Physiol Gastrointest Liver Physiol 285: G274-G281, 2003; 10.1152 10. /ajpgi.00052.2003 permeability transition, due to opening of the permeability transition pore (PTP), is triggered by Ca 2ϩ in conjunction with an inducing agent such as phosphate. However, incubation of rat liver mitochondria in the presence of low micromolar concentrations of Ca 2ϩ and millimolar concentrations of phosphate is known to also cause net efflux of matrix adenine nucleotides via the ATP-Mg/Pi carrier. This raises the possibility that adenine nucleotide depletion through this mechanism contributes to mitochondrial permeability transition. Results of this study show that phosphateinduced opening of the mitochondrial PTP is, at least in part, secondary to depletion of the intramitochondrial adenine nucleotide content via the ATP-Mg/Pi carrier. Delaying net adenine nucleotide efflux from mitochondria also delays the onset of phosphate-induced PTP opening. Moreover, mitochondria that are depleted of matrix adenine nucleotides via the ATP-Mg/Pi carrier show highly increased susceptibility to swelling induced by high Ca 2ϩ concentration, atractyloside, and the prooxidant tert-butylhydroperoxide. Thus the ATP-Mg/Pi carrier, by regulating the matrix adenine nucleotide content, can modulate the sensitivity of rat liver mitochondria to undergo permeability transition. This has important implications for hepatocytes under cellular conditions in which the intramitochondrial adenine nucleotide pool size is depleted, such as in hypoxia or ischemia, or during reperfusion when the mitochondria are exposed to increased oxidative stress.

Cytoplasmic and Mitochondrial Calcium Signaling: A Two-Way Relationship

Cold Spring Harbor Perspectives in Biology, 2019

Intracellular Ca 2+ signals are well organized in all cell types, and trigger a variety of vital physiological processes. The temporal and spatial characteristics of cytosolic Ca 2+ increases are mainly governed by the fluxes of this ion across the membrane of the endoplasmic/sarcoplasmic reticulum and the plasma membrane. However, various Ca 2+ transporters also allow for Ca 2+ exchanges between the cytoplasm and mitochondria. Increases in mitochondrial Ca 2+ stimulate the production of ATP, which allows the cells to cope with the increased energy demand created by the stimulus. Less widely appreciated is the fact that Ca 2+ handling by mitochondria also shapes cytosolic Ca 2+ signals. Indeed, the frequency, amplitude, and duration of cytosolic Ca 2+ increases can be altered by modifying the rates of Ca 2+ transport into, or from, mitochondria. In this review, we focus on the interplay between mitochondria and Ca 2+ signaling, highlighting not only the consequences of cytosolic Ca 2+ changes on mitochondrial Ca 2+ , but also how cytosolic Ca 2+ dynamics is controlled by modifications of the Ca 2+-handling properties and the metabolism of mitochondria.

The Ins and Outs of Mitochondrial Calcium

Circulation research, 2015

Calcium is thought to play an important role in regulating mitochondrial function. Evidence suggests that an increase in mitochondrial calcium can augment ATP production by altering the activity of calcium-sensitive mitochondrial matrix enzymes. In contrast, the entry of large amounts of mitochondrial calcium in the setting of ischemia-reperfusion injury is thought to be a critical event in triggering cellular necrosis. For many decades, the details of how calcium entered the mitochondria remained a biological mystery. In the past few years, significant progress has been made in identifying the molecular components of the mitochondrial calcium uniporter complex. Here, we review how calcium enters and leaves the mitochondria, the growing insight into the topology, stoichiometry and function of the uniporter complex, and the early lessons learned from some initial mouse models that genetically perturb mitochondrial calcium homeostasis.

Modulation of calcium signalling by mitochondria

Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2009

In this review we will attempt to summarise the complex and sometimes contradictory effects that mitochondria have on different forms of calcium signalling. Mitochondria can influence Ca 2+ signalling indirectly by changing the concentration of ATP, NAD(P)H, pyruvate and reactive oxygen specieswhich in turn modulate components of the Ca 2+ signalling machinery i.e. buffering, release from internal stores, influx from the extracellular solution, uptake into cellular organelles and extrusion by plasma membrane Ca 2+ pumps. Mitochondria can directly influence the calcium concentration in the cytosol of the cell by importing Ca 2+ via the mitochondrial Ca 2+ uniporter or transporting Ca 2+ from the interior of the organelle into the cytosol by means of Na + /Ca 2+ or H + /Ca 2+ exchangers. Considerable progress in understanding the relationship between Ca 2+ signalling cascades and mitochondrial physiology has been accumulated over the last few years due to the development of more advanced optical techniques and electrophysiological approaches.