Fig. 7.

Bid links ferroptosis to neuronal oxytosis. Glutamate and erastin inhibit the X_c^--antiporter in paradigms of oxytosis and ferroptosis, respectively. Blocking the cellular cystine import results in decreased GSH levels and reduced Gpx4 activity, and the subsequent activation of 12/15 LOX mediates significant formation of reactive oxygen species (ROS). In erastin-induced ferroptosis cell death is induced through oxidative stress and independently of mitochondrial demise. In neuronal cells, ROS-induced transactivation of BID to the mitochondria links both pathways of oxytosis and ferroptosis, and causes mitochondrial ROS formation that is associated with irreversible morphological and functional damage, e.g. loss of MMP, decline of ATP levels and release of apoptosis inducing factor (AIF). The BID-inhibitor BI-6c9 and the ferroptosis inhibitors ferrostatin-1 and liproxstatin-1 are able to block these fatal pathways upstream of mitochondrial impairments. BI-6c9 directly inhibits BID and its detrimental effects at the level of mitochondria while ferrostatin-1 acts upstream of BID preventing ROS formation through 12/15 LOX.