Calcium-Calpain-ATG5-BH3 Pathway

The article describes a positive prodeath route from stress to calcium, calpain, ATG5 cleavage, BH3, and the mitochondrial apoptotic switch. The model concludes that cytoplasmic calcium promotes apoptosis mainly through calpain-mediated ATG5 cleavage rather than primarily through calcineurin activation. Caspase activation cleaves Beclin-1, shutting down autophagosome formation while remaining autophagosomes are degraded. The apoptotic response in the model is driven mainly by calcium-dependent calpain activation, ATG5 cleavage, reduced autophagosome production, and truncated ATG5 generation. Truncated ATG5 is modeled as promoting apoptosis through BH3 upregulation because its detailed mechanism against mitochondrial antiapoptotic BCL-2 is unknown.