Mitochondrial calcium uniporter is essential for hearing and hair cell preservation in congenic FVB/NJ mice.

Mitochondrial Ca regulates a wide range of cell processes, including morphogenesis, metabolism, excitotoxicity, and survival. In cochlear hair cells, the activation of mechano-electrical transduction and voltage-gated Ca channels result in a large influx of Ca. The intracellular rise in Ca is partly balanced by the mitochondria which rapidly uptakes Ca via a highly selective channel comprised of the main pore-forming subunit, the mitochondrial Ca uniporter (MCU), and associated regulatory proteins. MCU thus contributes to Ca buffering, ensuring cytosolic homeostasis, and is posited to have a critical role in hair cell function and hearing. To test this hypothesis, Ca homeostasis in hair cells and cochlear function were investigated in FVB/NJ mice carrying the knockout allele of Mcu (Mcu or Mcu). The Mcu knockout allele, which originated in C57BL/6 strain cosegregated along with Cdh23 allele to the FVB/NJ strain, due to the close proximity of these genes. Neither Mcu nor Mcu genotypes affected cochlear development, morphology, or Ca homeostasis of auditory hair cells in the first two postnatal weeks. However, Mcu mice displayed high-frequency hearing impairment as early as 3 weeks postnatal, which then progressed to profound hearing loss at all frequencies in about 6 months. In Mcu mice, significantly elevated ABR thresholds were observed at 6 months and 9 months of age only at 32 kHz frequency. In three-month-old Mcu mice, up to 18% of the outer hair cells and occasionally some inner hair cells were missing in the mid-cochlear region. In conclusion, mitochondrial Ca uniporter is not required for the development of cochlea in mice, but is essential for hearing and hair cell preservation in congenic FVB/NJ mice.