Synaptic mitochondria regulate hair-cell synapse size and function

Hiu-Tung C Wong; Qiuxiang Zhang; Alisha J Beirl; Ronald S Petralia; Ya-Xian Wang; Katie Kindt

doi:10.7554/eLife.48914

Synaptic mitochondria regulate hair-cell synapse size and function

Elife. 2019 Oct 14:8:e48914. doi: 10.7554/eLife.48914.

Authors

Hiu-Tung C Wong^{1

2}, Qiuxiang Zhang¹, Alisha J Beirl¹, Ronald S Petralia³, Ya-Xian Wang³, Katie Kindt¹

Affiliations

¹ Section on Sensory Cell Development and Function, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, United States.
² National Institutes of Health-Johns Hopkins University Graduate Partnership Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, United States.
³ Advanced Imaging Core, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, United States.

Abstract

Sensory hair cells in the ear utilize specialized ribbon synapses. These synapses are defined by electron-dense presynaptic structures called ribbons, composed primarily of the structural protein Ribeye. Previous work has shown that voltage-gated influx of Ca²⁺ through Ca_V1.3 channels is critical for hair-cell synapse function and can impede ribbon formation. We show that in mature zebrafish hair cells, evoked presynaptic-Ca²⁺ influx through Ca_V1.3 channels initiates mitochondrial-Ca²⁺ (mito-Ca²⁺) uptake adjacent to ribbons. Block of mito-Ca²⁺ uptake in mature cells depresses presynaptic-Ca²⁺ influx and impacts synapse integrity. In developing zebrafish hair cells, mito-Ca²⁺ uptake coincides with spontaneous rises in presynaptic-Ca²⁺ influx. Spontaneous mito-Ca²⁺ loading lowers cellular NAD⁺/NADH redox and downregulates ribbon size. Direct application of NAD⁺ or NADH increases or decreases ribbon size respectively, possibly acting through the NAD(H)-binding domain on Ribeye. Our results present a mechanism where presynaptic- and mito-Ca²⁺ couple to confer proper presynaptic function and formation.

Keywords: developmental biology; metabolism; mitochondrial calcium; neuroscience; ribbon synapse; sensory cell; zebrafish.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / pharmacology
Animals
Animals, Genetically Modified
Calcium / metabolism*
Calcium Channel Agonists / pharmacology
Calcium Channel Blockers / pharmacology
Calcium Channels, L-Type / genetics
Calcium Channels, L-Type / metabolism*
Calcium Signaling
Cell Size
Embryo, Nonmammalian
Evoked Potentials, Auditory / physiology*
Eye Proteins / chemistry
Eye Proteins / genetics
Eye Proteins / metabolism*
Gene Expression
Hair Cells, Auditory / cytology
Hair Cells, Auditory / drug effects
Hair Cells, Auditory / metabolism*
Isradipine / pharmacology
Mitochondria / drug effects
Mitochondria / metabolism*
Mitochondria / ultrastructure
NAD / metabolism
Oxidation-Reduction
Protein Binding
Protein Interaction Domains and Motifs
Ruthenium Compounds / pharmacology
Synapses / drug effects
Synapses / metabolism*
Synapses / ultrastructure
Synaptic Transmission
Zebrafish
Zebrafish Proteins / agonists
Zebrafish Proteins / antagonists & inhibitors
Zebrafish Proteins / chemistry
Zebrafish Proteins / genetics
Zebrafish Proteins / metabolism*

Substances

Calcium Channel Agonists
Calcium Channel Blockers
Calcium Channels, L-Type
Eye Proteins
Ru 360
Ruthenium Compounds
Zebrafish Proteins
cacna1da protein, zebrafish
ctbp2a protein, zebrafish
NAD
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
Calcium
Isradipine

Abstract

Publication types

MeSH terms

Substances

Grants and funding