Synaptic mitochondria are critical for hair-cell synapse formation and function

Abstract

SummarySensory 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 formation. Direct application of NAD+or NADH increases or decreases ribbon formation 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.