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 Ca 21 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 Ca 21 levels, reduced K 1 -induced Ca 21 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.

Morphological principles of neuronal mitochondria

“…Some of the features reported here have been measured previously for axonal and presynaptic mitochondria like the lengths, widths, cristae junction diameters [35,27,43], crista shape factors [37,7], density of cristae junctions [39,40] and are in reasonable agreement with the values reported in the literature. In particular, a high crista shape factor have been already associated with organelles located at high energy demanding locations [37,7]. In addition to the above listed features, we also calculated the principal curvatures for the membrane surfaces…”

“…The variability of the density of cristae junctions and of the cristae membrane surface area-to-volume ratio, also called crista shape factor in the literature [37], with the aspect ratio was analyzed ( Figure 5C-D). We found that both quantities are larger for globular organelles, i.e.…”

Morphological principles of neuronal mitochondria

“…These geometric features have been previously associated with the energy capacity of a given organelle. In particular, the density of CJs, the crista shape factor, and the crista density (CM surface area divided by the OM volume) were reported to be larger in outer hair cells mitochondria from young mice in comparison to older animals (Perkins et al, 2020). Moreover, larger crista shape factor and crista density were also reported to be larger in presynaptic mitochondria from fast-spiking interneurons in comparison to regular-spiking interneurons (Cserep et al, 2018).…”

“…Variability of CJ density and the CM surface area-to-volume ratio, also called crista shape factor in the literature (Perkins et al, 2020),…”

Prestin amplifies cardiac motor functions

“…Single-molecule fluorescence in situ hybridization (smFISH) SmFISH was performed as previously described (Lee et al, 2019;Perkins et al, 2020) in single isolated ventricular myocytes from WT and Slc26a5 À/À mice using probes developed for Slc26a5 and Slc26a6. Probe hybridization closely followed the manufacturer's instructions (Advanced Cell Diagnostics, Newark, CA, U.S.A.).…”