c-Jun N-terminal Phosphorylation: Biomarker for Cellular Stress rather than Cell Death in the Injured Cochlea

Abstract

Prevention of auditory hair cell death offers therapeutic potential to rescue hearing. Pharmacological blockade of JNK/c-Jun signaling attenuates injury-induced hair cell loss, but with unsolved mechanisms. We have characterized the c-Jun stress response in the mouse cochlea challenged with acoustic overstimulation and ototoxins, by studying the dynamics of c-Jun N-terminal phosphorylation. It occurred acutely in glial-like supporting cells, inner hair cells and in the cells of the cochlear ion trafficking route, and was rapidly downregulated after exposures. Notably, death-prone outer hair cells lacked c-Jun phosphorylation. As phosphorylation was triggered also by non-traumatic noise levels and as none of the cells showing this activation were lost, c-Jun phosphorylation is a biomarker for cochlear stress rather than an indicator of a death-prone fate of hair cells. Preconditioning with a mild noise exposure before a stronger traumatizing noise exposure attenuated the cochlear c-Jun stress response, suggesting that the known protective effect of sound preconditioning on hearing is linked to suppression of c-Jun activation. Finally, mice with mutations in the c-Jun N-terminal phosphoacceptor sites showed partial, but significant hair cell protection. These data identify the c-Jun stress response as a paracrine mechanism that mediates outer hair cell death.

Significance Statement: The current study reveals a detailed time course and cellular pattern of the c-Jun stress response in the cochlea following traumas. It identifies N-terminal phosphorylation of c-Jun as a biomarker for acute cellular stress. Obtained results suggest a novel function for c-Jun phosphorylation in the adult cochlea, not as an intrinsic mediator of cell death, but as a part of a paracrine response that regulates hair cell death following traumas. These results are important for the development of protective therapies against hair cell loss.