Synaptic mitochondria regulate hair cell synapse size and function
Wong, Hiu Tung Candy
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Mechanosensitive hair cells of the inner ear and lateral line are specialized sensory cells that are required to evoke vital behaviors such as hearing, maintaining an upright posture and evading predators. To encode these sensory signals, hair cells use specialized ribbon synapses. Mitochondrial dysfunction has been implicated in hearing loss but the role of healthy mitochondria in hair cells or at ribbon synapses is unclear. I show that mitochondrial Ca2+ couples with presynaptic activity and plays distinct roles at hair cell synapses in mature and developing cells. I show that in mature hair cells, evoked-presynaptic-Ca2+ influx initiates mitochondrial-Ca2+ uptake; block of mitochondrial-Ca2+ uptake depresses presynaptic-Ca2+ activity and long-term block of mitochondrial-Ca2+ uptake can impact synapse integrity. I show that in developing hair cells, mitochondrial-Ca2+ uptake coincides with spontaneous presynaptic rises in Ca2+. Block of spontaneous presynaptic rises in Ca2+ or mitochondrial-Ca2+ uptake in developing hair cells enlarges presynaptic ribbon structure during synapse formation. Presynaptic ribbon size is composed primarily of the self-aggregating structural protein Ribeye. My work indicates that mitochondrial-Ca2+ may impact ribbon formation by modulating Ribeye-Ribeye protein interactions via the NAD(H) binding domain on Ribeye. Spontaneous mitochondrial-Ca2+ loading lowers cellular NAD+/NADH and ultimately downregulates ribbon formation. Furthermore, I found that direct application of NAD+ or NADH can directly increase or decrease ribbon formation respectively. Our results propose that mitochondrial-Ca2+ is an important component of presynaptic function and formation.