Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.
EMBO J. 2014 Apr 1;33(7):762-78. doi: 10.1002/embj.201386392. Epub 2014 Feb 12.
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.
能量守恒和细胞死亡信号转导的关键转换器是线粒体 H(+)-ATP 合酶。ATP 酶抑制因子 1（IF1）的表达是癌细胞用来抑制 H(+)-ATP 合酶活性以产生 ROS 信号的一种策略，该信号会激活细胞的生存程序。我们已经生成了一种在大脑神经元中表达人源 IF1 突变体的小鼠模型，以评估 H(+)-ATP 合酶在体内细胞死亡中的作用。hIF1 的表达抑制氧化磷酸化的活性，并介导神经元向增强的有氧糖酵解转变。代谢重编程诱导脑预适应，从而提供对抗喹啉酸诱导的兴奋性毒性的保护。从机制上讲，预适应涉及 Akt/p70S6K 和 PARP 修复途径的激活以及 Bcl-xL 对细胞死亡的保护。总的来说，我们的研究结果提供了体内证据，首次强调 H(+)-ATP 合酶是预防神经元细胞死亡的靶点。
