Figure 2: A simplified schematic of the cell death cascade in hair cells damaged by aminoglycosides. Reactive oxygen species (ROS), stress kinases, and the caspase family of proteases are activated and mediate hair cell degeneration caused by aminoglycoside exposure, whereas overexpression of Bcl-2 protects against caspase activation and hair cell loss. Aminoglycosides damage the mitochondria and can result in generation of ROS and activation of stress kinases. Both ROS and stress kinases can cause cell death directly as well as amplify insults targeting the mitochondria. The balance between pro-apoptotic and anti-apoptotic Bcl-2 family members determines the integrity of the mitochondria. Cytochrome c leaking out of damaged mitochondria leads to caspase-9 activation, which in turn activates caspase-3 to execute cell death.