Pediatric Genomics Discovery Program, Department of Pediatrics and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA; Section of Endocrinology, Department of Internal Medicine, Yale University, New Haven, CT 06510, USA.
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Dev Cell. 2023 Nov 20;58(22):2597-2613.e4. doi: 10.1016/j.devcel.2023.08.015. Epub 2023 Sep 5.
An instructive role for metabolism in embryonic patterning is emerging, although a role for mitochondria is poorly defined. We demonstrate that mitochondrial oxidative metabolism establishes the embryonic patterning center, the Spemann-Mangold Organizer, via hypoxia-inducible factor 1α (Hif-1α) in Xenopus. Hypoxia or decoupling ATP production from oxygen consumption expands the Organizer by activating Hif-1α. In addition, oxygen consumption is 20% higher in the Organizer than in the ventral mesoderm, indicating an elevation in mitochondrial respiration. To reconcile increased mitochondrial respiration with activation of Hif-1α, we discovered that the "free" c-subunit ring of the FF ATP synthase creates an inner mitochondrial membrane leak, which decouples ATP production from respiration at the Organizer, driving Hif-1α activation there. Overexpression of either the c-subunit or Hif-1α is sufficient to induce Organizer cell fates even when β-catenin is inhibited. We propose that mitochondrial leak metabolism could be a general mechanism for activating Hif-1α and Wnt signaling.
代谢在胚胎模式形成中起着重要作用，尽管线粒体的作用还没有被很好地定义。我们证明了线粒体氧化代谢通过缺氧诱导因子 1α（Hif-1α）在非洲爪蟾中建立了胚胎模式形成中心，即 Spemann-Mangold 组织者。缺氧或通过从氧消耗中分离 ATP 生产来扩大组织者，通过激活 Hif-1α 来实现。此外，与腹侧中胚层相比，组织者中的耗氧量高 20%，表明线粒体呼吸增加。为了协调增加的线粒体呼吸与 Hif-1α 的激活，我们发现 FF ATP 合酶的“游离”c 亚基环会在内膜上产生一个渗漏，从而使 ATP 生产与呼吸在组织者上解偶联，驱动 Hif-1α 在那里激活。即使β-catenin 被抑制，过表达 c 亚基或 Hif-1α 也足以诱导组织者细胞命运。我们提出，线粒体渗漏代谢可能是激活 Hif-1α 和 Wnt 信号的一般机制。
