Synaptic mitochondria regulate hair-cell synapse size and function

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 Ca through Ca 1.3 channels is critical for hair-cell synapse function and can impede ribbon formation. We show that in mature zebrafish hair cells, evoked presynaptic-Ca influx through Ca 1.3 channels initiates mitochondrial-Ca (mito-Ca ) uptake adjacent to ribbons. Block of mito-Ca uptake in mature cells depresses presynaptic-Ca influx and impacts synapse integrity. In developing zebrafish hair cells, mito-Ca uptake coincides with spontaneous rises in presynaptic-Ca influx. Spontaneous mito-Ca 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-Ca couple to confer proper presynaptic function and formation.