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

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...

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Autores principales:	Mayakannan Manikandan, Steven Walker, Aditi R. Deshmukh, Elizabeth Perea, Danqi Wang, Kumar N. Alagramam, Ruben Stepanyan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7b994349ac5141cc975fc7bdd5f3f50d
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spelling	oai:doaj.org-article:7b994349ac5141cc975fc7bdd5f3f50d2021-12-02T15:38:23ZMitochondrial calcium uniporter is essential for hearing and hair cell preservation in congenic FVB/NJ mice10.1038/s41598-021-88841-02045-2322https://doaj.org/article/7b994349ac5141cc975fc7bdd5f3f50d2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88841-0https://doaj.org/toc/2045-2322Abstract 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 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 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.Mayakannan ManikandanSteven WalkerAditi R. DeshmukhElizabeth PereaDanqi WangKumar N. AlagramamRuben StepanyanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mayakannan Manikandan Steven Walker Aditi R. Deshmukh Elizabeth Perea Danqi Wang Kumar N. Alagramam Ruben Stepanyan Mitochondrial calcium uniporter is essential for hearing and hair cell preservation in congenic FVB/NJ mice
description	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 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 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.
format	article
author	Mayakannan Manikandan Steven Walker Aditi R. Deshmukh Elizabeth Perea Danqi Wang Kumar N. Alagramam Ruben Stepanyan
author_facet	Mayakannan Manikandan Steven Walker Aditi R. Deshmukh Elizabeth Perea Danqi Wang Kumar N. Alagramam Ruben Stepanyan
author_sort	Mayakannan Manikandan
title	Mitochondrial calcium uniporter is essential for hearing and hair cell preservation in congenic FVB/NJ mice
title_short	Mitochondrial calcium uniporter is essential for hearing and hair cell preservation in congenic FVB/NJ mice
title_full	Mitochondrial calcium uniporter is essential for hearing and hair cell preservation in congenic FVB/NJ mice
title_fullStr	Mitochondrial calcium uniporter is essential for hearing and hair cell preservation in congenic FVB/NJ mice
title_full_unstemmed	Mitochondrial calcium uniporter is essential for hearing and hair cell preservation in congenic FVB/NJ mice
title_sort	mitochondrial calcium uniporter is essential for hearing and hair cell preservation in congenic fvb/nj mice
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/7b994349ac5141cc975fc7bdd5f3f50d
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Mitochondrial calcium uniporter is essential for hearing and hair cell preservation in congenic FVB/NJ mice

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