Dkk3-Cyp11b2/aldosterone signaling couples ion-homeostatic failure to mitochondrial apoptosis in cochlear aging.

Abstract

Cellular responses to aging require coordinated control of extracellular signaling, ion transport, redox balance, and mitochondrial metabolism. Here, we identify Dickkopf-3 (Dkk3) as an age-associated signal linked to the Cyp11b2/aldosterone pathway in cochlear sensory cells. Exploratory analysis of a public cell-type-specific bulk RNA-sequencing dataset showed higher Dkk3 expression in aged inner and outer hair-cell library profiles. In HEI-OC1 cells, Dkk3 overexpression suppressed Cyp11b2 expression and aldosterone release, increased cytosolic and mitochondrial reactive oxygen species, reduced mitochondrial membrane potential, impaired basal, ATP-linked, maximal, and spare respiratory capacity, and activated BAX-APAF1-caspase-3-dependent apoptosis. Conversely, Dkk3 silencing increased Cyp11b2 and aldosterone. In naturally aged mice, systemic Dkk3 knockdown or aldosterone supplementation improved endocochlear potential and auditory thresholds, preserved cochlear hair-cell organization, increased Na+/K + -ATPase alpha1 and NKCC1 expression, reinforced antioxidant defenses, and reduced apoptosis. Systemic mineralocorticoid-receptor blockade with spironolactone attenuated these benefits without reversing upstream Dkk3 or Cyp11b2 expression. These findings support a model in which Dkk3-Cyp11b2/aldosterone signaling contributes to ion-homeostatic failure, mitochondrial oxidative stress, and sensory-cell apoptosis during cochlear aging. Tissue-specific studies will be required to distinguish cochlear from systemic endocrine mechanisms and to determine whether Wnt-dependent survival or progenitor responses also contribute.