The metabolic coupling of Schwann cells (SCs) and peripheral axons is poorly understood. Few molecules in SCs are known to regulate axon stability. Using SC-specific Rheb knockout mice, we demonstrate that Rheb-regulated mitochondrial pyruvate metabolism is critical for SC-mediated non-cell-autonomous regulation of peripheral axon stability. Rheb knockout suppresses pyruvate dehydrogenase (PDH) activity (independently of mTORC1) and shifts pyruvate metabolism toward lactate production in SCs. The increased lactate causes age-dependent peripheral axon degeneration, affecting peripheral nerve function. Lactate, as an energy substrate and a potential signaling molecule, enhanced neuronal mitochondrial metabolism and energy production of peripheral nerves. Albeit beneficial to injured peripheral axons in the short term, we show that persistently increased lactate metabolism of neurons enhances ROS production, eventually damaging mitochondria, neuroenergetics, and axon stability. This study highlights the complex roles of lactate metabolism to peripheral axons and the importance of lactate homeostasis in preserving peripheral nerves.

雪旺细胞 (SCs) 和外周轴突的代谢耦合知之甚少。已知 SCs 中很少有分子可以调节轴突稳定性。使用 SC 特异性 Rheb 敲除小鼠，我们证明 Rheb 调节的线粒体丙酮酸代谢对于 SC 介导的外周轴突稳定性的非细胞自主调节至关重要。Rheb 敲除抑制丙酮酸脱氢酶 (PDH) 活性（独立于 mTORC1）并将丙酮酸代谢转变为 SCs 中的乳酸产生。乳酸增加导致年龄依赖性外周轴突变性，影响外周神经功能。乳酸作为能量底物和潜在的信号分子，增强了神经元线粒体代谢和周围神经的能量产生。虽然短期内对受伤的外周轴突有益，我们表明，持续增加的神经元乳酸代谢会增强 ROS 的产生，最终破坏线粒体、神经能量学和轴突稳定性。这项研究强调了乳酸代谢对外周轴突的复杂作用以及乳酸稳态在保护外周神经方面的重要性。