Caspase cleavage of cytochrome cl disrupts mitochondrial function and enhances cytochrome c release

Mitochondrial catastrophe can be the cause or consequence of apoptosis and is associated with a number of pathophysiological conditions. The exact relationship between mitochondrial catastrophe and caspase activation is not completely understood. Here we addressed the underlying mechanism, explaining how activated caspase could feedback to attack mitochondria to amplify further cytochrome c （cyto.c） release. We discovered that cytochrome cl （cyto.cl） in the be1 complex of the mitochondrial respiration chain was a novel substrate of caspase 3 （casp.3）. We found that cyto.cl was cleaved at the site of D106, which is critical for binding with cyto.c, following apoptotic stress- es or targeted expression of casp.3 into the mitochondrial intermembrane space. We demonstrated＇that this cleav- age was closely linked with further cyto.c release and mitoehondrial catastrophe. These mitoehondrial events could be effectively blocked by expressing non-cleavable cyto.cl （D106A） or by caspase inhibitor z-VAD-fmk. Our results demonstrate that the cleavage of cyto.cl represents a critical step for the feedback amplification of cyto.c release by caspases and subsequent mitochondrial catastrophe.