ER-Mitochondrial Calcium Flow Underlies Vulnerability of Mechanosensory Hair Cells to Damage

Mechanosensory hair cells are vulnerable to environmental insult, resulting in hearing and balance disorders. We demonstrate that directional compartmental flow of intracellular Ca2+ underlies death in zebrafish lateral line hair cells after exposure to aminoglycoside antibiotics, a well characterized hair cell toxin. Ca2+ is mobilized from the ER and transferred to mitochondria via IP3 channels with little cytoplasmic leakage. Pharmacological agents that shunt ER-derived Ca2+ directly to cytoplasm mitigate toxicity, indicating that high cytoplasmic Ca2+ levels alone are not cytotoxic. Inhibition of the mitochondrial transition pore sensitizes hair cells to the toxic effects of aminoglycosides, contrasting with current models of excitotoxicity. Hair cells display efficient ER-mitochondrial Ca2+ flow, suggesting that tight coupling of these organelles drives mitochondrial activity under physiological conditions at the cost of increased susceptibility to toxins.