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 to 3 h; the formation of a RhoA-p140mDia complex was consistent with an activation of Rho GTPase pathways. Also at 1 to 3 h after exposure, the caspase-independent cell death marker, endonuclease 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.

Receptor-interacting protein kinases modulate noise-induced sensory hair cell death

“…15 We therefore analyzed the relationship between RIP3 and p-AMPK α . First, western blotting of cochlear homogenates resulted in a single anti-p-AMPK band for each sample, with no difference in band densities between control and noise-exposed groups (data not shown).…”

FVB/NJ Mice Demonstrate a Youthful Sensitivity to Noise-Induced Hearing Loss and Provide a Useful Genetic Model for the Study of Neural Hearing Loss

“…2005]. Increased vulnerability to NIHL has been attributed to the Dystrophin gene [Chen et al, 2012], Vasodilator-stimulated phosphoprotein [Schick et al, 2004], and Heat shock factor 1 genes [Sugahara et al, 2003; Farber et al, 2011]. In addition to Cdh23 Ahl , Cdh23 v transgenic mice with knockouts of the genes Cp, GPx1, Pmca2, Sod1 , and Trpv4 show vulnerability to noise damage [Ohlemiller, 2006].…”

Emerging therapeutic interventions against noise-induced hearing loss

“…This assessment is based on morphological and molecular features where apoptotic cell death is actively regulated and characterized by condensed nuclei with activation of multiple cell death pathways that are primarily regulated by caspases 18–20 . In addition, noise exposure causes the release of cytochrome C and the translocation of endonuclease G in apoptotic OHCs 19–21 . Swollen nuclei, a marker of necrotic cell death, in OHCs after noise exposure indeed suggest involvement of necrosis 18 .…”

“…However, high-intensity noise exposure decreases capillary blood flow and causes local vasoconstriction 32, 33 . The resulting ischemia reduces ATP levels within the inner ear, including the lateral wall structures which are responsible for upholding the endocochlear potential 19, 34–36 . Consequently, a reduction of ATP levels in the cochlea is associated with noise-induced permanent hearing loss 19, 34, 35 .…”

“…The resulting ischemia reduces ATP levels within the inner ear, including the lateral wall structures which are responsible for upholding the endocochlear potential 19, 34–36 . Consequently, a reduction of ATP levels in the cochlea is associated with noise-induced permanent hearing loss 19, 34, 35 . Conversely, maintenance of ATP levels by supplying creatine as an energy source attenuates temporary and permanent NIHL in guinea pigs 37 .…”