Age-related spiral ganglion neuron (SGN) loss can occur independently of hair cell degeneration, suggesting that vascular or metabolic support structures contribute directly to neuronal decline [1]. Here we propose that mitochondrial calcium overload in the marginal cells of the stria vascularis initiates a signaling cascade that reduces cochlear blood flow and precipitates SGN loss. With advancing age, increased reactive oxygen species production within marginal cell mitochondria sensitizes the mitochondrial calcium uniporter, leading to sustained matrix calcium elevation [2]. This calcium load triggers opening of the mitochondrial permeability transition pore, causing cytosolic calcium release and activation of calcium-sensitive phospholipase A2. The resulting arachidonic acid metabolism elevates endothelin-1 secretion from marginal cells. Endothelin-1 acts on endothelin‑A receptors of strial capillaries, inducing vasoconstriction and reducing perfusion of the lateral wall. Diminished oxygen and nutrient delivery compromises the metabolic support that SGNs rely on for survival, thereby driving neuronal loss even when hair cells remain intact.

This hypothesis generates several testable predictions. First, aged mice with marginal cell‑specific knockout of the mitochondrial calcium uniporter (McU) should exhibit lower endothelin-1 levels in the stria vascularis, preserved capillary diameter, and reduced SGN loss compared with wild‑type controls, despite comparable hair cell counts. Second, pharmacological blockade of endothelin‑A receptors (e.g., with bosentan) in aged animals should rescue SGN numbers without affecting hair cell survival. Third, elevating mitochondrial calcium in young marginal cells via targeted expression of a calcium‑mimetic protease should prematurely increase endothelin-1 production, induce strial vasoconstriction, and accelerate SGN degeneration.

Experimental validation can combine cell‑type‑specific genetics, in vivo imaging, and molecular assays. Marginal cell‑specific Cre lines (e.g., Kcnj10‑Cre) crossed with floxed McU alleles will allow precise manipulation of mitochondrial calcium handling. Laser‑Doppler flowmetry or two‑photon imaging of fluorescently labeled strial capillaries will quantify vascular diameter and blood flow dynamics. Endothelin-1 concentrations can be measured by ELISA in microdissected stria vascularis tissue. SGN survival will be assessed via confocal counting of neurofilament‑positive neurons in cochlear whole mounts, while hair cell integrity is evaluated with phalloidin labeling of stereocilia bundles. All measurements should be performed at multiple ages (e.g., 3, 12, and 24 months) to capture the temporal progression of the proposed cascade.

Falsification would occur if marginal cell‑specific McU deletion fails to alter endothelin-1 levels, strial perfusion, or SGN survival, or if endothelin‑A receptor blockade does not rescue SGNs despite confirmed target engagement. Conversely, confirmation of the predicted relationships would establish a mechanistic link between mitochondrial calcium dysregulation in the stria vascularis, endothelin‑mediated vasoconstriction, and age‑related SGN loss, offering a novel therapeutic target for preserving hearing independent of hair cell rescue strategies.