Calpain I induces cleavage and release of apoptosis-inducing factor from isolated mitochondria

摘要: The translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus has been implicated in mechanism glutamate excitotoxicity cortical neurons and observed vivo following acute rodent brain injuries. However, time course AIF redistribution is highly controversial. Because elevated intracellular calcium one most ubiquitous features neuronal cell death, this study tested hypothesis that cleavage by calcium-activated protease calpain mediates its release mitochondria. Both precursor mature forms recombinant were cleaved near amino terminus I vitro. Mitochondrial outer membrane permeabilization truncated Bid induced cytochrome c isolated liver or but only presence active calpain. Enzymatic inhibition calpeptin precluded release, demonstrating proteolytic activity was required for release. Calpeptin mitochondrial permeability transition pore antagonist cyclosporin A also inhibited calcium-induced mouse mitochondria, implicating involvement an endogenous during transition. Cleavage directly decreased association with pure lipid vesicles inner composition. Taken together, these results define a novel involving processing identify potential molecular checkpoint cytoprotective interventions.