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Altered Outer Hair Cell Mitochondrial and Subsurface Cisternae Connectomics Are Candidate Mechanisms for Hearing Loss in Mice.

ABSTRACT: Organelle crosstalk is vital for cellular functions. The propinquity of mitochondria, ER, and plasma membrane promote regulation of multiple functions, which include intracellular Ca²⁺ flux, and cellular biogenesis. Although the purposes of apposing mitochondria and ER have been described, an understanding of altered organelle connectomics related to disease states is emerging. Since inner ear outer hair cell (OHC) degeneration is a common trait of age-related hearing loss, the objective of this study was to investigate whether the structural and functional coupling of mitochondria with subsurface cisternae (SSC) was affected by aging. We applied functional and structural probes to equal numbers of male and female mice with a hearing phenotype akin to human aging. We discovered the polarization of cristae and crista junctions in mitochondria tethered to the SSC in OHCs. Aging was associated with SSC stress and decoupling of mitochondria with the SSC, mitochondrial fission/fusion imbalance, a remarkable reduction in mitochondrial and cytoplasmic Ca²⁺ levels, reduced K⁺-induced Ca²⁺ uptake, and marked plasticity of cristae membranes. A model of structure-based ATP production predicts profound energy stress in older OHCs. This report provides data suggesting that altered membrane organelle connectomics may result in progressive hearing loss.

SUBMITTER: Perkins G

PROVIDER: S-EPMC7605424 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Age-related hearing loss (ARHL) is the most common sensory deficit in aging society, which is accompanied by increased speech discrimination difficulties in noisy environments, social isolation, and cognitive decline. The audiometric degree of ARHL is largely correlated with sensory hair cell loss in addition to age-related factors not captured by histopathological analysis of the human cochlea. Previous studies have identified the senescence-accelerated mouse prone strain 8 (SAMP8) as a model for studying ARHL and age-related modifications of the cochlear redox environment. However, the SAMP8 population exhibits a large variability in auditory function decline over age, whose underlying cause remains unknown. In this study, we analyzed auditory function of SAMP8 mice by measuring auditory brainstem response (ABR) thresholds at the age of 6 weeks (juvenile), 12 weeks (young adult), and 24 weeks (adult). Consistent with previous studies, SAMP8 mice exhibit an early progressive, age-related decline of hearing acuity. However, a spatiotemporal cytohistological analysis showed that the significant increase in threshold variability was not concurrently reflected in outer hair cell (OHC) loss observed in the lower and upper quartiles of the ABR threshold distributions over age. This functional loss was found to precede OHC loss suggesting that age-related phenotypic changes may be contributing factors not represented in cytohistological analysis. The expression of potassium channels KCNQ4 (KV7.4), which mediates the current IK,n crucial for the maintenance of OHC membrane potential, and KCNQ1 (KV7.1), which is an essential component in potassium circulation and secretion into the endolymph generating the endocochlear potential, showed differences between these quartiles and age groups. This suggests that phenotypic changes in OHCs or the stria vascularis due to variable oxidative deficiencies in individual mice may be predictors of the observed threshold variability in SAMP8 mice and their progressive ARHL. In future studies, further phenotypic predictors affected by accumulated metabolic challenges over age need to be investigated as potentially underlying causes of ARHL preceding irreversible OHC loss in the SAMP8 mouse model.

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Altered Outer Hair Cell Mitochondrial and Subsurface Cisternae Connectomics Are Candidate Mechanisms for Hearing Loss in Mice.

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