In vivo inhibition of the mitochondrial H+-ATP synthase in neurons promotes metabolic preconditioning

Synopsis image Overexpression of an ATPase inhibitory factor 1 (IF1) gain-of-function mutant in mouse brains rewires neuronal metabolism toward glycolysis and confers protection from excitotoxic death stimuli, providing first in vivo evidence for the importance of the mitochondrial F0F1-ATPase/H+-ATP synthase as a physiological cell death regulator. Regulated expression of the H49K mutant of human IF1 in mouse brain neurons inhibits the ATP synthase activity of the mitochondrial H+-ATP synthase in vivo. H+-ATP synthase inhibition causes metabolic reprogramming from oxidative phosphorylation to glycolysis, and ROS-mediated brain preconditioning. Metabolic preconditioning helps to minimize neuronal cell death and preserve locomotor function of mice in response to excitotoxic stimuli. The transgenic IF1 H49K mouse model can be used to conditionally inhibit oxidative phosphorylation and to study pathologies related to dysfunction of mitochondrial bioenergetic activity in various tissues. The pivotal cell death regulatory role of H+-ATP synthase indicates it as a potential therapeutic target. Abstract A key transducer in energy conservation and signaling cell death is the mitochondrial H+-ATP synthase. The expression of the ATPase inhibitory factor 1 (IF1) is a strategy used by cancer cells to inhibit the activity of the H+-ATP synthase to generate a ROS signal that switches on cellular programs of survival. We have generated a mouse model expressing a mutant of human IF1 in brain neurons to assess the role of the H+-ATP synthase in cell death in vivo. The expression of hIF1 inhibits the activity of oxidative phosphorylation and mediates the shift of neurons to an enhanced aerobic glycolysis. Metabolic reprogramming induces brain preconditioning affording protection against quinolinic acid-induced excitotoxicity. Mechanistically, preconditioning involves the activation of the Akt/p70S6K and PARP repair pathways and Bcl-xL protection from cell death. Overall, our findings provide the first in vivo evidence highlighting the H+-ATP synthase as a target to prevent neuronal cell death.