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

Mayakannan Manikandan,Danqi Wang,Ruben Stepanyan,Steven Walker,Aditi R Deshmukh,Kumar N Alagramam,Elizabeth Perea

doi:10.1038/s41598-021-88841-0

Mayakannan Manikandan, Danqi Wang + Show 5 more

Open Access

https://doi.org/10.1038/s41598-021-88841-0

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Abstract

Mitochondrial Ca2+ 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 Ca2+ channels result in a large influx of Ca2+. The intracellular rise in Ca2+ is partly balanced by the mitochondria which rapidly uptakes Ca2+ via a highly selective channel comprised of the main pore-forming subunit, the mitochondrial Ca2+ uniporter (MCU), and associated regulatory proteins. MCU thus contributes to Ca2+ buffering, ensuring cytosolic homeostasis, and is posited to have a critical role in hair cell function and hearing. To test this hypothesis, Ca2+ 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 Cdh23ahl allele to the FVB/NJ strain, due to the close proximity of these genes. Neither Mcu+/− nor Mcu−/− genotypes affected cochlear development, morphology, or Ca2+ 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 Ca2+ 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.

Highlights

Acquired hearing impairment is mostly associated with deficiency or loss of cochlear cells laden with mitochondria: the inner and outer hair cells (HCs), the spiral ganglion neurons (SGNs), and the cells of the stria vascularis[1,2]
Since the Mcu knockout allele is very closely located to the Cdh23ahl allele, which is linked to age-related hearing loss, they cosegregated to the FVB/NJ background
The Cdh23ahl allele is essentially inseparable from the Mcu knockout allele by conventional breeding, and the FVB/NJ Mcu−/− mice are homozygous for Cdh23ahl

Summary

Introduction

Acquired hearing impairment is mostly associated with deficiency or loss of cochlear cells laden with mitochondria: the inner and outer hair cells (HCs), the spiral ganglion neurons (SGNs), and the cells of the stria vascularis[1,2]. Like in many other cell types in an organism, mitochondria in the cochlear cells are responsible for vital cellular functions, including energy production, apoptosis, cell signaling, and calcium storage. These functions are dependent on the ability of mitochondria to modulate Ca2+ levels[9,10,11,12,13,14,15]. While slightly smaller in size, mice lacking MCU have a normal life-span and exhibit no adverse phenotype when u nchallenged[17] These mice were generated on a mixed C57BL/6-CD1 (B6-CD1) background[17] and the loss of MCU was not conclusively shown to affect hearing[18]. This study demonstrates that Mcu is essential for hearing preservation in congenic FVB/NJ mice

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