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Mitochondrial Regulation of Intracellular Ca²⁺ Signaling: More Than Just Simple Ca²⁺ Buffers

Anant B. Parekh

Department of Physiology, University of Oxford, Oxford OX1 3PT, UK

	Abstract

 
Mitochondrial Ca²⁺ uptake shapes the profile of intracellular Ca²⁺ signals, both spatially and temporally. In addition, such uptake controls the gating of Ca²⁺ release and store-operated Ca²⁺ entry channels, partitions cells into subcellular Ca²⁺ hotspots, and can result in the release of diffusible signals into the cytosol that subsequently regulate protein function.

	Introduction

Top Introduction Mitochondrial Ca2+ transport Mitochondria spatially restrict... Mitochondrial regulation of... Mitochondrial regulation of... Multiple pools of mitochondria Mitochondria-derived... References

 
Mitochondria have long been known to be the major site for aerobic production of intracellular ATP in eukaryotic cells; however, their role in intracellular Ca²⁺ signaling has had a much more checkered past. The view that mitochondrial Ca²⁺ transport was central to intracellular Ca²⁺ signaling, which was pervasive up until the late 1970s, was summarily dismissed in the 1980s when the ubiquitous Ca²⁺-releasing messenger inositol 1,4,5-trisphosphate (InsP₃) was found to mobilize Ca²⁺ specifically from the endoplasmic reticulum. In addition, use of the newly available Ca²⁺-sensitive fluorescent dyes revealed that mitochondria released very little Ca²⁺ into the cytosol. Furthermore, intracellular Ca²⁺ concentration could reach, at least globally, the micromolar range upon stimulation, levels considerably smaller than the apparent K_m for mitochondrial Ca²⁺ uptake (10–20 µM). All of this changed in the mid-1990s, and mitochondria have now returned with a vengeance to occupy a key position in intracellular Ca²⁺ dynamics (17). Underpinning this mitochondrial renaissance was the localization of genetically targeted Ca²⁺-selective probes (like the bioluminescent protein aequorin) or fluorescent dyes like rhod-2 to the mitochondrial matrix, which provided a direct and unambiguous readout of mitochondrial Ca²⁺ changes in living cells following receptor stimulation (17). In addition, following an increase in cytosolic Ca²⁺ to the micromolar range, careful single-cell analysis revealed that the rate of recovery of the Ca²⁺ signal to prestimulation values was sculpted by mitochondrial Ca²⁺ buffering (2).

	Mitochondrial Ca2+ transport

Top Introduction Mitochondrial Ca2+ transport Mitochondria spatially restrict... Mitochondrial regulation of... Mitochondrial regulation of... Multiple pools of mitochondria Mitochondria-derived... References

 
Mitochondria rapidly take up Ca²⁺ from the cytosol via a ruthenium red-sensitive uniporter spanning the inner mitochondrial membrane. This electrogenic passive uptake is driven mainly by the enormous negative potential across the inner mitochondrial membrane (–180 mV), a consequence of proton extrusion along the electron transport chain. Inhibition of mitochondrial Ca²⁺ uptake, either by blocking the uniporter with ruthenium red and related compounds or by dissipating the mitochondrial membrane potential with protonophores like FCCP, results, for a given amount of Ca²⁺ entering the cytosol, in a larger-amplitude cytosolic Ca²⁺ transient and a slower rate of recovery (2, 17). The paradox of how mitochondria can buffer global cytosolic Ca²⁺ transients in the micromolar range despite having a low-affinity uptake mechanism was neatly resolved by the finding that mitochondria sense local microdomains of elevated Ca²⁺ at the mouth of open Ca²⁺ channels, either in the endoplasmic reticulum or the plasma membrane (4, 17, 18). Although the Ca²⁺ concentration in such microdomains falls off steeply with distance from the open channel, they nevertheless reach estimated concentrations of several micromolar within a few tens of nanometers of the pore. Because mitochondria can be juxtaposed to both the stores and the plasma membrane, they are ideally situated for sensing such local Ca²⁺ domains (17). Recent evidence suggests that the voltage-dependent anion channel of the outer mitochondrial membrane might facilitate the transfer of such microdomains to the uniporter (16). Interestingly, Ca²⁺ itself has been found to reversibly promote close apposition between mitochondria and endoplasmic reticulum, a process that could contribute to the dynamics of spatiotemporal Ca²⁺ signaling (20).

The uniporter itself is activated by a rise in Ca²⁺, and recent work demonstrates that channel activity can be enhanced by calmodulin (Csordas G and Hajnoczky G, personal communication). Even after cytosolic Ca²⁺ levels have returned to low concentrations, Ca²⁺-calmodulin gating of the uniporter imparts a time-dependent enhancement of activity such that a subsequent increase in cytosolic Ca²⁺ results in more pronounced mitochondrial Ca²⁺ uptake. Sensing microdomains of both Ca²⁺ release from stores and Ca²⁺ influx across the plasma membrane enables the Ca²⁺ concentration within the mitochondrial matrix to reach up to 500 µM (12). In the adrenaline-secreting chromaffin cells of the adrenal medulla, such local Ca²⁺ buffering shapes the pattern of exocytosis (12). The ability of mitochondria to accumulate such large amounts of Ca²⁺, and to do this rapidly (within seconds), is due in part to the high Ca²⁺-binding ratio within their matrix [estimated to be >2,000 (2); corresponding values for the cytosol are typically 50–100]. Moreover, the Ca²⁺-binding ratio may well be dynamic, in that it can be increased by uptake of buffer (e.g., phosphate), which then binds to and reversibly precipitates Ca²⁺ within the matrix (5). In this way, mitochondria may accumulate extraordinary amounts of Ca²⁺ yet maintain a disproportionately low free Ca²⁺ concentration within the matrix such that the permeability transition pore does not open.

Hence a large body of evidence demonstrates that mitochondria can shape intracellular Ca²⁺ signals, both spatially and temporally, as a direct consequence of their rapid Ca²⁺ buffering. But mitochondria handle Ca²⁺ in a manner quite distinct from that of simple intracellular buffers. Rapid cytosolic Ca²⁺ buffers like ATP and calbindin release Ca²⁺ as cytosolic Ca²⁺ concentration falls, as dictated by the law of mass action. Mitochondria also release Ca²⁺ that has been accumulated following a cytosolic Ca²⁺ increase, but they do so in a kinetically complex manner that is dictated by the prevalent activities of the Ca²⁺/Na⁺ and Ca²⁺/H⁺ exchangers in the inner mitochondrial membrane. Mitochondrial Ca²⁺ release is probably both too slow and too small to be taken back up through the uniporter, and this slow Ca²⁺ release is particularly important because it represents a form of Ca²⁺ memory. It develops several seconds after the initial stimulus has been removed and is believed to account for presynaptic, posttetanic potentiation of synaptic transmission (19) as well as expediting the refilling of endoplasmic reticulum Ca²⁺ stores (1).

	Mitochondria spatially restrict Ca2+ signals

Top Introduction Mitochondrial Ca2+ transport Mitochondria spatially restrict... Mitochondrial regulation of... Mitochondrial regulation of... Multiple pools of mitochondria Mitochondria-derived... References

 
Mitochondria can also function as fixed buffers, thereby partitioning the cell into discrete Ca²⁺ compartments. The most poignant example of this is seen in pancreatic acinar cells (15). In these highly polarized epithelia, moderate stimulation of receptors in the basolateral membrane results in Ca²⁺ oscillations restricted to the apical pole, where the zymogen granules are located. The Ca²⁺ signals are confined to the apical region by mitochondria, which form a three-dimensional belt or firewall that neatly separates the two poles of the cell. Only when mitochondrial Ca²⁺ buffering is compromised or excessive receptor stimulation is used does the apical Ca²⁺ signal invade the basolateral region. Mitochondria are normally mobile organelles, readily fusing with one another to form long tubular structures that undergo subsequent fission. Just how a subset of mitochondria in the acinar cell is removed from this dynamic pool and restricted to a role as fixed buffers is unclear at present, but unraveling the underlying mechanisms may well provide further insight into compartmentalization of intracellular Ca²⁺ signals.

	Mitochondrial regulation of InsP3 receptors

Top Introduction Mitochondrial Ca2+ transport Mitochondria spatially restrict... Mitochondrial regulation of... Mitochondrial regulation of... Multiple pools of mitochondria Mitochondria-derived... References

 
Although mitochondria do not seem to release Ca²⁺ directly in response to cell-surface receptor stimulation, they nevertheless play a pivotal role in controlling Ca²⁺ release patterns through effects on InsP₃-evoked Ca²⁺ mobilization. The ubiquitous second messenger InsP₃ releases Ca²⁺ from internal stores by binding to tetrameric ligand-gated Ca²⁺-permeable channels that span the endoplasmic reticulum membrane. Molecular cloning studies have revealed at least three types of InsP₃ receptor (InsP₃R1, InsP₃R2, and InsP₃R3). InsP₃R1 is strongly modulated by cytosolic Ca²⁺ concentration. Channel activity in the presence of a submaximal concentration of InsP₃ is increased substantially as cytosolic Ca²⁺ increases. Ca²⁺ therefore acts as a coagonist of the InsP₃ receptor, and this positive feedback is thought to underlie the explosive nature of the Ca²⁺ release transient. As cytosolic Ca²⁺ concentration increases further, however, Ca²⁺ ions feed back to inactivate the InsP₃ receptor, thereby curtailing further Ca²⁺ release. Such inactivation is probably mediated by calmodulin. This results in a bell-shaped Ca²⁺ dependence of InsP₃-mediated Ca²⁺ release. By virtue of their low Ca²⁺ affinity and very close apposition to Ca²⁺ release channels, mitochondrial uniporters are ideally designed to modulate InsP₃ receptor activity through effects on the Ca²⁺ dependence of Ca²⁺ release. In Xenopus oocytes, InsP₃-mediated Ca²⁺ waves were synchronized and increased in both amplitude and velocity following the addition of substrates that increased mitochondrial respiration (9). Such energized mitochondria have a more hyperpolarized membrane potential, which increases the electrical driving force for Ca²⁺ uptake through the uniporter. This enhanced uptake was proposed to lower cytosolic Ca²⁺ concentration in the vicinity of open InsP₃ receptors to a level below that required to induce Ca²⁺-dependent inactivation. In this scheme, mitochondria are promoting more extensive Ca²⁺ mobilization by preventing inactivation of the Ca²⁺ release channels. In other systems, however, the converse is observed. In permeabilized hepatocytes, impairment of mitochondrial Ca²⁺ uptake results in more extensive Ca²⁺ release to submaximal concentrations of InsP₃ and regions devoid of mitochondria are more sensitive to ambient InsP₃ levels (8). By rapidly buffering cytosolic Ca²⁺, mitochondria are able to reduce the positive feedback effect of Ca²⁺ on Ca²⁺ release, thereby resulting in less effective Ca²⁺ mobilization by InsP₃ receptors. A similar mechanism seems to underlie the reduced speed of propagating Ca²⁺ waves in astrocytes following mitochondrial depolarization (3). Hence mitochondria can result in either greater or lesser Ca²⁺ release to InsP₃, depending on their precise location and hence whether they affect the ascending or descending limbs of the bell-shaped curve for Ca²⁺ release via InsP₃R1. Whether InsP₃R2 and InsP₃R3 also exhibit a bell-shaped dependence on Ca²⁺ release is more controversial. But both of these receptors can and do form heteromultimers with InsP₃R1, and in such complexes the properties of InsP₃R1 seem to dominate. Hence mitochondria are likely to affect Ca²⁺ release profiles in heteromultimers if at least one subunit is InsP₃R1.

"Mitochondria can also function as fixed buffers, thereby partitioning the cell into discrete Ca²⁺ compartments."

Ryanodine receptor-mediated Ca²⁺ signals are also efficiently propagated into mitochondria, and this transfer seems to involve both local microdomains of elevated Ca²⁺ around the mouth of each ryanodine receptor as well as close apposition between sarcoplasmic reticulum and mitochondria (17).

	Mitochondrial regulation of store-operated Ca2+ channels

Top Introduction Mitochondrial Ca2+ transport Mitochondria spatially restrict... Mitochondrial regulation of... Mitochondrial regulation of... Multiple pools of mitochondria Mitochondria-derived... References

 
Mitochondria are also able to buffer Ca²⁺ that enters through both voltage-operated and store-operated Ca²⁺ channels in the plasma membrane. In nonexcitable cells, store-operated Ca²⁺ channels, which are activated by the emptying of intracellular Ca²⁺ stores, provide a major route for Ca²⁺ influx. Ca²⁺ entry through these channels is required for controlling a host of Ca²⁺-dependent processes ranging from exocytosis to cell growth and proliferation. In many cell types, store-operated Ca²⁺ entry is manifest as a non-voltage-gated Ca²⁺ current called the Ca²⁺ release-activated Ca²⁺ current (I_CRAC). Under physiological conditions of weak intracellular Ca²⁺ buffering, the second messenger InsP₃ fails to activate any macroscopic I_CRAC despite substantial Ca²⁺ release. Hence the inability of InsP₃ to activate macroscopic I_CRAC in weak Ca²⁺ buffer does not reflect a failure to mobilize Ca²⁺ from the stores. It turns out that the sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA) pumps, which refill the stores with Ca²⁺ following InsP₃-evoked Ca²⁺ release, are very powerful and can prevent InsP₃ from depleting the stores sufficiently or long enough for macroscopic I_CRAC to activate (14). If the SERCA pumps are blocked, then InsP₃ can activate a robust I_CRAC in weak buffer. SERCA pump activity therefore appears to be one of the main determinants of whether I_CRAC activates or not under physiological conditions (14). How might SERCA pump activity be reduced under physiological conditions of weak Ca²⁺ buffering? Clearly, an increase in the rate of Ca²⁺ removal from the cytosol by another clearance mechanism would be rather effective, because this would compete with SERCA pumps for Ca²⁺ and hence reduce the rate and extent of store refilling. Moreover, enhanced Ca²⁺ clearance away from the endoplasmic reticulum might also reduce Ca²⁺-dependent inactivation of InsP₃ receptors. Combined, this would empty the stores to a greater extent and I_CRAC should activate. An unexpected discovery was that mitochondrial Ca²⁺ uptake is key (6). In the presence of energized mitochondria, InsP₃ is able to routinely activate I_CRAC even in the presence of active SERCA pumps (6, 14). The size of the current can be increased further by inhibiting SERCA pumps, consistent with the idea that competition between these two major Ca²⁺-removal mechanisms dictates the extent of store depletion and hence amplitude of I_CRAC (14). Moreover, mitochondrial Ca²⁺ buffering shifts the relationship between InsP₃ concentration and extent of I_CRAC to the left (14). A subthreshold concentration of InsP₃ becomes capable of activating I_CRAC when mitochondria are energized. Mitochondrial Ca²⁺ uptake therefore lowers the threshold concentration of InsP₃ that is required to activate I_CRAC, thereby increasing the dynamic range of concentrations over which InsP₃ is able to function as the physiological messenger that triggers activation of store-operated Ca²⁺ influx.

"...store-operated channels...provide a major route for Ca²⁺ influx...."

Following activation of I_CRAC, the subsequent rise in cytosolic Ca²⁺ concentration can feed back to inactivate the CRAC channels. Three independent mechanisms have been described whereby a rise in cytosolic Ca²⁺ can inhibit CRAC channel activity (see Ref. 14 and references therein). Ca²⁺-dependent fast inactivation occurs when permeating Ca²⁺ ions feed back to partially inactivate the channel through which they permeated. Inactivation occurs over tens of milliseconds, is largely independent of the macroscopic current (consistent with local feedback), and is more effectively reduced by BAPTA than EGTA, suggesting that the intracellular Ca²⁺ binding site is within a few nanometers of the pore. Two slower Ca²⁺-dependent regulatory pathways also exist, operating over a time frame of several tens of seconds: Ca²⁺-dependent store refilling and Ca²⁺ entry-dependent but store-independent inactivation (14). Either energizing or depolarizing mitochondria has little impact on the rate or extent of fast inactivation, suggesting that mitochondria do not modulate this form of inactivation (6, 7). However, through their competition with SERCA pumps for removing Ca²⁺, mitochondrial Ca²⁺ uptake would slow down the rate of store refilling. Strikingly, mitochondria Ca²⁺ buffering also slows down the rate and extent of Ca²⁺-dependent but store-independent slow inactivation (6, 14). Hence once I_CRAC has activated, mitochondria prolong the duration of Ca²⁺ entry. Indeed, buffering of store-operated Ca²⁺ entry by mitochondria has been observed in many nonexcitable cells, and this might be a ubiquitous way to alleviate Ca²⁺-dependent inactivation of the entry channels.

	Multiple pools of mitochondria

Top Introduction Mitochondrial Ca2+ transport Mitochondria spatially restrict... Mitochondrial regulation of... Mitochondrial regulation of... Multiple pools of mitochondria Mitochondria-derived... References

 
So far, I have focussed on how mitochondrial Ca²⁺ buffering can help shape the pattern of Ca²⁺ release and Ca²⁺ influx as well as confine Ca²⁺ signals to subcellular regions. It is not entirely clear if mitochondria are a relatively homogenous population and that their effects on Ca²⁺ signaling are simply a consequence of those mitochondria that just happen to be in the local vicinity or whether specific subpopulations of mitochondria exist with different transport properties that enable them to carry out their local tasks effectively. The latter scenario seems more realistic. In pancreatic acinar cells, three different populations of mitochondria were found (15). One group, in the basolateral area close to the plasma membrane, preferentially buffered incoming Ca²⁺ through store-operated channels. The second pool of mitochondria circled the nucleus and neatly separated nuclear and cytosolic Ca²⁺ signals. A third pool formed the belt in the lower apical area that was described earlier. This pool preferentially buffered Ca²⁺ oscillations originating in the granule-rich apical section. The different pools of mitochondria were distinct entities, because local photobleaching studies revealed that they did not share a connected lumen. It would be very interesting to see whether these different pools differ in key properties like Ca²⁺ transport activities, membrane potential (and hence driving force for electrogenic Ca²⁺ uptake), and so on.

	Mitochondria-derived intracellular messenger

Top Introduction Mitochondrial Ca2+ transport Mitochondria spatially restrict... Mitochondrial regulation of... Mitochondrial regulation of... Multiple pools of mitochondria Mitochondria-derived... References

 
The mitochondrial matrix contains a morass of metabolic pathways, many of which are Ca²⁺ dependent. Could mitochondrial Ca²⁺ uptake result in the release of factors/signals from the matrix into the cytosol that then regulate key physiological processes? Perhaps the best-known example of this form of signaling is mitochondrial release of ATP. Three rate-limiting enzymes of the Krebs cycle within the matrix (pyruvate dehydrogenase, NAD⁺-isocitrate dehydrogenase, and 2-oxoglutarate dehydrogenase) are activated by a rise in Ca²⁺ concentration to the micromolar range, and, in the presence of metabolic substrates, this results in an increased production of ATP, which is subsequently transported into the cytosol. ATP can act as a local messenger between mitochondria and juxtaposed endoplasmic reticulum (10). For example, InsP₃-dependent Ca²⁺ release is modulated by ATP levels, an effect thought to reflect direct binding of the nucleotide to the release channels. Inhibition of local mitochondrial ATP production significantly reduces the rate of InsP₃-mediated Ca²⁺ release in fibroblasts (10). More intriguingly, SERCA pumps, which utilize the free energy that is released from ATP hydrolysis to drive active transport of Ca²⁺ into the stores, seem to preferentially favor ATP produced locally by mitochondria within a subcellular metabolic microdomain (10). Short-range signals emanating from mitochondria can therefore involve ATP acting as a diffusible messenger. Could mitochondria release other messengers too? In the insulin-secreting ß-cells of the pancreas, mitochondria have been reported to release small molecules like glutamate, which then prime secretory vesicles such that their sensitivity to cytosolic Ca²⁺ increases (11), although this is finding is controversial. We have speculated that a related mechanism might be operating for mitochondrial regulation of CRAC channels in mast cells under physiological conditions of weak Ca²⁺ buffering (7). Mitochondrial depolarization after store depletion impairs both store-operated Ca²⁺ influx and the extent of I_CRAC. Since the depolarization occurs after store depletion, mitochondria are unlikely to be modifying Ca²⁺ release. Moreover, because the Ca²⁺ current is suppressed without initially developing at all, it is difficult to envisage how this can be explained entirely by Ca²⁺ feedback inactivation mechanisms. One possible explanation is that mitochondria release factors in a Ca²⁺-dependent manner, which subsequently modulate (but do not activate) CRAC channels in the mast cell membrane. Interestingly, a novel signal involving an as yet undefined chemical messenger is thought to be generated by mitochondria in skeletal muscle, where it then diffuses to the plasma membrane to activate Na⁺ channels (13). Mitochondria may integrate Ca²⁺ signals following entry into the matrix and then release messengers that help coordinate an appropriate response.

The multifarious effects of mitochondrial Ca²⁺ uptake are summarized in Fig. 1. Given that mitochondria are a source, among other things, of reactive oxygen species, can alter cytosolic pH, and release an array of messengers like ATP and glutamate as well as cytochrome C, which is associated with apoptosis, it is likely that their role in Ca²⁺ signaling will be extended from just a role, albeit an important one, in Ca²⁺ buffering.

View larger version (37K): [in this window] [in a new window]   FIGURE 1. Summary of processes that can be regulated by mitochondrial Ca2+ uptake. See text for further details. Note that, for display purposes, the channels and transporters of the inner mitochondrial membrane are shown to span both membranes. The voltage-dependent anion channels, which facilitate transfer of microdomains from inositol 1,4,5-trisphosphate (InsP3) receptors (InsP3R) on the endoplasmic reticulum (ER) to the mitochondrial uniporter (see text), have been omitted for clarity. CRAC, Ca2+ release-activated Ca2+ current; RyR, ryanodine receptor; SERCA, sarco(endo)plasmic reticulum Ca2+-ATPase; SR, sarcoplasmic reticulum; VOCC, voltage-operated Ca2+ channel.

	Acknowledgments

 
I would like to thank Daniel Bakowski for help with the figure.

Because of strict space constraints, it has not been possible to cite all relevant papers, and I apologize to colleagues for this.

Research in my laboratory is supported by a Medical Research Council Programme Grant and the Lister Institute.

	References

Top Introduction Mitochondrial Ca2+ transport Mitochondria spatially restrict... Mitochondrial regulation of... Mitochondrial regulation of... Multiple pools of mitochondria Mitochondria-derived... References

 

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