IF(1) limits the apoptotic-signalling cascade by preventing mitochondrial remodelling

Mitochondrial structure has a central role both in energy conversion and in the regulation of cell death. We have previously shown that IF(1) protects cells from necrotic cell death and supports cristae structure by promoting the oligomerisation of the F(1)F(o)-ATPsynthase. As IF(1) is upregulated in a large proportion of human cancers, we have here explored its contribution to the progression of apoptosis and report that an increased expression of IF(1), relative to the F(1)F(o)-ATPsynthase, protects cells from apoptotic death. We show that IF(1) expression serves as a checkpoint for the release of Cytochrome c (Cyt c) and hence the completion of the apoptotic program. We show that the progression of apoptosis engages an amplification pathway mediated by: (i) Cyt c-dependent release of ER Ca(2+), (ii) Ca(2+)-dependent recruitment of the GTPase Dynamin-related protein 1 (Drp1), (iii) Bax insertion into the outer mitochondrial membrane and (iv) further release of Cyt c. This pathway is accelerated by suppression of IF(1) and delayed by its overexpression. IF(1) overexpression is associated with the preservation of mitochondrial morphology and ultrastructure, consistent with a central role for IF(1) as a determinant of the inner membrane architecture and with the role of mitochondrial ultrastructure in the regulation of Cyt c release. These data suggest that IF(1) is an antiapoptotic and potentially tumorigenic factor and may be a valuable predictor of responsiveness to chemotherapy.