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 CaV1.3 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 CaV1.3 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.
- Hiu-tung C Wong
- Qiuxiang Zhang
- Alisha J Beirl
- Katie Kindt
- Ronald S Petralia
- Ya-Xian Wang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All husbandry and experiments were approved by the NIH Animal Care and Use program under protocol #1362-13.
- Tanya T Whitfield, University of Sheffield, United Kingdom
- Received: May 30, 2019
- Accepted: October 13, 2019
- Accepted Manuscript published: October 14, 2019 (version 1)
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