title: Mitochondrial Calcium Uptake Modulates Synaptic Vesicle Endocytosis in Central Nerve Terminals.
abstract: Presynaptic calcium influx triggers synaptic vesicle (SV) exocytosis and modulates subsequent SV endocytosis. A number of calcium clearance mechanisms are present in central nerve terminals that regulate intracellular free calcium levels both during and after stimulation. During action potential stimulation, mitochondria rapidly accumulate presynaptic calcium via the mitochondrial calcium uniporter (MCU). The role of mitochondrial calcium uptake in modulating SV recycling has been debated extensively, but a definitive conclusion has not been achieved. To directly address this question, we manipulated the expression of the MCU channel subunit in primary cultures of neurons expressing a genetically encoded reporter of SV turnover. Knockdown of MCU resulted in ablation of activity-dependent mitochondrial calcium uptake but had no effect on the rate or extent of SV exocytosis. In contrast, the rate of SV endocytosis was increased in the absence of mitochondrial calcium uptake and slowed when MCU was overexpressed. MCU knockdown did not perturb activity-dependent increases in presynaptic free calcium, suggesting that SV endocytosis may be controlled by calcium accumulation and efflux from mitochondria in their immediate vicinity.
authors.affiliation: From the Centre for Integrative Physiology, George Square, University of Edinburgh, Edinburgh EH8 9XD, Scotland, United Kingdom.
authors.forename: Jamie Roslin Keynes
authors.initials: JR
authors.lastname: Marland
authors.affiliation: From the Centre for Integrative Physiology, George Square, University of Edinburgh, Edinburgh EH8 9XD, Scotland, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Hasel
authors.affiliation: From the Centre for Integrative Physiology, George Square, University of Edinburgh, Edinburgh EH8 9XD, Scotland, United Kingdom.
authors.forename: Katherine
authors.initials: K
authors.lastname: Bonnycastle
authors.affiliation: From the Centre for Integrative Physiology, George Square, University of Edinburgh, Edinburgh EH8 9XD, Scotland, United Kingdom M.Cousin@ed.ac.uk.
authors.forename: Michael Alan
authors.initials: MA
authors.lastname: Cousin
mesh_terms: D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D004705:Endocytosis / Q000502:physiology*; D005089:Exocytosis; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; C034703:mitochondrial calcium uniporter; D002118:Calcium
keywords: calcium; endocytosis; mitochondria; neuron; synapse; vesicles