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.