Role of the mitochondrial energetic function in regulation of cell death pathways following exposure to intense noise
The coexistence of apoptotic and necrotic outer hair cell (OHC) death has been found in the organ of Corti following exposure to intense noise. However, the cellular mechanisms that regulate the propensity of cell death toward apoptosis or necrosis following exposure to intense noise are unknown. The current study was designed to test the hypothesis that the status of the mitochondrial bioenergetic function plays an important role in controlling the cell death propensity toward apoptosis or necrosis following exposure to intense noise. Chinchillas were exposed to 75 pairs of impulses at 155 dB pSPL. Before or after the noise exposure, the chinchilla cochleae were treated with 3-Nitropropionic acid (3-NP, 20 mM or 50 mM), an irreversible inhibitor of succinate dehydrogenase (SDH), to disrupt the mitochondrial energy production. This experiment revealed four major findings. First, inhibition of SDH activity could reduce the rate of the progression of certain apoptotic events, including F-actin cleavage and nuclear degradation, at the early phase of cochlear pathogenesis, following exposure to the intense noise. However, SDH inhibition could not prevent the initiation of OHC apoptosis. Second, although SDH inhibition drove a small portion of OHCs to die through secondary necrosis, there was no major shift of cell death pathways from apoptosis to necrosis following mitochondrial impairment. Third, activation of caspases, including caspase-8 and caspase-9, persisted in the 3-NP treated cochleae following exposure to the impulse noise. This result suggests the continuous functioning of both mitochondrial and membrane pathways in OHC apoptosis following the 3-NP treatment. Finally, the study showed that the pretreatment of the cochleae with 3-NP could not improve the OHC tolerance to the subsequent traumatic noise exposure. In summary, these results suggest that while the mitochondrial energetic function plays an important role in the apoptotic process, it is not an obligatory component for initiation of OHC apoptosis. Other energy sources, such as cytosolic glycolysis, might be a participant in the regulation of the apoptotic process in the event of mitochondrial dysfunction.