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(2+) through Ca(V)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(2+) influx through Ca(V)1.3 channels initiates mitochondrial-Ca(2+) (mito-Ca(2+)) uptake adjacent to ribbons. Block of mito-Ca(2+) uptake in mature cells depresses presynaptic-Ca(2+) influx and impacts synapse integrity. In developing zebrafish hair cells, mito-Ca(2+) uptake coincides with spontaneous rises in presynaptic-Ca(2+) influx. Spontaneous mito-Ca(2+) 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(2+) couple to confer proper presynaptic function and formation.