Neurons require mechanisms to maintain ATP homeostasis in axons, which are highly vulnerable to bioenergetic failure. Here, we elucidate a transcellular signaling mechanism by which oligodendrocytes support axonal energy metabolism via transcellular delivery of NAD-dependent deacetylase SIRT2. SIRT2 is undetectable in neurons but enriched in oligodendrocytes and released within exosomes. By deleting sirt2, knocking down SIRT2, or blocking exosome release, we demonstrate that transcellular delivery of SIRT2 is critical for axonal energy enhancement. Mass spectrometry and acetylation analyses indicate that neurons treated with oligodendrocyte-conditioned media from WT, but not sirt2-knockout, mice exhibit strong deacetylation of mitochondrial adenine nucleotide translocases 1 and 2 (ANT1/2). In vivo delivery of SIRT2-filled exosomes into myelinated axons rescues mitochondrial integrity in sirt2-knockout mouse spinal cords. Thus, our study reveals an oligodendrocyte-to-axon delivery of SIRT2, which enhances ATP production by deacetylating mitochondrial proteins, providing a target for boosting axonal bioenergetic metabolism in neurological disorders.

神经元需要维持轴突中 ATP 稳态的机制，轴突极易受到生物能量衰竭的影响。在这里，我们阐明了一种跨细胞信号传导机制，少突胶质细胞通过跨细胞传递 NAD 依赖性脱乙酰酶 SIRT2 来支持轴突能量代谢。SIRT2 在神经元中无法检测到，但富含少突胶质细胞并在外泌体中释放。通过删除sirt2、敲低 SIRT2 或阻断外泌体释放，我们证明 SIRT2 的跨细胞传递对于轴突能量增强至关重要。质谱和乙酰化分析表明，用来自 WT 的少突胶质细胞条件培养基处理的神经元，但不是sirt2-敲除后，小鼠表现出线粒体腺嘌呤核苷酸转位酶 1 和 2 (ANT1/2) 的强烈去乙酰化。将充满 SIRT2 的外泌体体内递送至有髓轴突可挽救sirt2基因敲除小鼠脊髓中的线粒体完整性。因此，我们的研究揭示了 SIRT2 的少突胶质细胞到轴突的传递，它通过使线粒体蛋白去乙酰化来增强 ATP 的产生，为促进神经系统疾病中的轴突生物能量代谢提供了一个靶点。