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

Mitochondrial Ca(2+) 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(2+) channels result in a large influx of Ca(2+). The intracellular rise in Ca(2+) is partly balanced by the mitochondria which rapidly uptakes Ca(2+) via a highly selective channel comprised of the main pore-forming subunit, the mitochondrial Ca(2+) uniporter (MCU), and associated regulatory proteins. MCU thus contributes to Ca(2+) buffering, ensuring cytosolic homeostasis, and is posited to have a critical role in hair cell function and hearing. To test this hypothesis, Ca(2+) 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(ahl) 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(2+) 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(2+) 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.