page 1115. The article by Breckenridge et al. identifies Ca21 as an interorganellar signal that sensitizes mitochondria to death-inducing injuries.
The link between ER-associated events and mitochondrial remodeling during cell death lies in the BAP31 protein, an integral ER membrane protein that is a target of caspase-8. Previous studies indicated that full-length BAP31 inhibits mitochondrial release of cyt c during apoptosis, whereas overexpression of BAP31's caspase cleavage product, p20, induces cell death. The current study demonstrates that p20 exerts its apoptosis-inducing activity from the ER by inducing mitochondrial fission.
ER and mitochondria were found to communicate through an exchange of Ca2+. Expression of p20 induced Ca2+ release from the ER and near simultaneous Ca2+ uptake into the mitochondria. The high mitochondrial Ca2+ levels recruited a dynamin- related protein called Drp1, which is known to effect fission. The resulting fragmentation sensitized mitochondria to downstream caspase-8 activities that cause cyt c release. Compared with caspase-8 action alone, the addition of p20 increased cyt c release several fold in vivo. Although isolated mitochondria readily release cyt c in response to caspase signals alone, mitochondria in intact cells may have structural differences that require priming by Drp1 for efficient release of cyt c. ▪