Permanent Threshold Shift Caused by Acute Cochlear Mitochondrial Dysfunction Is Primarily Mediated by Degeneration of the Lateral Wall of the Cochlea

Okamoto, Yoshiwo; Hoya, Noriyuki; Kamiya, Kanichi; Fujisawa, Masato; Ogawa, Kaoru; Matsunaga, Tatsuo

doi:10.1159/000084843

Cited by 40 publications

(31 citation statements)

References 106 publications

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“…The Na + /K + /Cl − co-transporter expressed by strial marginal cells lies within the~30 cM 95% confidence for Nirep. There are some similarities between the acute pathology we find in BALB and CBA and the effects of metabolic poisons (Hoya et al 2004;Okamoto et al 2005;Yamasoba et al 2006) and locally applied furosemide , suggesting that Nirep encodes the co-transporter, or some factor involved in metabolism.…”

Section: Anatomic Correlates Of Permanent Ep Reductionmentioning

confidence: 67%

Different Cellular and Genetic Basis of Noise-Related Endocochlear Potential Reduction in CBA/J and BALB/cJ Mice

Ohlemiller

Rosen

Rellinger

et al. 2010

JARO

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The acute and permanent effects of noise exposure on the endocochlear potential (EP) and cochlear lateral wall were evaluated in BALB/cJ (BALB) inbred mice, and compared with CBA/J (CBA) and C57BL/6 (B6) mice. Two-hour exposure to broadband noise (4-45 kHz) at 110 dB SPL leads to a~50 mV reduction in the EP in BALB and CBA, but not B6. EP reduction in BALB and CBA is reliably associated with characteristic acute cellular pathology in stria vascularis and spiral ligament. By 8 weeks after exposure, the EP in CBA mice has returned to normal. In BALBs, however, the EP remains depressed by an average~10 mV, so that permanent EP reduction contributes to permanent threshold shifts in these mice. We recently showed that the CBA noise phenotype in part reflects the influence of a large effect quantitative trait locus on Chr. 18, termed Nirep (Ohlemiller et al., Hear Res 260:47-53, 2010b). While CBA "EP susceptibility" alleles are dominant to those in B6, examination of (B6×BALB) F1 hybrid mice and (F1×BALB) N2 backcross mice revealed that noise-related EP reduction and associated cell pathology in BALBs are inherited in an autosomal recessive manner, and are dependent on multiple genes. Moreover, while N2 mice formed from B6 and CBA retain strong correspondence between acute EP reduction, ligament pathology, and strial pathology, N2s formed from B6 and BALB include subsets that dissociate pathology of ligament and stria. We conclude that the genes and cascades that govern the very similar EP susceptibility phenotypes in BALB and CBA mice need not be the same. BALBs appear to carry alleles that promote more pronounced long term effects of noise on the lateral wall. Separate loci in BALBs may preferentially impact stria versus ligament.

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Section: Anatomic Correlates Of Permanent Ep Reductionmentioning

confidence: 67%

Different Cellular and Genetic Basis of Noise-Related Endocochlear Potential Reduction in CBA/J and BALB/cJ Mice

Ohlemiller

Rosen

Rellinger

et al. 2010

JARO

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“…Yet this need not promote overt strial pathology. Notably, mitochondrial inhibitors applied in guinea pigs reproduce many of the features of noise injury (Hoya et al 2004;Okamoto et al 2005), while gap junction inhibitors only somewhat reproduce the effects of noise (Spiess et al 2002). In any event, the appearance of the lateral wall does not readily indicate which cells or genes may drive phenotypic differences.…”

Section: Genes and Processes That Establish Or Modulate The Epmentioning

confidence: 97%

QTL Mapping of Endocochlear Potential Differences between C57BL/6J and BALB/cJ mice

Ohlemiller

Kiener

Gagnon

2016

JARO

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We reported earlier that the endocochlear potential (EP) differs between C57BL/6J (B6) and BALB/cJ (BALB) mice, being lower in BALBs by about 10 mV (Ohlemiller et al. Hear Res 220: 10-26, 2006). This difference corresponds to strain differences with respect to the density of marginal cells in cochlear stria vascularis. After about 1 year of age, BALB mice also tend toward EP reduction that correlates with further marginal cell loss. We therefore suggested that early sub-clinical features of the BALB stria vascularis may predispose these mice to a condition modeling Schuknecht's strial presbycusis. We further reported (Ohlemiller et al. J Assoc Res Otolaryngol 12: 45-58, 2011) that the acute effects of a 2-h 110 dB SPL noise exposure differ between B6 and BALB mice, such that the EP remains unchanged in B6 mice, but is reduced by 40-50 mV in BALBs. In about 25 % of BALBs, the EP does not completely recover, so that permanent EP reduction may contribute to noise-induced permanent threshold shifts in BALBs. To identify genes and alleles that may promote natural EP variation as well as noiserelated EP reduction in BALB mice, we have mapped related quantitative trait loci (QTLs) using 12 recombinant inbred (RI) strains formed from B6 and BALB (CxB1-CxB12). EP and strial marginal cell density were measured in B6 mice, BALB mice, their F1 hybrids, and RI mice without noise exposure, and 1-3 h after broadband noise (4-45 kHz, 110 dB SPL, 2 h). For unexposed mice, the strain distribution patterns for EP and marginal cell density were used to generate preliminary QTL maps for both EP and marginal cell density. Six QTL regions were at least statistically suggestive, including a significant QTL for marginal cell density on chromosome 12 that overlapped a weak QTL for EP variation. This region, termed Maced (Marginal cell density QTL) supports the notion of marginal cell density as a genetically influenced contributor to natural EP variation. Candidate genes for Maced notably include Foxg1, Foxa1, Akap6, Nkx2-1, and Pax9. Noise exposure produced significant EP reductions in two RI strains as well as significant EP increases in two RI strains. QTL mapping of the EP in noise-exposed RI mice yielded four suggestive regions. Two of these overlapped with QTL regions we previously identified for noise-related EP reduction in CBA/J mice (Ohlemiller et al. Hear Res 260: 47-53, 2010) on chromosomes 5 and 18 (Nirep). The present map may narrow the Nirep interval to a~10-Mb region of proximal Chr. 18 that includes Zeb1, Arhgap12, Mpp7, and Gjd4. This study marks the first exploration of natural gene variants that modulate the EP. Their orthologs may underlie some human hearing loss that originates in the lateral wall.Electronic supplementary material The online version of this article

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“…Mitochondrial degeneration in the SL, as in the SG, plays a crucial role; in a mouse model of DFN3, fibrocytes had fewer mitochondria (Minowa et al 1999), and in mice exposed to a mitochondrial toxin, 3-nitropropionic acid (3-NP) (Okamoto et al 2005), SL pathology was accompanied by hearing loss. Systemic administration of a caspase inhibitor prior to and during 3-NP administration suggested that caspasedependent apoptosis of fibrocytes takes place as a result of mitochondrial damage (Mizutari et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Relative Time Course of Degeneration of Different Cochlear Structures in the CD/1 Mouse Model of Accelerated Aging

Mahendrasingam

MacDonald

Furness

2011

JARO

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Presbycusis (age-related hearing loss) can result from various cochlear pathologies. We have studied the time course of degeneration in a mouse that shows accelerated presbycusis, the CD/1 mouse, as a possible model to investigate stem-cell strategies to prevent or ameliorate presbycusic changes. CD/1 mice from 0 to 72 weeks old were examined by light and electron microscopy. Early pathological changes were detected in basal turn spiral ligament fibrocytes and spiral ganglion, but the latter was variable as both satellite cells and neurons were normal in some cochleae. Light microscopic counts in the spiral ligament of 20-week-old mice revealed that of the five main types (types I-V), only type V fibrocytes showed no reduction in numbers compared with 3-week-old animals, and type IV showed the greatest losses. However, all types of fibrocyte showed subtle damage when examined using electron microscopy, in the form of swollen mitochondria, as early as 2 weeks. The extent of mitochondrial damage showed a degree of correspondence with the light microscopic pattern of fibrocyte loss in that types III and IV fibrocytes had the most abnormal mitochondria and type V the least, especially at early stages. By 10-15 weeks, ultrastructural features of fibrocyte damage were similar to longer term changes reported in gerbils. Stria vascularis, spiral ganglion and hair cells showed few consistent early signs of damage but became increasingly affected, lagging behind the fibrocyte damage. Our data suggest that fibrocyte pathology may precede other presbycusic changes; breakdown of homeostatic mechanisms to which they contribute may cause the subsequent degeneration of the hair cells. Overall, there were many similarities to presbycusic changes in other rodents and humans. Therefore, the features of accelerated aging in this mouse make it a suitable model for rapidly assessing possible strategies to prevent or ameliorate presbycusic changes.

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Permanent Threshold Shift Caused by Acute Cochlear Mitochondrial Dysfunction Is Primarily Mediated by Degeneration of the Lateral Wall of the Cochlea

Cited by 40 publications

References 106 publications

Different Cellular and Genetic Basis of Noise-Related Endocochlear Potential Reduction in CBA/J and BALB/cJ Mice

Different Cellular and Genetic Basis of Noise-Related Endocochlear Potential Reduction in CBA/J and BALB/cJ Mice

QTL Mapping of Endocochlear Potential Differences between C57BL/6J and BALB/cJ mice

Relative Time Course of Degeneration of Different Cochlear Structures in the CD/1 Mouse Model of Accelerated Aging

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