Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA.
Cell Metab. 2011 Jun 8;13(6):712-9. doi: 10.1016/j.cmet.2011.03.024.
Rapid regulation of oxidative phosphorylation is crucial for mitochondrial adaptation to swift changes in fuels availability and energy demands. An intramitochondrial signaling pathway regulates cytochrome oxidase (COX), the terminal enzyme of the respiratory chain, through reversible phosphorylation. We find that PKA-mediated phosphorylation of a COX subunit dictates mammalian mitochondrial energy fluxes and identify the specific residue (S58) of COX subunit IV-1 (COXIV-1) that is involved in this mechanism of metabolic regulation. Using protein mutagenesis, molecular dynamics simulations, and induced fit docking, we show that mitochondrial energy metabolism regulation by phosphorylation of COXIV-1 is coupled with prevention of COX allosteric inhibition by ATP. This regulatory mechanism is essential for efficient oxidative metabolism and cell survival. We propose that S58 COXIV-1 phosphorylation has evolved as a metabolic switch that allows mammalian mitochondria to rapidly toggle between energy utilization and energy storage.
快速调节氧化磷酸化对于线粒体适应燃料供应和能量需求的快速变化至关重要。一种线粒体内信号通路通过可逆磷酸化调节细胞色素氧化酶（COX），即呼吸链的末端酶。我们发现，PKA 介导的 COX 亚基磷酸化决定了哺乳动物线粒体的能量通量，并确定了 COX 亚基 IV-1（COXIV-1）中参与这种代谢调节机制的特定残基（S58）。通过蛋白质诱变、分子动力学模拟和诱导契合对接，我们表明 COXIV-1 的磷酸化通过防止 ATP 对 COX 的变构抑制来调节线粒体能量代谢。这种调节机制对于有效的氧化代谢和细胞存活至关重要。我们提出，S58 COXIV-1 磷酸化已演变为一种代谢开关，使哺乳动物线粒体能够在能量利用和能量储存之间快速切换。
