Harris, Kristen M.

Ivannikov, Maxim V.

Macleod, Gregory T.

English

PubMed

Maxim V. Ivannikov

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Frontiers in Synaptic Neuroscience www.frontiersin.org October 2010 | Volume 2 | Article 145 | 1
SYNAPTIC NEUROSCIENCE
GENERAL COMMENTARY
published: 04 October 2010
doi: 10.3389/fnsyn.2010.00145
Mitochondria: enigmatic stewards of the synaptic vesicle 
reserve pool
Maxim V. Ivannikov1, Kristen M. Harris2 and Gregory T. Macleod1*
1 Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
2 Center for Learning and Memory, Section of Neurobiology, Institute for Neuroscience, University of Texas at Austin, Austin, TX, USA
*Correspondence: macleod@uthscsa.edu
A commentary on
Synaptic mitochondria in synaptic trans-
mission and organization of vesicle pools 
in health and disease
by Melissa Vos, Elsa Lauwers and Patrik 
Verstreken.
Studies on isolated mitochondria and those 
in cultured cells have revealed much about 
their inherent biology, and yielded two Nobel 
prizes, but our knowledge of their role(s) in 
the onset and progression of neurodegener-
ative diseases is still limited. In large part, this 
is because little is known about how mito-
chondrial biology integrates with neuronal 
physiology under non-pathological condi-
tions. In this issue of Frontiers in Synaptic 
Neuroscience, Vos et al. (2010) recognize 
this gap in our knowledge in their compre-
hensive review of the role of mitochondria 
in neurotransmission in health and disease. 
They bring a novel perspective by consider-
ing the mitochondrion’s role in the context 
of functionally defined pools of synaptic 
vesicles. They conclude that presynaptic 
mitochondria wield substantial influence 
on neurotransmission through their ability 
to mobilize the great majority of synaptic 
vesicles (∼85%; Rizzoli and Betz, 2005) held 
in the reserve pool. It is the reserve pool that 
is called upon to sustain neurotransmitter 
release during intense neuronal activity 
approaching the output limits of presynaptic 
axons. Under pathological conditions, there 
are conceivably more occasions for operat-
ing near output limits, hence even where 
the primary deficit might not be within the 
mitochondrion, the limits of mitochondrial 
function are tested.
In the process of considering which 
aspects of mitochondrial function are 
important in neurotransmission the authors 
open a can of worms which is left in the 
reader’s peripheral vision. The issue is this: 
different aspects of mitochondrial function 
are interdependent. This  interdependence 
makes it exceedingly difficult to isolate a 
particular mitochondrial function for an 
incisive test of its contribution to neuro-
transmission. It is this inscrutable quality 
that has earned the mitochondrion the 
reputation as an enigmatic player in neu-
rotransmission under both pathological 
and non-pathological conditions.
Presynaptic mitochondria likely contrib-
ute to neurotransmission through a number 
of aspects of their biology: ATP and neu-
rotransmitter synthesis, the production of 
reactive oxygen species (ROS), modulation 
of the local cytosolic pH and redox state 
(Giniatullin and Giniatullin, 2003), and 
regulation of plasma-membrane excitability 
via K
ATP
 channels (Matsumoto et al., 2002). 
However, it is the ability of mitochondria 
to take up and release Ca2+ that attracts the 
most attention – for several reasons. First, 
the probability of neurotransmitter release 
has a steep dependence on the concentra-
tion of Ca2+ (Brose et al., 1992), enticing 
many to test for linkages between mito-
chondrial Ca2+ handling, neurotransmitter 
release, and calcium-dependent endocyto-
sis. Secondly, Ca2+ is a potent stimulant of 
mitochondrial respiration, increasing pro-
duction of both ATP and ROS (Dugan et al., 
1995; Jouaville et al., 1999). Ca2+ stimulates 
mitochondrial production of ATP, which 
powers the  plasma-membrane pumps 
needed to maintain ion balances essential 
for Ca2+ homeostasis, thus confounding 
experiments that seek to elucidate whether 
it is mitochondrial Ca2+ sequestration or 
ATP production that is most influential on 
cytosolic Ca2+ buffering. At the same time, 
Ca2+-stimulated ROS production makes the 
mitochondrion a “subject of interest” in 
studies concerned with activity-dependent 
acute oxidative stress. Lastly, mitochondria 
exposed to excessive levels of Ca2+ can “over-
load” and initiate apoptosis through the 
release of pro-apoptotic proteins (Kokoszka 
et al., 2004). Their role as executioner points 
to mitochondrial dysfunction and the asso-
ciated Ca2+-dysregulation as possible mech-
anisms of neurodegeneration.
Advances in optical fluorescence imag-
ing techniques, and the development of syn-
thetic and genetically encoded fluorescent 
Ca2+-reporters have reinvigorated studies 
on mitochondrial Ca2+ handling. Despite 
the advances in imaging techniques, the 
lack of specific pharmacological tools and 
information on the genetic identity of mito-
chondrial proteins (but see Jiang et al., 2009; 
Perocchi et al., 2010) has hampered progress 
in elucidating the mechanisms and impact 
of mitochondrial Ca2+ handling. Meanwhile, 
data on Ca2+-dependent changes in neuronal 
ATP levels are essentially absent, except for 
a small number of studies using luciferase. 
If we are to understand the relative contri-
butions of mitochondrial Ca2+ sequestra-
tion and ATP production to cytosolic Ca2+ 
buffering and neurotransmission we need 
a highly dynamic fluorescent ATP or ATP/
ADP reporter. Such reporters are being 
developed, both synthetic (Hasegawa 
et al., 2007; Xu et al., 2009) and geneti-
cally encoded (Berg et al., 2009; Imamura 
et al., 2009), but they remain unproven in 
presynaptic axons. Questions regarding 
the relative influence of mitochondrial 
Ca2+ sequestration versus ATP production 
in Ca2+-buffering and neurotransmission 
might appear to be quibbling, but the fact 
remains that it has yet to be shown whether 
mitochondrial Ca2+ sequestration serves to 
limit presynaptic Ca2+ levels during axonal 
firing patterns that are physiological in rate 
and duration (Chouhan et al., 2010).
On a final note, the experimental sys-
tems represented in this review highlight an 
impediment to our prospects for understand-
ing the role(s) mitochondria play in synaptic 
transmission in health and disease. Most of 
the data come from cultured neurons or large 
experimentally accessible nerve  termini (e.g., 
Ivannikov et al. Mitochondrial control of synaptic vesicles
Frontiers in Synaptic Neuroscience www.frontiersin.org October 2010 | Volume 2 | Article 145 | 2
during metabolic inhibition of rat hippocampal CA1 
neurons. J. Physiol. 541, 511–520.
Perocchi, F., Gohil, V. M., Girgis, H. S., Bao, X. R., 
McCombs, J. E., Palmer, A. E., and Mootha, V. K. 
(2010). MICU1 encodes a mitochondrial EF hand 
protein required for Ca2+ uptake. Nature. doi:10.1038/
nature09358.
Rizzoli, S. O., and Betz, W. J. (2005). Synaptic vesicle pools. 
Nat. Rev. Neurosci. 6, 57–69.
Shepherd, G. M., and Harris, K. M. (1998). Three-
dimensional structure and composition of 
CA3 → CA1 axons in rat hippocampal slices: impli-
cations for presynaptic connectivity and compart-
mentalization. J. Neurosci. 18, 8300–8310.
Vos, M., Lauwers, E., and Verstreken, P. (2010). 
Synaptic mitochondria in synaptic transmission 
and organization of vesicle pools in health and 
disease. Front. Syn. Neurosci. 2, 139. doi:10.3389/
fnsyn.2010.00139.
Xu, Z., Singh, N. J., Lim, J., Pan, J., Kim, H. N., Park, 
S., Kim, K. S., and Yoon, J. (2009). Unique sandwich 
stacking of pyrene-adenine-pyrene for selective and 
ratiometric fluorescent sensing of ATP at physiologi-
cal pH. J. Am. Chem. Soc. 131, 15528–15533.
Xu-Friedman, M. A., Harris, K. M., and Regehr, W. G. 
(2001). Three-dimensional comparison of ultrastruc-
tural characteristics at depressing and facilitating 
synapses onto cerebellar Purkinje cells. J. Neurosci. 
21, 6666–6672.
Received: 09 September 2010; accepted: 10 September 2010; 
published online: 04 October 2010.
Citation: Ivannikov MV, Harris KM and Macleod GT 
(2010) Mitochondria: enigmatic stewards of the synap-
tic vesicle reserve pool. Front. Syn. Neurosci. 2:145. doi: 
10.3389/fnsyn.2010.00145
Copyright © 2010 Ivannikov, Harris and Macleod. This is 
an open-access article subject to an exclusive license agree-
ment between the authors and the Frontiers Research 
Foundation, which permits unrestricted use, distribution, 
and reproduction in any medium, provided the original 
authors and source are credited.
Chouhan, A. K., Zhang, J., Zinsmaier, K. E., and Macleod, 
G. T. (2010). Presynaptic mitochondria in functionally 
different motor neurons exhibit similar affinities for 
Ca2+ but exert little influence as Ca2+ buffers at nerve 
firing rates in situ. J. Neurosci. 30, 1869–1881.
Dugan, L. L., Sensi, S. L., Canzoniero, L. M., Handran, S. 
D., Rothman, S. M., Lin, T. S., Goldberg, M. P., and 
Choi, D. W. (1995). Mitochondrial production of 
reactive oxygen species in cortical neurons follow-
ing exposure to N-methyl-d-aspartate. J. Neurosci. 
15, 6377–6388.
Giniatullin, A. R., and Giniatullin, R. A. (2003). Dual 
action of hydrogen peroxide on synaptic transmis-
sion at the frog neuromuscular junction. J. Physiol. 
552, 283–293.
Hasegawa, T., Hagihara, M., Fukuda, M., and Morii, 
T. (2007). Stepwise functionalization of ribonucle-
opeptides: optimization of the response of fluores-
cent ribonucleopeptide sensors for ATP. Nucleosides 
Nucleotides Nucleic Acids 26, 1277–1281.
Imamura, H., Nhat, K. P., Togawa, H., Saito, K., Iino, 
R., Kato-Yamada, Y., Nagai, T., and Noji, H. (2009). 
Visualization of ATP levels inside single living cells 
with fluorescence resonance energy transfer-based 
genetically encoded indicators. Proc. Natl. Acad. Sci. 
U.S.A. 106, 15651–15656.
Jiang, D., Zhao, L., and Clapham, D. E. (2009). Genome-
wide RNAi screen identifies Letm1 as a mitochondrial 
Ca2+/H+ antiporter. Science 326, 144–147.
Jouaville, L. S., Pinton, P., Bastianutto, C., Rutter, G. A., 
and Rizzuto, R. (1999). Regulation of mitochondrial 
ATP synthesis by calcium: evidence for a long-term 
metabolic priming. Proc. Natl. Acad. Sci. U.S.A. 96, 
13807–13812.
Kokoszka, J. E., Waymire, K. G., Levy, S. E., Sligh, J. E., 
Cai, J., Jones, D. P., MacGregor, G. R., and Wallace, D. 
C. (2004). The ADP/ATP translocator is not essential 
for the mitochondrial permeability transition pore. 
Nature 427, 461–465.
Matsumoto, N., Komiyama, S., and Akaike, N. (2002). Pre- 
and postsynaptic ATP-sensitive potassium  channels 
neuromuscular junctions and the Calyx of 
Held), yet most nerve termini in the mam-
malian CNS have only a single release site, 
and only half of them have an attendant 
mitochondrion (Figure 1; Shepherd and 
Harris, 1998; Xu-Friedman et al., 2001). 
Models that recapitulate the architecture of 
these CNS synapses are required to reveal 
those mitochondrial roles relevant to neu-
rotransmission in human health and disease. 
It will be interesting to learn how synaptic 
boutons without mitochondria derive their 
ATP to fuel synaptic release, i.e., is it provided 
by glycolysis or diffusion from a neighboring 
bouton or perisynaptic astroglia? Are release 
sites in synaptic boutons without mitochon-
dria competent to release synaptic vesicles? 
Similarly, it will be fascinating to determine 
the consequences, if any, for PTP and LTP at 
synapses that do not possess a presynaptic 
mitochondrion.
Acknowledgments
This work was supported by NIH grants R01 
EB002170 and R01 NS021184 to Kristen M. 
Harris, and R01 NS061914 to Gregory T. 
Macleod.
RefeRences
Berg, J., Hung, Y. P., and Yellen, G. (2009). A genetically 
encoded fluorescent reporter of ATP:ADP ratio. Nat. 
Methods 6, 161–166.
Brose, N., Petrenko, A. G., Südhof, T. C., and Jahn, R. 
(1992). Synaptotagmin: a calcium sensor on the syn-
aptic vesicle surface. Science 256, 1021–1025.
Figure 1 | Approximately one-half of synaptic varicosities are devoid of 
mitochondria in some areas of the mammalian CNS. Ultrastructural features 
of two 3D reconstructed stratum radiatum axons of area CA1 of the rat 
hippocampus. Post synaptic densities (red), vesicles (speckled), and 
mitochondria (light blue) are shown for each axon. Modified and reprinted, with 
permission, from Shepherd and Harris (1998). See original article for full details.


Mitochondria: Enigmatic Stewards of the Synaptic Vesicle Reserve Pool

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