title: Traumatic noise activates Rho-family GTPases through transient cellular energy depletion.
abstract: Small GTPases mediate transmembrane signaling and regulate the actin cytoskeleton in eukaryotic cells. Here, we characterize the auditory pathology of adult male CBA/J mice exposed to traumatic noise (2-20 kHz; 106 dB; 2 h). Loss of outer hair cells was evident 1 h after noise exposure in the basal region of the cochlea and spread apically with time, leading to permanent threshold shifts of 35, 60, and 65 dB at 8, 16, and 32 kHz. Several biochemical and molecular changes correlated temporally with the loss of cells. Immediately after exposure, the concentration of ATP decreased in cochlear tissue and reached a minimum after 1 h while the immunofluorescent signal for p-AMPKα significantly increased in sensory hair cells at that time. Levels of active Rac1 increased, whereas those of active RhoA decreased significantly 1 h after noise attaining a plateau at 1-3 h; the formation of a RhoA-p140mDia complex was consistent with an activation of Rho GTPase pathways. Also at 1-3 h after exposure, the caspase-independent cell death marker, Endo G, translocated to the nuclei of outer hair cells. Finally, experiments with the inner ear HEI-OC1 cell line demonstrated that the energy-depleting agent oligomycin enhanced both Rac1 activity and cell death. The sum of the results suggests that traumatic noise induces transient cellular ATP depletion and activates Rho GTPase pathways, leading to death of outer hair cells in the cochlea.
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Fu-Quan
authors.initials: FQ
authors.lastname: Chen
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Zheng
authors.forename: Kayla
authors.initials: K
authors.lastname: Hill
authors.forename: Su-Hua
authors.initials: SH
authors.lastname: Sha
mesh_terms: D000161:Acoustic Stimulation / Q000009:adverse effects; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003051:Cochlea / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology*; D006198:Hair Cells, Auditory / Q000378:metabolism* / Q000473:pathology; D006317:Hearing Loss, Noise-Induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D009479:Neuropeptides / Q000378:metabolism*; D009622:Noise / Q000009:adverse effects; D015854:Up-Regulation / Q000502:physiology; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein
chemical_list: D009479:Neuropeptides; C484602:Rac1 protein, mouse; D000255:Adenosine Triphosphate; C526380:RhoA protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein