In vivo inhibition of the mitochondrial H+-ATP synthase in neurons promotes metabolic preconditioning
Entity
UAM. Departamento de Biología MolecularPublisher
EMBO PressDate
2014-04-01Citation
10.1002/embj.201386392
EMBO Journal 33.7 (2014): 762-778
ISSN
0261-4189 (print); 1460-2075 (online)DOI
10.1002/embj.201386392Funded by
This work was supported by grants from the MEC (BFU2010-18903), CIBERER and by Comunidad de Madrid (S2011/BMD-2402) to JMC; MINECO (PLE2009-0101 and SAF2010-17167), TerCel (RD12/0019/0013), and Neurostem-CM (S2010-BMD-2336) to AMS and ISCIII Grant PI 10/02628 to CN, SpainProject
Comunidad de Madrid. S2010/BMD-2402/MITOLAB; Comunidad de Madrid. S2010/BMD-2336/NEUROSTEMSubjects
brain preconditioning; energy metabolism; inhibitory factor 1 (IF1); mitochondria; Biología y Biomedicina / BiologíaRights
© 2014 The AuthorsAbstract
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
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Google Scholar:Formentini, Laura
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Pereira, Marta P.
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Sánchez-Cenizo, Laura
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Santacatterina, Fulvio
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Lucas, José J.
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Navarro, Carmen
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Martínez Serrano, Alberto
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Cuezva Marcos, José Manuel
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