Abstract
We demonstrated that ATP synthase serves the functions of a primary mitochondrial K(+) "uniporter," i.e., the primary way for K(+) to enter mitochondria. This K(+) entry is proportional to ATP synthesis, regulating matrix volume and energy supply-vs-demand matching. We show that ATP synthase can be upregulated by endogenous survival-related proteins via IF(1). We identified a conserved BH3-like domain of IF(1) which overlaps its "minimal inhibitory domain" that binds to the β-subunit of F(1). Bcl-xL and Mcl-1 possess a BH3-binding-groove that can engage IF(1) and exert effects, requiring this interaction, comparable to diazoxide to augment ATP synthase's H(+) and K(+) flux and ATP synthesis. Bcl-xL and Mcl-1, but not Bcl-2, serve as endogenous regulatory ligands of ATP synthase via interaction with IF(1) at this BH3-like domain, to increase its chemo-mechanical efficiency, enabling its function as the recruitable mitochondrial K(ATP)-channel that can limit ischemia-reperfusion injury. Using Bayesian phylogenetic analysis to examine potential bacterial IF(1)-progenitors, we found that IF(1) is likely an ancient (∼2 Gya) Bcl-family member that evolved from primordial bacteria resident in eukaryotes, corresponding to their putative emergence as symbiotic mitochondria, and functioning to prevent their parasitic ATP consumption inside the host cell.