Journal
FUNCTION
Volume 3, Issue 2, Pages -Publisher
OXFORD UNIV PRESS
DOI: 10.1093/function/zqac001
Keywords
ATP synthase regulation; ATPase Inhibitory Factor-1 (IF); Bcl-2 family proteins; mitochondrial potassium transport; volume regulation; mitochondrial permeability transition pore
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Funding
- Intramural Research Program, National Institute on Aging, NIH
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ATP synthase serves as the primary way for K+ to enter mitochondria, and its activity can be upregulated by endogenous survival-related proteins via IF1. The interaction between IF1 and Bcl-xL or Mcl-1 enhances ATP synthase's efficiency and limits ischemia-reperfusion injury.
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 IF1. We identified a conserved BH3-like domain of IF1 which overlaps its minimal inhibitory domain that binds to the beta-subunit of F-1. Bcl-xL and Mcl-1 possess a BH3-binding-groove that can engage IF1 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 IF1 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 IF1-progenitors, we found that IF1 is likely an ancient (similar to 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.
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