Oligodendrocytes enhance axonal energy metabolism by deacetylation of mitochondrial proteins through transcellular delivery of SIRT2.
Oligodendrocytes enhance axonal energy metabolism by deacetylation of mitochondrial proteins through transcellular delivery of SIRT2.
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少突胶质细胞通过SIRT2的跨细胞递送通过线粒体蛋白的脱乙酰化增强轴突能量代谢。
DOI：
10.1016/j.neuron.2021.08.011
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发表时间：
2021-11-03
期刊：
影响因子：
16.2
通讯作者：
Sheng ZH
中科院分区：
文献类型：
--
作者：
Chamberlain KA;Huang N;Xie Y;LiCausi F;Li S;Li Y;Sheng ZH
神经元需要机制来维持轴突中的ATP稳态，而轴突非常容易受到生物能量失效的影响。在这里，我们阐明了一个跨细胞的信号转导机制，少突胶质细胞支持轴突能量代谢通过跨细胞的NAD依赖性脱乙酰酶SIRT 2。SIRT 2在神经元中检测不到，但在少突胶质细胞中富集并在外来体中释放。通过删除sirt 2，敲低SIRT 2或阻断外泌体释放，我们证明了SIRT 2的跨细胞递送对于轴突能量增强至关重要。质谱和乙酰化分析表明，神经元处理少突胶质细胞条件培养基野生型，但不是sirt 2敲除小鼠，表现出强烈的脱乙酰化线粒体腺嘌呤核苷酸转位酶1和2（ANT 1/2）。体内递送SIRT 2填充的外泌体到有髓鞘轴突中拯救sirt 2敲除小鼠脊髓中的线粒体完整性。因此，我们的研究揭示了SIRT 2的少突胶质细胞到轴突的递送，其通过使线粒体蛋白脱乙酰化来增强ATP的产生，从而为促进神经系统疾病中的轴突生物能量代谢提供了靶点。神经元需要维持轴突ATP的机制。Chamberlain和Huang等人鉴定了一种外泌体介导的跨细胞途径，通过该途径将少突胶质细胞来源的sirtuin-2递送至轴突，通过线粒体蛋白的脱乙酰化增强生物能量学以增加ATP生成。揭示这一通路促进了对健康和神经系统疾病中轴突能量维持的理解。
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. Neurons require mechanisms to maintain axonal ATP. Chamberlain and Huang et al. identify an exosome-mediated transcellular pathway through which oligodendrocyte-derived sirtuin-2 is delivered to axons, enhancing bioenergetics by deacetylation of mitochondrial proteins for increased ATP generation. Revealing this pathway advances understanding of axonal energy maintenance in health and neurological disorders.
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影响因子：
2.5
作者：
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DOI：
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