title: In vivo inhibition of the mitochondrial H+-ATP synthase in neurons promotes metabolic preconditioning.
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.
authors: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.
authors: Laura
authors: L
authors: Formentini
authors: Marta P
authors: MP
authors: Pereira
authors: Laura
authors: L
authors: Sánchez-Cenizo
authors: Fulvio
authors: F
authors: Santacatterina
authors: José J
authors: JJ
authors: Lucas
authors: Carmen
authors: C
authors: Navarro
authors: Alberto
authors: A
authors: Martínez-Serrano
authors: José M
authors: JM
authors: Cuezva
mesh_terms: D000818:Animals; D017209:Apoptosis; D001522:Behavior, Animal; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023421:Models, Animal; D020125:Mutation, Missense; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D009498:Neurotoxins / Q000494:pharmacology; D010085:Oxidative Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D017378:Quinolinic Acid / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D000097795:ATPase Inhibitory Protein
chemical_list: D025261:Mitochondrial Proton-Translocating ATPases; D009498:Neurotoxins; D011506:Proteins; D017378:Quinolinic Acid; D017382:Reactive Oxygen Species; D000097795:ATPase Inhibitory Protein