doi: 10.1161/01.RES.0000234949.61052.9f
© 2006 American Heart Association, Inc.
Editorials |
Mitochondrial Buffering of Calcium in the Heart
Potential Mechanism for Linking Cyclic Energetic Cost With Energy Supply?
From the Spinal Cord & Brain Injury Research Center (P.G.S.) and the Departments of Anatomy & Neurobiology (P.G.S.), Medicine (C.W.B.), and Physiology (C.W.B., K.A.E.), University of Kentucky College of Medicine, Lexington.
Correspondence to C. William Balke, University of Kentucky, College of Medicine, MN150, Chandler Medical Center, 800 Rose Street, Lexington Kentucky 40536-0298. E-mail b.balke{at}uky.edu
See related article, pages 172–182
Key Words: heart • mitochondria • calcium buffering
The kinetics of mitochondrial Ca2+ cycling and its precise role in controlling local Ca2+ fluxes in intact cardiac myocytes has not been fully elucidated. In the case of cardiac excitation–contraction (E-C) coupling in normal cardiac atrial cells, it has been established that cytosolic Ca2+ ([Ca2+]c) increases peripherally within the cell and propagates to the center.1 What is less clear has been the understanding of the time scale dynamics of the Ca2+ fluxes within the mitochondria. To began to address whether beat-to-beat changes in [Ca2+]c alter mitochondrial Ca2+ loading, Maack and colleagues2 use a novel technique to monitor, simultaneously, Ca2+ concentrations in the cytoplasm and mitochondrial matrix. Additionally, the authors’ probe the effect that mitochondrial Ca2+ efflux, due to elevated Na+, could have on mitochondrial Ca2+ buffering and bioenergetics. It is well recognized that the energetic cost of mechanical/contractile work plus ion handling associated with E-C coupling is very high and is supported by the large mitochondrial volume fraction of the cardiac myocyte. The link between regulation of ATP production and intracellular calcium fluxes has been suggested by studies that have demonstrated that the transport of Ca2+ into the mitochondrial matrix can activate several enzymes of the TCA cycle.
It is well-known that mitochondria sequester Ca2+ ([Ca2+]m) under conditions that increase [Ca2+]c concentrations in many different cell types.3–5 Changes in [Ca2+]m can have effects on energy production rates, amplitude, and temporal profiles of [Ca2+]c as well as its well described role in the initiation of cell death pathways.6,7 However, in cardiomyocytes, it is still debated whether or not mitochondrial Ca2+ uptake mechanisms can respond rapidly enough to accommodate beat-to-beat oscillations in [Ca2+]c. The two mechanisms described for mitochondrial Ca2+ uptake in cardiomyocytes are the electrogenic mitochondrial Ca2+ uniporter (mCU) and a mechanism termed "rapid mode of uptake" (RAM).8 mCU Ca2+ uptake is driven in a Nerstian fashion that is dependent on the mitochondrial membrane potential (
component) and extra-mitochondrial Ca2+ concentrations.9,10 Although the RAM uptake mechanism has been proposed to be at least 300 times faster than uptake via the mCU, it can only play a limited role during cardiac [Ca2+]c oscillations because of it’s slow recovery (>60 sec) after activation.
The mCU is a highly selective ion channel and has an exceptionally high affinity for Ca2+ (Kd < 2 nM) that allows it to be highly selective for Ca2+ even under conditions where [Ca2+]c are extremely low.11 The mCU is also inwardly rectifying which allows changes in to modulate mitochondrial Ca2+ uptake irrespective of [Ca2+]c such that depolarization results in a reduction in mitochondrial Ca2+ uptake. These properties also predict that mitochondrial Ca2+ uptake will have a biphasic temporal pattern because of the electrogenic nature of the mCU with Ca2+ uptake being countered by proton extrusion which reduces the component of the mitochondrial membrane potential. Two Ca2+ efflux mechanisms exist in mitochondria of which one is Na+-dependent and the other is Na+- independent. In heart mitochondria, it is currently thought that the Na+/Ca2+ is the primary efflux mechanism.12
Presently, two different theories have been put forth to explain how mitochondria can decode rapid oscillations in [Ca2+]c. In 1990, Crompton put forth the first scenario, which depends on a slow uptake of Ca2+ that is coupled to an even slower efflux of Ca2+, allowing fast [Ca2+]c oscillations to be integrated solely by Ca2+ transport machinery in the mitochondrial inner membrane.13 This model allows for increases in either the amplitude or frequency of [Ca2+]c to result in a cumulative increase in [Ca2+]m until a steady-state is reached in which Ca2+ uptake equals Ca2+ efflux during a single cycle.13 This scenario allows for small beat-to-beat changes in [Ca2+]m which reduce the energetic costs of Ca2+ transport in mitochondria.
In contrast, the second theory hypothesizes that changes in [Ca2+]c are translated directly into changes in [Ca2+]m, which requires the existence of both a rapid Ca2+ uptake and efflux mechanism to be active in mitochondria. It also requires that mitochondrial Ca2+ uptake be sufficient to overcome endogenous buffering of [Ca2+]c for changes in mitochondrial matrix Ca2+ to occur during each contraction. It also predicts that [Ca2+]c transients during E-C coupling would be effectively buffered by mitochondrial Ca2+ uptake. This logic in turn requires that SR Ca2+ uptake and release dynamics would have to be sufficiently large enough to compensate for this increased buffering by mitochondria.14
The current report by Maack and colleagues2 critically examines the role of mitochondrial Ca2+ buffering in cardiac myocytes during contractions using a novel method to monitor [Ca2+]c and [Ca2+]m in the same cell. Their findings demonstrate: (1) that mitochondria take up Ca2+ rapidly and buffer [Ca2+]c during E-C coupling, (2) the kinetics of the mitochondrial Ca2+ fluxes support the concept of "mitochondrial microdomains", and (3) elevation of Na+ in the cytosol reduces mitochondrial Ca2+ flux which impairs energy production by altering the NADH/NAD+ redox potential.
The finding that mitochondria rapidly sequester Ca2+ during E-C coupling directly supports the theory that fluxes in [Ca2+]c directly encode changes in [Ca2+]m. As the authors point out, this type of rapid signaling could act to couple energy production in the mitochondria with increases in ATP demand. This concept is very intriguing and suggests a model in which the calcium buffering of the mitochondria provides fine rheostat control to allow for the matching of energy/ATP production with demand. As a general rule, the intracellular concentration of ATP within a cardiac myocyte does not decrease significantly even under the highest energetic demands. Thus, the cell must have a mechanism in place to rapidly respond to significant increases in ATP consumption in a manner that does not lead to increased ATP supply. The authors also demonstrate that it is likely that the microdomain of the mitochondria and its proximity to the SR junction provide the necessary local calcium concentrations required to induce the rapid influx. The concept of mitochondrial microdomains within cells is becoming common and well accepted,15 but the demonstration in this article2 of a mitochondrial microdomain is the first to illustrate the critical local information flow in cardiac myocyte mitochondria.
Finally, the authors assess the role of the mitochondrial Na+/Ca2+ exchanger on [Ca2+]c, [Ca2+]m, and mitochondrial bioenergetics. Surprisingly, increasing the concentration of Na+ increased [Ca2+]c and accelerated the decay of [Ca2+]m. This could be interpreted as an indication that the limiting factor for mitochondrial Ca2+ efflux is Na+ movement. This is interesting because it provides a model through which impaired sodium homeostasis in the cardiac myocyte seen in different pathologies could lead to mismatched signaling response of the cardiac myocyte to the calcium signal from E-C coupling. However, these interpretations need to be made with some caution, as the levels of Na+ used in this work were quite high and could be triggering an effect not detected outside the normal physiological range. Nonetheless, this work has broad implications for cardiac disease, pharmacological treatment, and the cell biology through which the energetic cost of work is finely tuned to ATP supply mechanisms.
 |
Acknowledgments |
|---|
Source of Funding
This work was supported, in part, by National Institutes of Health and U.S. Public Health Service awards NS048191 & NS046426 (to P.G.S.); HL268733 & HL071865 (to C.W.B.); and AR050717 & AR043349 (to K.A.E.).
Disclosures
None.
|
Footnotes |
|---|
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
 Top References |
|---|
1. Huser J, Lipsius SL, Blatter LA. Calcium gradients during excitation-contraction coupling in cat atrial myocytes. J Physiol. 1996; 494: 641–651.
2. Maack C, Cortassa S, Aon MA, Ganesan AN, Liu T, O’Rourke B. Elevated cytosolic Na+ decreases mitochondrial Ca2+-uptake during excitation–contraction coupling and impairs energetic adaptation in cardiac myocytes. Circ Res. 2006; 99: 172–182.
3. Nicholls D, Akerman K. Mitochondrial calcium transport. Biochim Biophys Acta. 1982; 683: 57–88.[Medline] [Order article via Infotrieve]
4. Gunter TE, Gunter KK, Sheu SS, Gavin CE. Mitochondrial calcium transport: physiological and pathological relevance. Am J Physiol. 1994; 267: C313–C339.[Medline] [Order article via Infotrieve]
5. Sharma VK, Ramesh V, Franzini-Armstrong C, Sheu SS. Transport of Ca2+ from sarcoplasmic reticulum to mitochondria in rat ventricular myocytes. J Bioenerg Biomembr. 2000; 32: 97–104.[CrossRef][Medline] [Order article via Infotrieve]
6. Budd SL, Nicholls DG. Mitochondria in the life and death of neurons. Essays Biochem. 1998; 33: 43–52.[Medline] [Order article via Infotrieve]
7. Sullivan PG, Rabchevsky AG, Waldmeier PC, Springer JE. Mitochondrial permeability transition in CNS trauma: cause or effect of neuronal cell death? J Neurosci Res. 2005; 79: 231–239.[CrossRef][Medline] [Order article via Infotrieve]
8. Buntinas L, Gunter KK, Sparagna GC, Gunter TE. The rapid mode of calcium uptake into heart mitochondria (RaM): comparison to RaM in liver mitochondria. Biochim Biophys Acta. 2001; 1504: 248–261.[Medline] [Order article via Infotrieve]
9. Nicholls DG, Ward MW. Mitochondrial membrane potential and neuronal glutamate excitotoxicity: mortality and millivolts. Trends Neurosci. 2000; 23: 166–174.[CrossRef][Medline] [Order article via Infotrieve]
10. Brown MR, Sullivan PG, Geddes JW. Synaptic mitochondria are more susceptible to Ca2+ overload than nonsynaptic mitochondria. J Biol Chem. 2006; 281: 11658–11668.
11. Kirichok Y, Krapivinsky G, Clapham DE. The mitochondrial calcium uniporter is a highly selective ion channel. Nature. 2004; 427: 360–364.[CrossRef][Medline] [Order article via Infotrieve]
12. Gunter TE, Buntinas L, Sparagna G, Eliseev R, Gunter K. Mitochondrial calcium transport: mechanisms and functions. Cell Calcium. 2000; 28: 285–296.[CrossRef][Medline] [Order article via Infotrieve]
13. Crompton M. The role of calcium in the function and dysfunction of heart mitochondria. In: Langer GA, ed. Calcium and the Heart. New York: Raven Press; 1990: 167–198.
14. Huser J, Blatter LA, Sheu SS. Mitochondrial calcium in heart cells: beat-to-beat oscillations or slow integration of cytosolic transients? J Bioenerg Biomembr. 2000; 32: 27–33.[CrossRef][Medline] [Order article via Infotrieve]
15. Rizzuto R, Duchen MR, Pozzan T. Flirting in little space: the ER/mitochondria Ca2+ liaison. Sci STKE. 2004; 2004 (215): re1.
Related Article:
Circ. Res. 2006 99: 172-182.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||