All metazoans depend on the consumption of O2 by the mitochondrial oxidative phosphorylation system (OXPHOS) to produce energy. In addition, the OXPHOS uses O2 to produce reactive oxygen species that can drive cell adaptations1–4, a phenomenon that occurs in hypoxia4–8 and whose precise mechanism remains unknown. Ca2+ is the best known ion that acts as a second messenger9, yet the role ascribed to Na+ is to serve as a mere mediator of membrane potential10. Here we show that Na+ acts as a second messenger that regulates OXPHOS function and the production of reactive oxygen species by modulating the fluidity of the inner mitochondrial membrane. A conformational shift in mitochondrial complex I during acute hypoxia11 drives acidification of the matrix and the release of free Ca2+ from calcium phosphate (CaP) precipitates. The concomitant activation of the mitochondrial Na+/Ca2+ exchanger promotes the import of Na+ into the matrix. Na+ interacts with phospholipids, reducing inner mitochondrial membrane fluidity and the mobility of free ubiquinone between complex II and complex III, but not inside supercomplexes. As a consequence, superoxide is produced at complex III. The inhibition of Na+ import through the Na+/Ca2+ exchanger is sufficient to block this pathway, preventing adaptation to hypoxia. These results reveal that Na+ controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences for cellular metabolism. Na+ controls the function of the mitochondrial oxidative phosphorylation system and hypoxic redox signalling through an unexpected interaction with phospholipids.

中文翻译：

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Na+通过线粒体呼吸链控制缺氧信号

所有后生动物都依赖于线粒体氧化磷酸化系统 (OXPHOS) 消耗 O2 来产生能量。此外，OXPHOS 使用 O2 产生可驱动细胞适应的活性氧物质 1-4，这种现象发生在缺氧 4-8 中，其确切机制仍然未知。Ca2+ 是最著名的离子，它充当第二信使 9，但归于 Na+ 的作用只是充当膜电位的介质 10。在这里，我们表明 Na+ 作为第二信使，通过调节线粒体内膜的流动性来调节 OXPHOS 功能和活性氧的产生。急性缺氧期间线粒体复合物 I 的构象转变驱动基质酸化和磷酸钙 (CaP) 沉淀物中游离 Ca2+ 的释放。线粒体 Na+/Ca2+ 交换剂的伴随激活促进了 Na+ 进入基质。Na+ 与磷脂相互作用，降低线粒体内膜的流动性和游离泛醌在复合物 II 和复合物 III 之间的流动性，但不会在超复合物中发生。结果，在复合物 III 处产生了超氧化物。通过 Na+/Ca2+ 交换器抑制 Na+ 输入足以阻断该途径，防止适应缺氧。这些结果表明，Na+ 通过与磷脂的意外相互作用控制 OXPHOS 功能和氧化还原信号传导，对细胞代谢产生深远影响。Na+ 通过与磷脂的意外相互作用来控制线粒体氧化磷酸化系统和缺氧氧化还原信号的功能。