ATP Synthase K- and H-fluxes Drive ATP Synthesis and Enable Mitochondrial K-"Uniporter" Function: II. Ion and ATP Synthase Flux Regulation.

We demonstrated that ATP synthase serves the 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. We identified a conserved BH3-like domain of IF which overlaps its "minimal inhibitory domain" that binds to the β-subunit of F. Bcl-xL and Mcl-1 possess a BH3-binding-groove that can engage IF 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 at this BH3-like domain, to increase its chemo-mechanical efficiency, enabling its function as the recruitable mitochondrial K-channel that can limit ischemia-reperfusion injury. Using Bayesian phylogenetic analysis to examine potential bacterial IF-progenitors, we found that IF 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.