Hypothetical mechanisms of calpain in neuronal death.LAMP, Ataxin, and the complex of Beclin and Atg are activated by inactivated calpain, which inhibits autophagy. The inactivated complex of Beclin and Atg, induced by activated calpain, converts autophagy to apoptosis. Calpain is implicated in numerous steps during apoptosis, including the cleavage and activation of caspases, which lead to the release of cytochrome c and AIF. Hsp70 physiologically stabilizes AIF. Calpain also cleaves BCL 2 family members, including Bax and Bid, to promote apoptosis and promotes the formation of CDK5-P25 complex, which also promotes apoptosis. Except for AIF mediated apoptosis, AIF combined with H2AX, mediated by PARP-1, might lead to regulated necrosis. In addition, calpain cleaves a series of substrates, such as JNK-interacting protein-1, and activates proteins, including integrin and RIP-1, to promote necrosis.