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PMID: 12122046 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Presynaptic mitochondrial calcium sequestration influences transmission at mammalian central synapses.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 22 ·No. 14 ·2002-07-15 ·Pages 5840-7

Billups B, Forsythe ID

Abstract

Beyond their role in generating ATP, mitochondria have a high capacity to sequester calcium. The interdependence of these functions and limited access to presynaptic compartments makes it difficult to assess the role of sequestration in synaptic transmission. We addressed this important question using the calyx of Held as a model glutamatergic synapse by combining patch-clamp with a novel mitochondrial imaging method. Presynaptic calcium current, mitochondrial calcium concentration ([Ca(2+)](mito), measured using rhod-2 or rhod-FF), cytoplasmic calcium concentration ([Ca(2+)](cyto), measured using fura-FF), and the postsynaptic current were monitored during synaptic transmission. Presynaptic [Ca(2+)](cyto) rose to 8.5 +/- 1.1 microM and decayed rapidly with a time constant of 45 +/- 3 msec; presynaptic [Ca(2+)](mito) also rose rapidly to >5 microM but decayed slowly with a half-time of 1.5 +/- 0.4 sec. Mitochondrial depolarization with rotenone and carbonyl cyanide p-trifluoromethoxyphenylhydrazone abolished mitochondrial calcium rises and slowed the removal of [Ca(2+)](cyto) by 239 +/- 22%. Using simultaneous presynaptic and postsynaptic patch clamp, combined with presynaptic mitochondrial and cytoplasmic imaging, we investigated the influence of mitochondrial calcium sequestration on transmitter release. Depletion of ATP to maintain mitochondrial membrane potential was blocked with oligomycin, and ATP was provided in the patch pipette. Mitochondrial depolarization raised [Ca(2+)](cyto) and reduced transmitter release after short EPSC trains (100 msec, 200 Hz); this effect was reversed by raising mobile calcium buffering with EGTA. Our results suggest a new role for presynaptic mitochondria in maintaining transmission by accelerating recovery from synaptic depression after periods of moderate activity. Without detectable thapsigargin-sensitive presynaptic calcium stores, we conclude that mitochondria are the major organelle regulating presynaptic calcium at central glutamatergic terminals.

MeSH Terms
Adenosine Triphosphate/metabolism Animals Brain Stem/cytology,drug effects,physiology Calcium/metabolism Calcium Signaling/drug effects,physiology Cytoplasm/metabolism Electric Stimulation Enzyme Inhibitors/pharmacology Excitatory Postsynaptic Potentials/drug effects,physiology Fluorescent Dyes Glutamic Acid/metabolism In Vitro Techniques Mitochondria/drug effects,metabolism Oligomycins/pharmacology Patch-Clamp Techniques Presynaptic Terminals/drug effects,metabolism Rats Synapses/drug effects,metabolism Synaptic Transmission/drug effects,physiology Uncoupling Agents/pharmacology
Chemicals
Enzyme Inhibitors Fluorescent Dyes Oligomycins Uncoupling Agents Glutamic Acid Adenosine Triphosphate Calcium
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Billups Brian
Department of Cell Physiology and Pharmacology, University of Leicester, Leicester LE1 9HN, United Kingdom.
Forsythe Ian D
References (74)
74 references, click to expand
  1. Contributions of mitochondria to animal physiology: from homeostatic sensor to calcium signalling and cell death.
    J Physiol. 1999 Apr 1;516 ( Pt 1):1-17 PMID: 10066918
  2. Release of Ca2+ from the sarcoplasmic reticulum increases mitochondrial [Ca2+] in rat pulmonary artery smooth muscle cells.
    J Physiol. 1999 Apr 1;516 ( Pt 1):139-47 PMID: 10066929
  3. Sequestration of depolarization-induced Ca2+ loads by mitochondria and Ca2+ efflux via mitochondrial Na+/Ca2+ exchanger in bovine adrenal chromaffin cells.
    Jpn J Physiol. 1999 Feb;49(1):35-46 PMID: 10219107
  4. Mitochondria exert a negative feedback on the propagation of intracellular Ca2+ waves in rat cortical astrocytes.
    J Cell Biol. 1999 May 17;145(4):795-808 PMID: 10330407
  5. Caffeine and carbonyl cyanide m-chlorophenylhydrazone increased evoked and spontaneous release of luteinizing hormone-releasing hormone from intact presynaptic terminals.
    Neuroscience. 1999;92(4):1511-21 PMID: 10426503
  6. Mitochondrial clearance of cytosolic Ca(2+) in stimulated lizard motor nerve terminals proceeds without progressive elevation of mitochondrial matrix [Ca(2+)].
    J Neurosci. 1999 Sep 1;19(17):7495-506 PMID: 10460256
  7. The reduced release probability of releasable vesicles during recovery from short-term synaptic depression.
    Neuron. 1999 Aug;23(4):821-32 PMID: 10482247
  8. Mitochondria regulate the Ca(2+)-exocytosis relationship of bovine adrenal chromaffin cells.
    J Neurosci. 1999 Nov 1;19(21):9261-70 PMID: 10531430
  9. Disruption of Rab3-calmodulin interaction, but not other effector interactions, prevents Rab3 inhibition of exocytosis.
    EMBO J. 1999 Nov 1;18(21):5885-91 PMID: 10545100
  10. Plasma membrane calcium ATPases as critical regulators of calcium homeostasis during neuronal cell function.
    Front Biosci. 1999 Dec 01;4:D869-82 PMID: 10577388
  11. Mitochondria and neuronal survival.
    Physiol Rev. 2000 Jan;80(1):315-60 PMID: 10617771
  12. Ca(2+) influx inhibits dynamin and arrests synaptic vesicle endocytosis at the active zone.
    J Neurosci. 2000 Feb 1;20(3):949-57 PMID: 10648699
  13. Chromaffin-cell stimulation triggers fast millimolar mitochondrial Ca2+ transients that modulate secretion.
    Nat Cell Biol. 2000 Feb;2(2):57-61 PMID: 10655583
  14. The role of mitochondria in presynaptic calcium handling at a ribbon synapse.
    Neuron. 2000 Jan;25(1):229-37 PMID: 10707986
  15. Mitochondrial Ca2+ homeostasis during Ca2+ influx and Ca2+ release in gastric myocytes from Bufo marinus.
    J Physiol. 2000 Feb 1;522 Pt 3:375-90 PMID: 10713963
  16. Kinetics of Ca2+ binding to parvalbumin in bovine chromaffin cells: implications for [Ca2+] transients of neuronal dendrites.
    J Physiol. 2000 Jun 1;525 Pt 2:419-32 PMID: 10835044
  17. Mitochondria shape hormonally induced cytoplasmic calcium oscillations and modulate exocytosis.
    J Biol Chem. 2000 Aug 18;275(33):25465-70 PMID: 10835418
  18. Energetics in the pathogenesis of neurodegenerative diseases.
    Trends Neurosci. 2000 Jul;23(7):298-304 PMID: 10856939
  19. Mitochondrial calcium transients in adult rabbit cardiac myocytes: inhibition by ruthenium red and artifacts caused by lysosomal loading of Ca(2+)-indicating fluorophores.
    Biophys J. 2000 Jul;79(1):39-50 PMID: 10866936
  20. Calcium sensitivity of glutamate release in a calyx-type terminal.
    Science. 2000 Aug 11;289(5481):953-7 PMID: 10937999
  21. Intracellular calcium dependence of transmitter release rates at a fast central synapse.
    Nature. 2000 Aug 24;406(6798):889-93 PMID: 10972290
  22. Agonist-evoked mitochondrial Ca2+ signals in mouse pancreatic acinar cells.
    J Biol Chem. 2000 Dec 8;275(49):38680-6 PMID: 10995756
  23. Stimulation-evoked increases in cytosolic [Ca(2+)] in mouse motor nerve terminals are limited by mitochondrial uptake and are temperature-dependent.
    J Neurosci. 2000 Oct 1;20(19):7290-6 PMID: 11007886
  24. Presynaptic calcium stores underlie large-amplitude miniature IPSCs and spontaneous calcium transients.
    Nat Neurosci. 2000 Dec;3(12):1256-65 PMID: 11100146
  25. Chronic systemic pesticide exposure reproduces features of Parkinson's disease.
    Nat Neurosci. 2000 Dec;3(12):1301-6 PMID: 11100151
  26. Specialized synapse-associated structures within the calyx of Held.
    J Neurosci. 2000 Dec 15;20(24):9135-44 PMID: 11124991
  27. Combining deconvolution and noise analysis for the estimation of transmitter release rates at the calyx of held.
    J Neurosci. 2001 Jan 15;21(2):444-61 PMID: 11160425
  28. Calcium stores in hippocampal synaptic boutons mediate short-term plasticity, store-operated Ca2+ entry, and spontaneous transmitter release.
    Neuron. 2001 Jan;29(1):197-208 PMID: 11182091
  29. Cytoplasmic Ca2+ at low submicromolar concentration stimulates mitochondrial metabolism in rat luteal cells.
    Pflugers Arch. 2001 Feb;441(5):678-85 PMID: 11294250
  30. Mitochondrial Ca(2+) uptake depends on the spatial and temporal profile of cytosolic Ca(2+) signals.
    J Biol Chem. 2001 Jul 13;276(28):26411-20 PMID: 11333261
  31. Oscillations and hypoxic changes of mitochondrial variables in neurons of the brainstem respiratory centre of mice.
    J Physiol. 2001 May 15;533(Pt 1):227-36 PMID: 11351030
  32. Mitochondria as targets for nitric oxide-induced protection during simulated ischemia and reoxygenation in isolated neonatal cardiomyocytes.
    Circulation. 2001 May 29;103(21):2617-23 PMID: 11382733
  33. Organization of the cat trapezoid body and the discharge characteristics of its fibers.
    Brain Res. 1975 Sep 5;94(3):413-33 PMID: 1156852
  34. Calmodulin mediates rapid recruitment of fast-releasing synaptic vesicles at a calyx-type synapse.
    Neuron. 2001 Dec 20;32(6):1119-31 PMID: 11754842
  35. Ultrastructural basis of synaptic transmission between endbulbs of Held and bushy cells in the rat cochlear nucleus.
    J Physiol. 2002 Mar 15;539(Pt 3):713-23 PMID: 11897843
  36. Rapid changes of mitochondrial Ca2+ revealed by specifically targeted recombinant aequorin.
    Nature. 1992 Jul 23;358(6384):325-7 PMID: 1322496
  37. The spread of Na+ spikes determines the pattern of dendritic Ca2+ entry into hippocampal neurons.
    Nature. 1992 May 21;357(6375):244-6 PMID: 1350327
  38. Mechanisms by which mitochondria transport calcium.
    Am J Physiol. 1990 May;258(5 Pt 1):C755-86 PMID: 2185657
  39. Calcium entry into voltage-clamped presynaptic terminals of squid.
    J Physiol. 1985 Oct;367:143-62 PMID: 2414438
  40. Fluorescent indicators for cytosolic calcium based on rhodamine and fluorescein chromophores.
    J Biol Chem. 1989 May 15;264(14):8171-8 PMID: 2498308
  41. Reduced calcium uptake by rat brain mitochondria and synaptosomes in response to aging.
    Brain Res. 1985 Mar 11;329(1-2):177-83 PMID: 3978439
  42. Effects of probes of membrane potential on metabolism in synaptosomes.
    Biochim Biophys Acta. 1985 Nov 22;843(1-2):20-4 PMID: 4063387
  43. Differences in Na and Ca spikes as examined by application of tetrodotoxin, procaine, and manganese ions.
    J Gen Physiol. 1966 Mar;49(4):793-806 PMID: 5943615
  44. Presynaptic calcium currents in squid giant synapse.
    Biophys J. 1981 Mar;33(3):289-321 PMID: 7225510
  45. Ca2+ regulation in the presynaptic terminals of goldfish retinal bipolar cells.
    J Physiol. 1995 Feb 15;483 ( Pt 1):79-94 PMID: 7539842
  46. Direct patch recording from identified presynaptic terminals mediating glutamatergic EPSCs in the rat CNS, in vitro.
    J Physiol. 1994 Sep 15;479 ( Pt 3):381-7 PMID: 7837096
  47. Transport of calcium by mitochondria.
    J Bioenerg Biomembr. 1994 Oct;26(5):471-85 PMID: 7896763
  48. Inhibition of endocytosis by elevated internal calcium in a synaptic terminal.
    Nature. 1994 Aug 25;370(6491):652-5 PMID: 8065451
  49. Dominant role of mitochondria in clearance of large Ca2+ loads from rat adrenal chromaffin cells.
    Neuron. 1996 Jan;16(1):219-28 PMID: 8562086
  50. Subcellular imaging of intramitochondrial Ca2+ with recombinant targeted aequorin: significance for the regulation of pyruvate dehydrogenase activity.
    Proc Natl Acad Sci U S A. 1996 May 28;93(11):5489-94 PMID: 8643602
  51. Pre- and postsynaptic whole-cell recordings in the medial nucleus of the trapezoid body of the rat.
    J Physiol. 1995 Dec 15;489 ( Pt 3):825-40 PMID: 8788946
  52. Calcium influx and transmitter release in a fast CNS synapse.
    Nature. 1996 Oct 3;383(6599):431-4 PMID: 8837774
  53. Presynaptic calcium current modulation by a metabotropic glutamate receptor.
    Science. 1996 Oct 25;274(5287):594-7 PMID: 8849448
  54. Mitochondria support inositol 1,4,5-trisphosphate-mediated Ca2+ waves in cultured oligodendrocytes.
    J Biol Chem. 1996 Dec 27;271(52):33493-501 PMID: 8969213
  55. Ca2+ clearance mechanisms in isolated rat adrenal chromaffin cells.
    J Physiol. 1996 Apr 15;492 ( Pt 2):329-46 PMID: 9019533
  56. Mitochondrial participation in the intracellular Ca2+ network.
    J Cell Biol. 1997 Feb 24;136(4):833-44 PMID: 9049249
  57. Mitochondrial involvement in post-tetanic potentiation of synaptic transmission.
    Neuron. 1997 Mar;18(3):483-91 PMID: 9115741
  58. Calcium dynamics associated with a single action potential in a CNS presynaptic terminal.
    Biophys J. 1997 Mar;72(3):1458-71 PMID: 9138591
  59. Cytoplasmic Ca2+ signalling and reduction of mitochondrial pyridine nucleotides in adrenal glomerulosa cells in response to K+, angiotensin II and vasopressin.
    Biochem J. 1997 Mar 15;322 ( Pt 3):785-92 PMID: 9148750
  60. Kinetic studies of Ca2+ binding and Ca2+ clearance in the cytosol of adrenal chromaffin cells.
    Biophys J. 1997 Jul;73(1):532-45 PMID: 9199815
  61. Presynaptic depression at a calyx synapse: the small contribution of metabotropic glutamate receptors.
    J Neurosci. 1997 Nov 1;17(21):8137-46 PMID: 9334389
  62. Calcium current during a single action potential in a large presynaptic terminal of the rat brainstem.
    J Physiol. 1998 Jan 1;506 ( Pt 1):143-57 PMID: 9481678
  63. Mitochondrial Ca2+ uptake and release influence metabotropic and ionotropic cytosolic Ca2+ responses in rat oligodendrocyte progenitors.
    J Physiol. 1998 Apr 15;508 ( Pt 2):413-26 PMID: 9508806
  64. Cytosolic and mitochondrial Ca2+ signals in patch clamped mammalian ventricular myocytes.
    J Physiol. 1998 Mar 1;507 ( Pt 2):379-403 PMID: 9518700
  65. Evidence that mitochondria buffer physiological Ca2+ loads in lizard motor nerve terminals.
    J Physiol. 1998 May 15;509 ( Pt 1):59-65 PMID: 9547381
  66. Oxygen-bridged dinuclear ruthenium amine complex specifically inhibits Ca2+ uptake into mitochondria in vitro and in situ in single cardiac myocytes.
    J Biol Chem. 1998 Apr 24;273(17):10223-31 PMID: 9553073
  67. Developmental changes in calcium channel types mediating synaptic transmission in rat auditory brainstem.
    J Physiol. 1998 Jun 1;509 ( Pt 2):419-23 PMID: 9575291
  68. Inactivation of presynaptic calcium current contributes to synaptic depression at a fast central synapse.
    Neuron. 1998 Apr;20(4):797-807 PMID: 9581770
  69. Privileged access to mitochondria of calcium influx through N-methyl-D-aspartate receptors.
    Mol Pharmacol. 1998 Jun;53(6):974-80 PMID: 9614198
  70. Effects of mitochondrion on calcium transients at intact presynaptic terminals depend on frequency of nerve firing.
    J Neurophysiol. 1998 Jul;80(1):186-95 PMID: 9658040
  71. High-frequency firing helps replenish the readily releasable pool of synaptic vesicles.
    Nature. 1998 Jul 23;394(6691):384-8 PMID: 9690475
  72. Calcium dependence and recovery kinetics of presynaptic depression at the climbing fiber to Purkinje cell synapse.
    J Neurosci. 1998 Aug 15;18(16):6147-62 PMID: 9698309
  73. Activity-dependent modulation of the rate at which synaptic vesicles become available to undergo exocytosis.
    Neuron. 1998 Aug;21(2):415-24 PMID: 9728922
  74. Dense-cored vesicles, smooth endoplasmic reticulum, and mitochondria are closely associated with non-specialized parts of plasma membrane of nerve terminals: implications for exocytosis and calcium buffering by intraterminal organelles.
    J Comp Neurol. 1999 Jan 18;403(3):378-90 PMID: 9886037
Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
20026597
Published
2002-07-15
Pages
5840-7
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6757942
Subset
IM
Grants
Wellcome Trust · United Kingdom
External Links
PubMed source DOI: 20026597 PMC Full Text View journal details
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