c-Jun N-terminal phosphorylation: biomarker for cellular stress rather than cell death in the injured cochlea
journal contributionposted on 01.07.2020, 11:48 authored by Tommi Anttonen, Anni Herranen, Jussi Virkkala, Anna Kirjavainen, Pinja Elomaa, Maarja Laos, Xingqun Liang, Jukka Ylikoski, Axel Behrens, Ulla Pirvola
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 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 nontraumatic noise levels and 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.
c-Jun phosphorylationcell deathhair cellinner earnoisesupporting cellAnimalsAnimals, NewbornApoptosisBiomarkersCell DeathDNA-Binding ProteinsDisease Models, AnimalFemaleGreen Fluorescent ProteinsHair Cells, VestibularHearing Loss, Noise-InducedJNK Mitogen-Activated Protein KinasesKanamycinMaleMiceMice, Inbred CBAMice, TransgenicNoiseProtein Synthesis InhibitorsTime FactorsTranscription FactorsVestibulocochlear Nerve InjuriesBehrens FC001039