In vivo inhibition of the mitochondrial H+‐ATP synthase in neurons promotes metabolic preconditioning. (12th February 2014)

• Record Type: Journal Article
• Authors: Formentini, Laura; Pereira, Marta P; Sánchez‐Cenizo, Laura; Santacatterina, Fulvio; Lucas, José J; Navarro, Carmen; Martínez‐Serrano, Alberto; Cuezva, José M
• Is Part Of: EMBO journal. Volume 33:Number 7(2014)
• Page Start: 762
• Page End: 778
• Publication Date: 2014-02-12
• Subjects: Molecular biology -- Periodicals; 572.805
• DOI: 10.1002/embj.201386392
• Languages: English
• ISSNs: 0261-4189

Abstract

<abstract abstract-type="main" xml:lang="en" id="embj201386392-abs-0001"> <title>Abstract</title> <p>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 <italic>in vivo</italic>. 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 <italic>in vivo</italic> evidence highlighting the H⁺‐ATP synthase as a target to prevent neuronal cell death.</p> </abstract>