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The article by David et al. in this issue of The Journal of Physiology helps to solve a long-standing dilemma regarding the possible role of the mitochondrion in the regulation of transmitter release.
Transmitter is released from presynaptic nerve terminals as preformed multimolecular packages or quanta, most probably represented by synaptic vesicles (see Katz, 1969). One of the main determinants of the number of quanta released by the nerve impulse is the free intracellular calcium ion concentration ([Ca2+]i). There are many molecular mechanisms that control the [Ca2+]i. They include ion channels and transporters at the surface membrane and intracellular organelles (Pozzan et al. 1994). More than 20 years ago it was proposed that the mitochondrion is one of the intracellular organelles taking part in intracellular calcium homeostasis in the nerve terminal and is part of the repertoire of cellular processes regulating [Ca2+]i and thus transmitter release (Alnaes & Rahamimoff, 1975). This proposal was based on the abundance of the mitochondria in the nerve terminal (6·59 % of the cross-section of the frog terminal in electron microscopy), on their ability to take up calcium and on the increase in transmitter release when the mitochondria were inhibited; it encountered, however, substantial opposition, based on two indirect observations. First, it was found, using electron-probe microanalysis, that the amount of calcium in synaptosomal and in other mitochondria is low (Blaustein et al. 1980). The second finding was that the apparent KD for calcium uptake into isolated mitochondria is high compared with the presumed levels of [Ca2+]i. Hence it was considered highly unlikely that the mitochondria take a significant part in the physiological regulation of [Ca2+]i and thus of transmitter release.
Experiments done in a number of laboratories during the past 5 years indicate that a re- evaluation is probably necessary of the notion that mitochondria play only a minor role in the regulation of [Ca2+]i and thus of transmitter release in physiological conditions. The first set of experiments was done by Pozzan and co-workers (Rizzuto et al. 1995). Using techniques derived from molecular biology, they were able to add a targeting sequence to the calcium indicator aequorin and to direct this molecule into a number of intracellular organelles, including the mitochondria. Thus they were able to measure the mitochondrial [Ca2+] and found that there is a very substantial amount of calcium in the mitochondria in living tissue. Thus the first obstacle to the acceptance of the mitochondrial involvement in the regulation of transmitter release was removed. It now seems that the mitochondria are important members of an intracellular calcium network, which co-ordinates calcium controlling organelles (Babcock et al. 1997). The excitability of the mitochondria makes them highly suitable for signalling (Ichas et al. 1997).
The elegant article by David et al. in this issue of The Journal of Physiology provides direct proof of the role of mitochondria in the regulation of [Ca2+]i. They used the very powerful technique of laser scanning confocal microscopy of the presynaptic nerve terminals of the lizard neuromuscular junction, and different calcium indicators that report separately the changes in [Ca2+] in the cytosol and in the mitochondria. They made three very important findings. First, they found that repetitive nerve stimulation causes an increase in [Ca2+]i in the cytosol and, after some delay, in the mitochondria. It was sufficient to give only twenty-five or fifty action potentials to detect a significant increase in mitochondrial [Ca2+]. This was achieved after a very small increase in the cytosolic [Ca2+]i of about 200 nM. The second finding was that, after the end of the stimulation, there was a gradual decline in [Ca2+]i. The decay in the mitochondrial [Ca2+] was much slower than that of the cytosolic [Ca2+]i, making it a possible source of calcium in frequency modulation of transmitter release. The third finding was that inhibition of the calcium uptake by the mitochondria caused a much larger increase in the cytosolic [Ca2+]i after stimulation, which may correspond to the observed increase in transmitter release.
Taken together, these findings show in a very convincing way that the mitochondrion is one of the [Ca2+]i regulators in the nerve terminals in vivo and it may take part in the control of neurosecretion. It may also provide an important link between cellular metabolism and synaptic transmission. It will be of interest to see whether the reported periodic oscillations in the nerve terminal [Ca2+]i (Melamed et al. 1993) and in transmitter release (Meiri & Rahamimoff, 1978) are related to the periodic oscillations found in mitochondrial [Ca2+] (Hajnoczky, Robb-Gaspers, Seitz & Thomas, 1995).
One of the main features of the nervous system is its tremendous plasticity, achieved mainly by modulation of synaptic transmission. There is a growing body of evidence that the mitochondria make an important contribution to this plasticity by altering calcium signals and transmitter release. They seem to participate in short term frequency modulation such as post-tetanic potentiation (Tang & Zucker, 1997) and perhaps also in longer term phenomena due to the ability of NO to release calcium from the mitochondria (Richter et al. 1997).
Alnaes, E. & Rahamimoff, R. (1975). The Journal of Physiology 248, 285-306.
[Abstract] Babcock, D. F., Herrington, J., Goodwin, P. C., Park, Y. B. & Hille, B. (1997). Journal of Cell Biology 136, 833-844.
[Abstract/Full Text] Blaustein, M. P., McGraw, C. F., Somlyo, A. V. & Schweitzer, E. S. (1980). Journal de Physiologie 76, 459-470.
[Medline] David, G., Barrett, J. N. & Barrett, E. F. (1998). The Journal of Physiology 509, 59-65. &uid=9547381&dopt=r">
[Abstract/Full Text] Hajnoczky, G., Robb-Gaspers, L. D., Seitz, M. B. & Thomas, A. P. (1995). Cell 82, 415-424.
[Medline] Ichas, F., Jouaville, L. S. & Mazat, J. P. (1997). Cell 89, 1145-1155.
[Medline] Katz, B. (1969). The Sherrington Lecture, vol. 10. Liverpool University Press, Liverpool.
Meiri, H. & Rahamimoff, R. (1978). The Journal of Physiology 278, 513-523.
[Abstract] Melamed, N., Helm, P. J. & Rahamimoff, R. (1993). Journal of Neuroscience 13, 632-649.
[Abstract] Pozzan, T., Rizzuto, R., Volpe, P. & Meldolesi, J. (1994). Physiological Reviews 74, 595-636.
[Medline] Richter, C., Ghafourifar, P., Volpe, P. & Meldolesi, J. (1997). Biochemical Society Transactions 25, 914-918.
[Medline] Rizzuto, R., Brini, M., Bastianutto, C., Marsault, R. & Pozzan, T. (1995). Methods in Enzymology 260, 417-428.
[Medline] Tang, Y. G. & Zucker, R. S. (1997). Neuron 18, 483-491.
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