A BAD link to mitochondrial cell death in the cochlea of mice with noise-induced hearing loss.
Acoustic overstimulation induces calcium overload and activation of mitochondria-mediated cell death pathways in outer hair cells (OHC) of the cochlea. However, it is not known whether these events are interrelated or independent. We have recently reported that the calcium-dependent phosphatase calcineurin is activated in OHC following noise exposure and now postulate that calcium overload triggers mitochondria-mediated death pathways through activation of Bcl-2-associated death promoter (BAD) by calcineurin. CBA/J mice were exposed to broadband noise (2-20 kHz), causing a permanent threshold shift of about 40 dB at 12 and 20 kHz, corresponding to damage in the middle and basal turns of the cochlea. Loss of OHC in the basal region was evident in surface preparations. BAD immunostaining in control animals had a cytoplasmic distribution in the cells of the organ of Corti. Five hours after acoustic overstimulation, mitochondria and BAD redistributed to the perinuclear region of OHC in the basal and middle turns but not in the apical turn. The nonapoptotic phospho-BAD (Ser 112) was up-regulated in cells undamaged by noise (supporting cells and inner hair cells) but not in OHC. These data establish a connection between calcium overload and mitochondria-mediated death pathways in OHC and also suggest a dual role for BAD. The translocation of BAD to the mitochondria in degenerating cells is indicative of the activation of its proapoptotic capacity, whereas up-regulation of phospho-BAD is consistent with a nonapoptotic role of BAD in less vulnerable cells.
Vicente-Torres
M Angeles
MA
Kresge Hearing Research Institute, University of Michigan, Ann Arbor, Michigan, USA.
Schacht
Jochen
J
D000161:Acoustic Stimulation / Q000009:adverse effects; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D003051:Cochlea / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018072:Hair Cells, Auditory, Outer / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006317:Hearing Loss, Noise-Induced / Q000378:metabolism* / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008928:Mitochondria / Q000378:metabolism*; D009622:Noise / Q000009:adverse effects; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D051025:bcl-Associated Death Protein / Q000378:metabolism*
C494820:Bad protein, mouse; D051025:bcl-Associated Death Protein; D019703:Calcineurin; D002118:Calcium